7

Behavior-modifying drugs
Kersti Seksel

CLINICAL AND DIAGNOSTIC ● an inadequate length of time allowed for the

CONSIDERATIONS treatment program to take effect
● use of medications as ‘stand-alone’ therapy when
Behavior-modifying drugs are increasingly forming an they should have been combined with a behavior
important part of the management of companion animal modification program.
behavior problems. However, although the initial trials
of psychotropic medications were conducted on animals Client consent and compliance
(as early as the 1950s), most drugs in common use are Before prescribing any medication, basic pharmacody-
not registered for this purpose in animals. Most infor- namic and pharmacokinetic knowledge of the drug is
mation on behavior-modifying drugs is derived from needed. As most medications used in veterinary behav-
human literature and thus cannot necessarily be extra- ioral therapy are not registered for use in animals, it is
polated directly to other animal species. even more important that the rationale for drug use and
potential side effects should be clearly explained and the
Establishing a diagnosis owner should give informed consent to the use of the
The use of drugs to treat behavior problems without a drug on their pet. A signed consent form is recom-
concurrent behavior modification program is unlikely mended to ensure that a client has understood the impli-
to be of benefit. Some behavior problems can be managed cations of the treatment program, possible side effects
by behavior modification alone. Drugs should always and likely length of treatment required.
be an adjunct to behavior modification therapy, not a Client compliance is important, as many behavior-
replacement. modifying drugs may take up to 6–8 weeks to reach
Before prescribing any drug to modify an animal’s therapeutic blood concentrations or for a clinical re-
behavior, it is vitally important that the veterinarian has sponse to be evident. Owners should be aware that it
made a diagnosis based on a thorough physical exami- will take time to see the desired behavioral changes. The
nation and behavioral history. Additionally, the symp- choice of medication may be affected by the personal
tomatic treatment of nonspecific signs such as excessive experience of the veterinarian, reported efficacy of case
vocalization, aggression or inappropriate elimination is studies or trials, extrapolation from human literature,
not acceptable and will ultimately lead to treatment ease of medicating the animal, health status of the animal,
failures. and cost. Owners should be aware that, although one
Owners and veterinarians should be aware that there medication was not successful, either because of lack of
are no quick solutions and no magic overnight cures for discernible positive effects or because of unwanted side
behavioral disorders. In most cases, behavior problems effects, an alternative medication may still prove useful.
take time to develop and will therefore take time to An attempt should be made to gradually wean off
modify. Once behavioral modification is achieved it medication once the desired result is achieved and main-
needs to be maintained by lifelong commitment from tained for a period of 2–3 months. However, there are
the owner and continued support from the veterinarian. some patients that will require lifelong medication and
Most behavior problems are not ‘cured’ but can be this should be made clear to the owner at the outset of
managed or controlled. An appropriate medical analogy therapy.
is diabetes mellitus, which is not considered to be cured
but can be controlled by appropriate medication com-
bined with diet and lifestyle modification.
Clinical applications and drug classes
Assuming the diagnosis is correct, the most common Behavior problems where medication has proved useful
reasons for apparent treatment failures when behavior- include anxiety-related problems (including fears and
modifying medications are prescribed include: phobias), obsessive-compulsive behaviors, some types
● selection of an inappropriate medication for the of aggression, abnormal sexual behavior and geriatric
behavior problem behavior problems.

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 NEUROPHYSIOLOGY AND NEUROCHEMISTRY OF BEHAVIOR

Many classes of medication have been used in the ration in mitochondria) by the action of choline acetyl-
treatment of behavior problems. These include antihis- transferase. It acts as a neurotransmitter in both the
tamines, antipsychotics, anxiolytics, antidepressants, peripheral and central nervous systems. It is widely dis-
anticonvulsants, mood stabilizers, β-blockers, central tributed in the body. ACh is present at the neuromus-
nervous system (CNS) stimulants, hormones, opiate cular junction and is synthesized by all motor neurones
antagonists, monoamine oxidase inhibitors, neurolep- in the spinal cord. It is metabolized by acetylcholines-
tics, ergot alkaloids and phenothiazines. Medications terase to choline and acetic acid.
that may have anxiolytic actions include the benzodiaz- Cholinergic receptors (nicotinic and muscarinic) have
epines, tricyclic antidepressants (TCAs), antihistamines, numerous physiological (see Chapter 4) and behavioral
azaperones, barbiturates, selective serotonin reuptake effects. Muscarinic receptors appear to mediate the
inhibitors (SSRIs) and β-blockers. Only drugs in common behavioral effects of arousal, learning and short-term
use will be discussed in this chapter. memory. Muscarinic agonists (arecoline) and anti-
cholinesterase drugs (physostigmine) are reported to
Pretreatment screening improve performance in short-term memory while mus-
carinic antagonists (scopolamine) cause amnesia. Certain
Blood tests prior to prescribing medication are strongly
neurodegenerative diseases, especially dementia and
recommended, especially in very old or young animals or
parkinsonism, are thought to be associated with abnor-
those with a previous history of medical problems. A
malities in cholinergic pathways.
minimum database should include a complete blood
Many behavior-modifying drugs have anticholinergic
count, biochemistry panel and urinalysis. As most
effects. Adverse anticholinergic effects that may occur
behavior-modifying drugs are metabolized by the liver
include dry mouth, dry eyes, urinary and fecal retention
and renally excreted, it is important to assess liver enzymes
and pupillary dilation.
and renal function prior to starting drug treatment. It may
be prudent in some cases to reassess liver and renal func-
tion approximately 4–6 weeks after starting treatment, Catecholamines
depending on the animal, the drug and the effects observed.
Tyrosine is the precursor for the catecholamines (dopa-
All animals on long-term behavior-modifying medication
mine, noradrenaline (norepinephrine) and adrenaline
should be retested at least every 6–12 months.
(epinephrine)). Catecholaminergic neurones are found in
the midbrain, hypothalamus and limbic system. They are
NEUROPHYSIOLOGY AND involved in regulation of movement, mood and attention
NEUROCHEMISTRY OF BEHAVIOR as well as visceral function (see Chapter 4). They are
associated with the arousal of the autonomic nervous
The rationale for using behavior-modifying drugs is system. Their release during stressful or fearful episodes
based on their purported neurochemical actions in the results in stimulation of the CNS and anxiety.
brain. The drugs may act presynaptically, affecting the The actions of catecholamines are terminated in the
presynaptic action potential, synthesis, storage, metabo- synaptic cleft by selective reuptake into the axon termi-
lism, release, reuptake or degradation of the neurotrans- nal. Within the terminal they can be reused or destroyed
mitter. Alternatively, they may act postsynaptically, by monoamine oxidase (MAO) and by catechol-O-
binding to or modifying receptors. methyltransferase (COMT).
Neurotransmitters can be classed into three groups:
● amino acids, e.g. γ-aminobutyric acid (GABA), Dopamine
glutamate and glycine Tyrosine hydroxylase converts tyrosine to l-dopa.
● amines, e.g. acetylcholine (ACh) and monoamines Dopamine is produced from l-dopa by dopa decarbox-
(dopamine, serotonin and noradrenaline ylase in dopaminergic neurones. Dopamine is a neu-
(norepinephrine)) rotransmitter as well as precursor for noradrenaline
● peptides, e.g. cholecystokinin (CCK), substance P (norepinephrine). It is degraded to 3,4-dihydroxyphen-
and neuropeptide Y. ylacetic acid (DOPAC) and homovanillic acid (HVA),
which are excreted in urine.
ACh, dopamine, serotonin, noradrenaline (norepineph- There are at least five dopaminergic pathways in
rine) and GABA are particularly important in the actions the brain, with the mesolimbic-mesocortical cells in the
and side effects of behavior-modifying drugs. nucleus accumbens most closely related to behavior. The
nigrostriatal pathway is involved in the co-ordination of
Acetylcholine voluntary movement. Dopaminergic receptors are
Acetylcholine is derived from choline (important in fat divided into two families (D1 and D2), with most known
metabolism) and acetyl CoA (product of cellular respi- functions being mediated by the D2 family.

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 CHAPTER 7 BEHAVIOR-MODIFYING DRUGS

Deterioration of dopaminergic neurones in the brain medulla, projecting diffusely to the cortex, limbic
is responsible for diseases such as Parkinson’s disease in system, hypothalamus and spinal cord. Serotonin can
humans. Behavioral effects of excessive dopamine activ- exert inhibitory or excitatory effects and can act presyn-
ity include stereotypies observed with increased dopa- aptically or postsynaptically. Many serotonin-receptor
mine release (e.g. amfetamine) and dopamine agonists subtypes have been identified (5-HT1a, 5-HT1b, 5-HT1d,
(e.g. apomorphine). In humans, abnormalities of 5-HT2, 5-HT3). The exact functions of each subtype
dopaminergic neurones have also been implicated in have not yet been clearly identified.
schizophrenia – the side effects of antischizophrenic Serotonin is also thought to act as an anxiogenic
drugs include a variety of Parkinson-like movement dis- neurotransmitter in the limbic system. Serotonin path-
orders (dyskinesia). ways are thought to be involved in regulation of mood,
feeding behavior, sleep/wakefulness, control of sensory
Noradrenaline (norepinephrine) pathways including nociception, control of body tem-
Noradrenaline (norepinephrine) is produced by hydroxy- perature, vomiting and emotional behaviors such as
lation of dopamine by dopamine β-hydroxylase in syn- aggression.
aptic vesicles of noradrenergic neurones. Noradrenergic After release into the synaptic cleft the action of sero-
cell bodies within the CNS occur in discrete clusters, tonin is terminated by reuptake into the axon terminal
mainly in the pons and medulla. The locus ceruleus is by a specific transporter, where it is reused or degraded
one of the most important noradrenergic clusters related by MAO, forming 5-hydroxyindolacetic acid (5-HIAA).
to behavior. Stimulation of locus ceruleus neurones 5-HIAA is excreted in urine and provides a measure of
leads to an increased fear response (in monkeys). 5-HT turnover.
The actions of noradrenaline are mainly inhibitory in
Melatonin
the CNS (β-receptors) but some are excitatory (α- or β-
Melatonin is thought to play a role in diurnal cycles and
receptors). Excitatory actions occur by direct (blockade
sleep/wake patterns in humans. It is released mainly at
of potassium conductances that slow neuronal dis-
night. Three MEL1-receptor variants have been identi-
charge) and indirect methods (disinhibition, whereby
fied to date in the suprachiasmic nucleus of the hypo-
inhibitory neurones are inhibited). This facilitation of
thalamus. Melatonin is a potent inhibitor of dopamine
excitatory transmission is thought to be responsible for
release and its release appears to be linked with endog-
the behavioral effects of arousal, attention, etc. and has
enous opioids. Very little is known about this neurohor-
been characterized most in the α2-receptors in the locus
mone and its physiological effects. It has been shown to
ceruleus.
regulate sleep patterns in some studies in humans. Mela-
Noradrenergic transmission is thought to be impor-
tonin has been used to treat jet lag as well as seasonal
tant in control of mood, function of the ‘reward’ system,
affective disorder, self-injurious behavior and childhood
arousal, control of wakefulness and alertness and blood
depression in humans. It is freely available in the USA
pressure regulation. Medications that are noradrenaline
and some other countries, as it has been labelled a food,
agonists cause increased arousal through activation of
not a drug. However, it is not available worldwide. In
the reticular activating system.
a number of countries, melatonin implants have been
Noradrenaline is converted to adrenaline (epineph-
used in the reproductive management of ruminants.
rine) by phenylethanolamine N-methyltransferase.
Melatonin’s efficacy in companion animal medicine
Adrenaline (epinephrine) acts as a neurotransmitter in
is unknown, although its use has been reported in the
the brain and is also released by the adrenal gland.
treatment of thunderstorm phobias, recurrent flank alo-
pecia in dogs, to decrease isolation distress in chickens
Indoleamines and in the treatment of separation anxiety in a black
bear that would not hibernate. Additionally, it has been
The indolamines, serotonin (5-hydroxytryptamine) and
used concurrently with amitriptyline to successfully
melatonin (N-acetyl-5-methoxytryptamine), are synthe-
treat one case of noise phobia (especially to birdsong)
sized from tryptophan. In the pineal gland, serotonin
in a dog. The suggested dose rate in dogs is 0.1 mg/kg
acts as the precursor for melatonin. Over 90% of sero-
PO q.24 h or as needed. Side effects in humans include
tonin in the mammalian body is found in the entero-
sleepiness, headaches and hangover-type malaise. Mela-
chromaffin cells in the gastrointestinal tract.
tonin should not be given concurrently with MAO
inhibitors or corticosteroids in humans.
Serotonin
Serotonin is derived from tryptophan in a two-step
process and its availability is the rate-limiting step in
g-Aminobutyric acid (GABA)
synthesis. 5-Hydroxytryptamine (5-HT) neurones are Glutamate is converted to GABA by glutamic acid
concentrated in the midline raphe nuclei in the pons and decarboxylase. GABA is only synthesized by those

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 ANTIHISTAMINES

neurones that use it as a neurotransmitter. It is widely of urine spraying is currently being studied. The use of
distributed throughout the brain but very little is found cyproheptadine as an appetite stimulant in dogs and
in peripheral tissues. GABA-ergic neurones are the major cats has also been mooted (see Chapter 19) and may
inhibitory neurones in the mammalian nervous system. result from 5-HT antagonism.
GABA is the main inhibitory neurotransmitter in the
cerebral cortex and limbic system. There are three types Mechanism of action
of GABA receptor. GABAA receptors occur mainly post- Antihistamines act by competitive inhibition of H1
synaptically and are directly coupled with chloride receptors. They have mild hypnotic and sedative effects.
channels, which, when opened, reduce membrane excit- Cyproheptadine also acts as a serotonin antagonist, is
ability. Activation of GABAB receptors alters Ca2+ (pre- an appetite stimulant and may have a calcium channel-
synaptic) and K+ (postsynaptic) conductance via second blocking action.
messengers, resulting in hyperpolarization and reduced
outflow of other neurotransmitters. GABAC receptors Formulations and dose rates
have recently been described and are predominantly
located in the retina. DOGS
Drugs that interact with GABAA receptors and chan- Cyproheptadine
nels include the benzodiazepines and barbiturates (see • 0.3–2 mg/kg PO q.12 h (antihistamine dose)
Chapters 7 and 16). Diphenhydramine
GABA is removed from the synaptic cleft mainly • 2–4 mg/kg PO q.8–12 h
by reuptake but some is also deaminated by Hydroxyzine
GABA-transaminase. • 0.5–2.2 mg/kg PO q.8–12 h
CATS
Cyproheptadine
CLASSES OF BEHAVIOR-MODIFYING • 0.4–0.5 mg/kg PO q.12 h (2–4 mg/cat q.8–12 h)
DRUGS Diphenhydramine
• 2–4 mg/kg PO q.8–12 h
ANTIHISTAMINES Hydroxyzine
• 2.2 mg/kg PO q.8–12 h
EXAMPLES
Cyproheptadine, diphenhydramine, hydroxyzine. Pharmacokinetics
Antihistamines are well absorbed from the gastrointes-
Clinical applications tinal tract and are widely distributed throughout the
Antihistamines are not considered first-choice options body. Many antihistamines are extensively and quickly
in the treatment of anxiety disorders nor for long-term metabolized, resulting in low bioavailability after oral
treatment of anxiety. However, they have proved useful administration. They are excreted in urine and feces.
for treating inappropriate urination associated with The sedative effects are usually seen within 30–60 min
anxiety, to reduce anxiety and motion sickness associ- and may last 4–6 h.
ated with car travel and to reduce excessive unexplained
nocturnal activity of cats such as pacing and vocaliza- Adverse effects
tion while the owners are at home. A short-term positive ● Mild CNS depression or sleepiness
therapeutic response has sometimes been helpful in ● Anticholinergic effects
obtaining client compliance in carrying out the environ- ● Excitation, agitation and convulsions have been
mental changes needed to modify abnormal behavior, reported at therapeutic doses in humans, especially
as well as improving neighborly relations. children
Antihistamines may also be effective in the manage-
Contraindications and precautions
ment of pruritus associated with anxiety. However, rel-
Antihistamines should be used with care or alternatives
atively high doses are necessary and the positive effect
considered if the following conditions are present.
observed may be due to sedation. Doxepin, a tricyclic
● Urinary retention
antidepressant (TCA), has proved more useful than
● Glaucoma
antihistamines for the treatment of anxiety-related pru-
● Hyperthyroidism
ritus and self-mutilation.
There is a single case report of the successful use of Antihistamines should not be used within 2 weeks
cyproheptadine to treat urine spraying and masturba- of administration of monoamine oxidase inhibitors
tion in a neutered male cat. Its efficacy in the treatment (MAOIs).

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 CHAPTER 7 BEHAVIOR-MODIFYING DRUGS

Known drug interactions depth of effect are variable, depending on the animal
● Concurrent use of other drugs that cause CNS and the environmental stimuli. This makes accurate
depression can produce additive effects. dosing difficult. However, recent research demonstrated
● MAOIs may intensify the anticholinergic effects of that acepromazine is not as effective as other medica-
antihistamines. tions in decreasing perioperative concentrations of
stress-related hormones. Acetylpromazine and chlor-
promazine have also been used in the treatment of
ANTIPSYCHOTICS (NEUROLEPTICS) aggression, to reduce excitement and in the treatment
of anxiety-related conditions. Thioridazine was used in
Also known as major tranquilizers, antipsychotics can one case to control aberrant motor activity in a dog.
be divided in several groups, including phenothiazines, The aberrant behavior observed included running
thioxanthenes and butyrophenones. There are also a around barking frantically, erratic episodes of tail and
number of miscellaneous compounds. The mechanisms carpus chewing and apparent unprovoked aggression.
of action and pharmacokinetics of these drugs are However, other medications, such as TCAs and benzo-
described in more detail in Chapters 5 and 6. All are diazepines, are preferred in the treatment of aggression,
dopamine antagonists. aberrant behavior and anxiety, as their mechanism of
action is directed at the underlying neurochemical cause
Pharmacokinetics (general) of the behavior rather than at blunting the behavioral
response.
Most antipsychotics are readily but incompletely
absorbed from the gastrointestinal tract and undergo Formulations and dose rates
significant first-pass metabolism. Most are highly lipid-
soluble with a large volume of distribution. This may DOGS
account for longer than expected duration of action. Acetylpromazine
Metabolites of chlorpromazine can be excreted for • 0.1–2.2 mg/kg PO q.6–24 h
weeks after discontinuation of action after long-term Chlorpromazine
use in humans. Most are almost completely metabolized • 0.5–3.3 mg/kg PO q.6–24 h
and very little drug is excreted unchanged.
Thioridazine
• 1.1–2.2 mg/kg PO q.12–24 h
Phenothiazines
CATS
Acetylpromazine
EXAMPLES • 0.5–2.2 mg/kg PO as needed
Acetylpromazine, chlorpromazine, thioridazine. Chlorpromazine
• 0.5–3.3 mg/kg PO q.6–24 h

Clinical applications
Phenothiazines have a variety of effects on the central Adverse effects
nervous system (CNS) and the autonomic and endocrine ● Sedation
systems because of their ability to block dopamine, α- ● Anticholinergic effects
adrenergic, muscarinic, H1-histaminic and serotonin (5- ● Hypersensitivity to noise
HT2) receptors. They are commonly used in veterinary ● Sudden aggression and excitement have been
medicine as tranquilizers for restraint and sedation (see reported in dogs (acetylpromazine)
Chapter 6) or for brief treatment of arousal (which can ● Hypotension
be agitation, alertness to excitement or hypervigilance, ● Bradycardia
often associated with fear- or anxiety-provoking cir- ● Paradoxical excitability
cumstances or excitement from anticipation). However, ● Akathesia (motor restlessness, pacing, agitation
they are seldom used in long-term behavioral therapy reported in some animals)
because of potential extrapyramidal effects. In addition, ● Extrapyramidal signs (ataxia, muscle tremors,
other, more appropriate medications are available. inco-ordination)
Acetylpromazine maleate is nonspecific in its effects.
Because it decreases motor function and produces Contraindications and precautions
ataraxia (decreased emotional reactivity or awareness Traditionally, phenothiazines have been contraindicated
of external stimuli and indifference to stress), as well as in epileptic patients because they are believed to lower
being an antiemetic, it has been used for motion sickness the threshold to seizures. Although the evidence for this
and anxiety associated with car travel. The length and is anecdotal and far from convincing, some authors

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 ANTIPSYCHOTICS (NEUROLEPTICS)

suggest that prolonged use of neuroleptics may cause ble effects on D1-receptors. There is also some blockade
seizures by stimulation of the extrapyramidal motor of α-adrenergic receptors of the autonomic system.
pathways.
Extreme caution should be exercised when approach- Formulations and dose rates
ing animals that have been given acetylpromazine as
they may become more reactive to noise and startle PARROTS
easily. The effect of acetylpromazine on aggressive • 0.2–04 mg/kg PO q.12 h; start at lowest dose and increase
behavior is unpredictable and may depend on the level 0.02 q2d to effect
of arousal prior to medication as well as individual • 1–2 mg/kg haloperidol decanoate IM q.3 weeks, lower dose for
cockatoos, African greys and Quaker parrots
variation in effect. There is a large, unpredictable varia-
tion in drug effect and duration between individuals. DOGS
Fainting associated with high levels of vagal tone • 0.05–4 mg PO q.12 h
(sometimes termed vasovagal syncope) can occur in CATS
brachycephalic breeds, particularly boxers, given acetyl- • 0.1–1.0 mg/kg PO
promazine. In these cases, collapse is associated with
bradycardia and treatment involves the administration Adverse effects
of an anticholinergic drug such as atropine. Decreased activity and inappetence have been reported
in birds.
Butyrophenones
Contraindications and precautions
EXAMPLE Caution should be exercised when administering halo-
Haloperidol. peridol to macaws as death has been reported with its
use in this species. There has also been a report of recur-
rent bilateral hock dislocation associated with its admin-
istration in one Quaker parakeet.
Clinical applications
Haloperidol has been used in the acute treatment of
Miscellaneous antipsychotics – clozapine
aggressive and psychotic states, Huntington’s chorea
and Tourette’s syndrome in humans, as well as in the Clozapine is an atypical antipsychotic and has markedly
management of nausea and vomiting associated with different clinical effects in humans, i.e. different humans
chemotherapy. react or respond in different or various ways to the
Haloperidol has been used experimentally in dogs, drug.
rats and monkeys. It has been reported to assist in the
control of stress and therefore to prevent injuries when Clinical applications
several species of wild African herbivore are handled at Experimentally clozapine has shown to be effective in
game parks. Haloperidol has been reported to have a treating aggression in animal models of self-abuse.
slight effect in dogs with obsessive-compulsive disorders However, its use in treating aggressive dogs has been
and certain types of aggression but dose rates have not disappointing.
been established. It has been used long term (up to 9
years) in the management of self-mutilation and feather- Mechanism of action
plucking in birds, with some success. It is reported to Clozapine is classed as a dibenzodiazepine and seems
have greater efficacy in birds that mutilate soft tissue to have minimal central antidopaminergic activity, in
rather than just traumatize feathers. contrast to many antipsychotic drugs. This may account
for the different clinical effects observed in humans
Mechanism of action compared with other neuroleptics used to treat
Haloperidol is a butyrophenone-derivative antipsychotic schizophrenia.
with actions similar to the piperazine-derivative pheno-
thiazines. Haloperidol decanoate is a long-acting form Formulations and dose rates
of haloperidol. The precise mechanism of action is
unclear but it appears to inhibit the ascending reticular A suggested dose in dogs is 1.0–7.0 mg/kg PO. However, reliable
system, possibly through the caudate nucleus. It com- dose–response data have not been established in animals.
petitively blocks postsynaptic dopamine receptors in the
mesolimbic dopaminergic system and increases turnover Pharmacokinetics
of brain dopamine. It acts mainly on D2-receptors and The pharmacokinetics of clozapine have not been deter-
has some effect on 5-HT2 and α1-receptors but negligi- mined in animals. However, in humans it is well

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 CHAPTER 7 BEHAVIOR-MODIFYING DRUGS

absorbed orally and is subject to moderate first-pass

metabolism. Peak blood levels occur in 2.1 h, with mean Carbamazepine
• 4–10 mg/kg/day divided q.8 h or 5–10 mg/kg q.12 h
half-life of 12 h; 95% is bound to plasma proteins and
it is almost completely metabolized prior to excretion. CATS
Phenobarbital
Adverse effects • 1–4 mg/kg PO q. 12–24 h or as needed
● Significant risk of agranulocytosis in humans. Carbamazepine
● Clozapine should be used with care in patients • 25 mg PO q. 12–24 h or 4–8 mg/kg q. 12 h
with concurrent cardiovascular disease.
● In dogs clozapine caused excessive salivation and
ataxia, and blocked avoidance behaviors. Adverse effects
Phenobarbital
● Long-term use of phenobarbital may cause
ANTICONVULSANTS hepatotoxicity.

Anticonvulsants currently have a minor role in veteri- Carbamazepine

nary behavioral medicine, unless a neurological problem ● Carbamazepine is mildly sedating, mildly anticho-
such as epilepsy is suspected to be involved in the behav- linergic and does not cause muscle relaxation in
ioral problem being managed. The mechanism of action animals.
and pharmacokinetics of anticonvulsants are described ● Side effects reported in humans include ataxia,
in Chapter 16. clonic-tonic convulsions and gastrointestinal upsets.
● It has been reported to cause idiosyncratic blood
EXAMPLES dyscrasias. Deaths have been reported due to aplastic
anemia and agranulocytosis so careful monitoring is
Phenobarbital (phenobarbitone), carbamazepine. essential.
● Carbamazepine must be used with particular care in
patients with renal, hepatic, cardiovascular or hema-
Clinical applications tological disorders.
Phenobarbital has been used with some success to
manage mild overactivity and excessive vocalization in
cats. It is generally used for short-term management b-BLOCKERS
while environmental changes are being instituted and
when other therapeutic options have been explored and The mechanism of action, pharmacokinetics and side
proved unsuccessful. effects of β-blockers are described in detail in Chapter
Anticonvulsants such as phenobarbital have been 17.
used in the past to treat behavioral problems such as
tail chasing or spinning in bull terriers, hyperesthesia EXAMPLES
syndrome in cats and ‘rage syndrome’. However, they
Propranolol, pindolol.
are generally not recommended or used for these prob-
lems now unless there is clear evidence of a neurological
cause for the behavior. Clinical applications
Carbamazepine, an iminodiabenzyl derivative of Noradrenaline (norepinephrine) is released in fear- or
imipramine, has been used in humans to control explo- anxiety-provoking situations. Blocking some of the
sive aggressive events (episodic dyscontrol) and depres- effects of noradrenaline reduces the physical manifesta-
sion, in addition to its use in seizure control. It was tions of fear and anxiety such as muscle tremors, trem-
reported to control some forms of fear aggression in two bling, tachycardia and altered gastrointestinal motility.
cats and has been used to control motor activity in dogs As a result, β-blockers can have a calming effect on
that may have been associated with seizures. anxious animals. β-Blockers such as propranolol have
been used to treat some forms of anxiety such as noise
Formulations and dose rates phobias in animals and stage fright in humans. However,
these drugs appear to be more efficacious in humans.
DOGS Propranolol may also block brain serotonin receptors
Phenobarbital and therefore may be useful in inhibiting aggression. It
• 1–4 mg/kg PO q.12 h or as needed up to 16 mg/kg/day has been used for this purpose in humans (e.g. treatment
of violent outbursts associated with organic brain

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 CNS STIMULANTS – AMFETAMINES

syndromes) but has not proved as successful for this been treated, with variable results. The rationale for
purpose in companion animals. Pindolol, a partial β- treatment is the premise that opioid peptides are released
agonist, reportedly has a greater serotonergic effect, so during stress and activate the dopamine system, which
may be more effective in the treatment of aggression. may be responsible for compulsive behaviors. Addition-
ally, as endogenous opioid peptides induce analgesia, it
Formulations and dose rates is possible that they reduce the pain that might normally
inhibit self-mutilation.
DOGS Naloxone has been used as a diagnostic aid for com-
Propranolol pulsive disorders. However, its short duration of action
• Small: 5 mg/dog PO q.8 h and parenteral formulation does not make it useful in a
• Large 10–20 mg/dog PO q.8 h chronic treatment program. Naltrexone is longer acting
• 0.5–3.0 mg/kg PO q.12 h or as needed and has been used therapeutically. However, its expense
Pindolol usually makes long-term treatment impractical.
• 0.125–0.25 mg/kg PO q.12 h The opioid agonist hydrocodone has also been used
CATS successfully in some cases of self-mutilation in cats and
Propranolol chronic management of canine acral lick dermatitis.
• 0.2–1.0 mg/kg PO q.8 h
Mechanism of action
See Chapter 14.
Adverse effects
● Sedation and sleep disturbance have been reported Pharmacokinetics
in humans. See Chapter 14.
● β-Blockers should be gradually withdrawn after
chronic use because of potential problems with β- Formulations and dose rates
receptor blockade, as this can depress myocardial
contractility and excitability and cardiac decompen- DOGS
sation may ensue. Naloxone
• 11–22 µg/kg SC, IM, IV or 0.5 mg q.12 h
Contraindications and precautions Naltrexone
● Use with care in diabetics as β-blockers may • 2.2 mg/kg PO q.12–24 h
increase the likelihood of exercise-induced
Hydrocodone
hypoglycemia. • 0.25 mg/kg PO q.8–12 h
● Bradycardia
CATS
● Hypotension
● Bronchospasm Naltrexone
• 2–4 mg/kg PO q.24 h (up to 25–50 mg/cat)
Hydrocodone
OPIOID AGONISTS/ANTAGONISTS • 0.25–1.0 mg/kg PO q.12–24 h

Opioid alkaloids produce analgesia via endogenous Adverse effects

opioid peptide receptors. The pure opioid antagonists ● Constipation is reported to be a problem in
are morphine derivatives with substitutions at the N17 humans.
position and have a high affinity for µ opioid receptor- ● In cats a decrease in activity has been reported.
binding sites.

EXAMPLES CNS STIMULANTS – AMFETAMINES

Naloxone (antagonist), naltrexone (antagonist), hydrocodone
Amfetamines appear to act centrally by promoting
(agonist).
release of catecholaminergic neurotransmitters such as
dopamine, weakly inhibit MAO and possibly act as
catecholaminergic agonists.
Clinical applications
The opioid antagonists have been used to treat a number
of stereotypies and obsessive-compulsive disorders in EXAMPLES
humans. In companion animals problems such as self- Methylphenidate (Ritalin®), dexamfetamine.
mutilation, acral lick dermatitis and tail chasing have

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 CHAPTER 7 BEHAVIOR-MODIFYING DRUGS

Clinical applications BENZODIAZEPINES

Amfetamines are used to treat attention-deficit hyperac-
tivity disorders and narcolepsy in humans. True hyper- See Chapters 5 and 6 for further information.
activity (versus overactivity) is rare in dogs. CNS
stimulants have a paradoxical calming effect on truly EXAMPLES
hyperactive dogs while in normal dogs they increase
Diazepam (Valium®), clorazepate dipotassium
excitement and activity. Lifelong medication may be
(Tranxene®), alprazolam (Xanax®), clonazepam (Rivitrol®),
needed in some cases. Amfetamines have also been used
oxazepam (Serepax®), lorazepam, flurazepam.
in the treatment of narcolepsy in dogs.

Mechanism of action
Amfetamines cause release of noradrenaline (norepi- Mechanism of action
nephrine), dopamine and serotonin from presynaptic The benzodiazepines are classified as sedative hypnotics.
terminals, as opposed to having direct agonist effects on All benzodiazepines have structural similarity and
postsynaptic receptors. appear to work through the same mechanisms. They
potentiate the inhibitory effects of GABA by interacting
Pharmacokinetics allosterically with GABA-binding sites and chloride
Amfetamines have a very short biological life in humans channels. However, they differ pharmacokinetically and
and reach higher concentrations in the brain than in pharmacodynamically.
blood. They are metabolized by hepatic enzymes. Most benzodiazepines are 1,4-benzodiazepines and
most contain a carboxamide group in the 7-membered
Formulations and dose rates heterocyclic ring structure. A substituent such as a
halogen or nitro group in the 7 position is required for
DOGS sedative-hypnotic activity. The structure of alprazolam
Methylphenidate (Ritalin®) includes the addition of a triazole ring at the 1,2 posi-
• Hyperkinesis: 0.2–1 mg/kg PO should lead to 15% decrease in tion. Benzodiazepines are metabolized at varying rates
heart rate and respiration rate in 75–90 min (for diagnosis) and some have active metabolites that are more potent
• 2–4 mg/kg q.8–12 h or 5 mg PO q.12 h in small dogs to 20– than the parent compound. The long half-life of inter-
40 mg PO q.12 h in large dogs mediate metabolites such as N-desmethyldiazepam
• Narcolepsy: 0.05–0.25 mg/kg PO q.12–24 h (60 h in humans) accounts for the cumulative effects of
Dexamfetamine many of the benzodiazepines.
• Hyperkinesis: 0.2–1.3 mg/kg PO as needed The anxiolytic effects are believed to be due to the
• Narcolepsy: 5–10 mg q.24 h inhibitory action of benzodiazepines on neurones in the
• 1.25 mg/dog PO as needed limbic system, including the amygdala, and on seroto-
CATS nergic and noradrenergic neurones in the brainstem.
Dexamfetamine
• Narcolepsy: 1.25 mg as needed Clinical applications
Although benzodiazepines have been used in the treat-
ment of fear- and anxiety-related disorders in humans
Adverse effects and companion animals, they lack behavioral specific-
● Increased heart rate ity. The effect of benzodiazepines is dose dependent.
● Increased respiratory rate Low doses have a sedative effect, moderate doses have
● Tremors with possible hyperthermia an anxiolytic effect and may help with social interac-
● Decreased appetite tions, while high doses facilitate sleep.
● Insomnia Tolerance to the sedative effects may develop but not
usually to the anxiolytic effects. Cats appear to be par-
Contraindications and precautions ticularly sensitive to the muscle-relaxant effects of ben-
● Cardiovascular disease zodiazepines. This effect is independent of sedation.
● Concurrent use of MAOIs Anxiety has been shown to decrease locomotion and
● Hyperthyroidism ingestion and increase muscle tone. Therefore, treat-
● Glaucoma ment with benzodiazepines would be expected to
● Methylphenidate may lower the seizure threshold counter these effects of anxiety and make animals more
active.
Known drug interactions In cats benzodiazepines have been used to treat prob-
Amfetamines can potentiate narcotic analgesics. lems such as inappropriate elimination associated with

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 BENZODIAZEPINES

anxiety, urine marking or spraying, fear aggression and

overgrooming, as well as to stimulate appetite. They Flurazepam
• 0.2–0.4 mg/kg PO for 4–7 days (sleep/wake cycles) or 0.1–
have been used in dogs in the treatment of noise phobias,
0.5 mg/kg PO q.12–24 h (appetite stimulant)
panic attacks and sleep disorders such as night-time
waking. CATS
Because of its short half-life in dogs, the clinical use of Alprazolam
diazepam is limited in this species. However, it has • 0.0125–0.25 mg/cat PO q.12 h or as needed, or 0.1 mg/kg
proved useful as an adjunct in treating anxiety of short q.8 h or as needed
duration, for example noise phobia. Clorazepate, because Diazepam
of its longer half-life, may be more suitable for dogs. • 0.2–0.5 mg/kg PO q.12–24 h
In one study diazepam was reported to be effective in Clorazepate dipotassium
reducing urine spraying in 75% of cats and eliminating • 0.5–2.0 mg/kg PO q.12–24 h or as needed.
the problem in 43% of treated cats. It was reported to There is a sustained-release formulation of clorazepate.
be more efficacious in males and in cats living in multi- Clonazepam
cat households. However, in another study a recidivism • 0.016 mg/kg PO q.6–24 h
rate of 91% was reported when medication was Oxazepam
withdrawn. • 0.2–1.0 mg/kg PO q.12–24 h
As benzodiazepines have a disinhibiting effect, they Flurazepam
have also been used in cases of intercat aggression to • 0.2–0.4 mg/kg PO for 4–7 days (sleep/wake cycles) or 0.1–
decrease the fear or anxiety of the victim. Alprazolam 0.2 mg/kg PO q.12–24 h (appetite stimulant)
has been used successfully for panic attacks in humans Triazolam
and also in dogs in the anticipatory phase of thunder- • 0.03 mg/kg q.12 h or 2.5–5 mg/cat PO q.8 h
storm phobias and separation anxiety.
Flurazepam is used to treat insomnia in humans and
has been used, as has alprazolam and triazolam, to treat Pharmacokinetics
night-time waking or changed sleep patterns that may Diazepam is rapidly absorbed following oral adminis-
be associated with anxiety in companion animals. Tri- tration. It is slowly and incompletely absorbed after
azolam has also been used to treat some cases of aggres- intramuscular administration. It is highly lipid soluble
sion in cats. and widely distributed throughout the body. Diazepam
When drug therapy is no longer required gradual readily crosses the blood–brain barrier and is highly
withdrawal from therapy is recommended by reducing protein bound.
the daily dose by 10–25% per week. Diazepam is metabolized in the liver. The common
intermediate metabolite of diazepam and clorazepate,
Formulations and dose rate N-desmethyldiazepam (nordiazepam), is in turn bio-
transformed to the active compound, oxazepam. Diaz-
DOGS epam has a short half-life in dogs (2.5 h) compared with
Alprazolam cats (5.5–20 h). Additionally, its active metabolite nor-
• 0.25–2.0 mg/dog q.8–12 h, or 0.02–0.1 mg/kg q.4h, or 0.125– diazepam also has a short half-life in dogs (3 h versus
1.0 mg/kg PO q.12 h. No more than 4 mg/day. For example, 21 h in cats).
0.5 mg to small dogs, 1.0 mg to medium dogs and 2.0 mg to
large dogs q.12 h Adverse effects
Diazepam ● Diazepam affects depth perception, so cats may fall
• 0.5–2.0 mg/kg PO q.4–12 h or as needed off objects or miss objects when they jump until they
Clorazepate dipotassium learn to compensate.
• 0.50–2.0 mg/kg q.8–24 h or 11.25–22.5 mg/dog PO q.12–24 h ● Increased appetite.
There is a sustained-release formulation of clorazepate. ● Transient ataxia. This should resolve within 3–4
Clonazepam days of continued use; if it doesn’t the dose should
• 0.1–0.5 mg/kg PO q.8–12 h be decreased or the drug withdrawn as the potential
Oxazepam for cumulative effects and toxicity due to accumula-
• 0.2–0.5 mg/kg PO q.8–24 h tion of the intermediate metabolite exists.
● Paradoxical hyperactivity in some cats.
Lorazepam
• 0.02–0.5 mg/kg PO q.12–24 h. For example, 1 mg for small ● Increased affection/friendliness (can become over-
dogs, 2.0 mg for medium dogs and 4.0 mg for large dogs to whelming for the owner, especially in Oriental
start breeds).
● Increased vocalization in cats.

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 CHAPTER 7 BEHAVIOR-MODIFYING DRUGS

● Drug tolerance.
● Interference with memory (amnesia with intravenous
EXAMPLES
dosing in humans). Tertiary amines: Amitriptyline, clomipramine, doxepin,
● Disinhibition of suppressed behavior, e.g. imipramine.
aggression. Secondary amines: Desipramine, nortriptyline.
● Interference with learning conditioned responses.
● Anxiety.
● Insomnia.
● Diazepam may increase predation in cats (possibly Clinical applications
through its effects on the lateral hypothalamus and Medication with TCAs has proved helpful and is in fact
its inhibitory effect on ACh). often necessary as an adjunct to a behavior modification
● Fatal idiopathic hepatic necrosis has been reported program in cases, especially in anxiety, that are long-
rarely in cats. standing or particularly severe.
In cats, TCAs have been recommended as part of the
Contraindications and precautions treatment protocol for anxiety-related disorders such as
● Hepatic or renal failure. spraying/marking behavior, intercat aggression, fear
● Use with caution in aggressive animals. aggression, overgrooming and excessive licking in
● The patient must be weaned off treatment obsessive-compulsive disorder. They have also proved
gradually if they have been dosed daily. useful in the treatment of excessive vocalization due to
anxiety. Success rates of up to 80% have been reported
for the treatment of urine spraying with amitriptyline.
Up to a 90% success rate has been reported with clo-
ANTIDEPRESSANTS mipramine treatment for urine spraying. Additionally,
clomipramine has been effective in controlling over
Antidepressants have been used extensively in human 90% of cases of obsessive-compulsive disorder when
psychiatry and are increasingly used in the treatment of used in combination with a behavior modification
companion animal behavior problems. Although the program. TCAs with strong anticholinergic activity
name implies that their main clinical indication is for have also been used to reduce predation in cats, as ACh
alleviating depression, they are also used in humans to is the principal neurotransmitter involved in predatory
treat problems such as agoraphobia, enuresis, narco- aggression.
lepsy, recurrent fears and anxieties and to decrease some In dogs, TCAs have been used as part of the treatment
types of volatile or explosive aggression. In companion protocol in cases of dominance aggression, fear aggres-
animal medicine they have proved useful as part of sion, separation anxiety, obsessive-compulsive disor-
behavior modification treatment programs. ders, including acral lick granulomas, fears and
A number of different chemical structures have phobias such as thunderstorm phobia, enuresis and
been found to have antidepressant activity. The three narcolepsy.
most common types are the tricyclic antidepressants In a double-blind placebo-controlled study, clomip-
(TCAs), the selective serotonin reuptake inhibitors ramine was shown to be effective in contributing to the
(SSRIs) and the monoamine oxidase inhibitors resolution of separation anxiety in dogs after 2 months
(MAOIs). of treatment in 70% of cases compared with less than
All antidepressants take about 2 weeks to produce 20% of cases where behavior modification alone was
any beneficial effects (in humans), even though their used. Other trials have reported a 50–70% improve-
pharmacological effects are produced immediately. This ment in licking behavior in lick granulomas and 65–
suggests that secondary adaptive changes are important, 100% response in the treatment of stereotypic and
such as drug modification of receptor sites. obsessive-compulsive disorders in dogs. TCAs are more
successful when the animal presents with only one
problem, as opposed to multiple behavior problems.
Tricyclic antidepressants Amitriptyline has been used in the management of
Tricyclic antidepressants (TCAs) are closely related to cats with lower urinary tract disease. Imipramine has
phenothiazines in chemical structure, both having three been used successfully in the treatment of urethral
linked rings. The TCAs, however, lack a sulfur constitu- incompetence because of its anticholinergic and α-
ent in the middle ring. They are less related pharmaco- adrenergic effects.
logically. They differ principally by the incorporation of Doxepin and amitriptyline have considerable antihis-
an extra atom in the central ring; thus the molecule is taminergic effects so they are useful in cases where anti-
no longer planar. pruritic or sedating effects are also needed.

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 ANTIDEPRESSANTS

Mechanism of action
CATS
The TCAs have five principal modes of action.
● They block reuptake of serotonin. Amitriptyline
● They block reuptake of noradrenaline
• 0.5–1.0 mg/kg PO q.24 h
(norepinephrine). Clomipramine
● They have anticholinergic, antimuscarinic effects. • 0.25–0.5 mg/kg PO q.24 h; may need up to 1 mg/kg to manage
● They have α1-adrenergic antagonist effects.
some disorders
● They have antihistaminic effects to varying degrees. Doxepin
• 0.5–1.0 mg/kg PO q.12–24 h
Thus TCAs produce three major effects.
Imipramine
● Blocking reuptake of brain amines (antidepressant • 0.5–1 mg/kg PO q.12–24 h
effect in humans).
Nortriptyline
● Anticholinergic (atropine-like) effects.
• 0.5–2.0 mg/kg PO q.12–24 h
● Sedation.
Generic forms of most TCAs are inexpensive and generally make a
TCAs act by inhibiting the amine (noradrenaline (nor- good choice (where a veterinary product is not indicated) for treatment
epinephrine) or serotonin) reuptake pumps, which pre- programs that are expected to be long-standing or lifelong.
sumably permits longer duration of action of the
neurotransmitter at the receptor site. In chronic use they
may cause a decrease in the number of β-adrenergic and Pharmacokinetics
5-HT2 receptors. Tricyclic antidepressants are rapidly absorbed from
Prototypic drugs, imipramine and amitriptyline, are the gastrointestinal tract and bind strongly to
mixed noradrenaline (norepinephrine) and serotonin plasma albumin (90–95%). Clomipramine undergoes
uptake inhibitors and have antimuscarinic, antihista- substantial first-pass metabolism that reduces its bio-
minic and α-adrenoreceptor blocking actions. Clomip- availability to 50%. They preferentially bind hepato-
ramine hydrochloride is the 3-chloro analog of cytes, myocardial cells, pulmonary and brain tissue.
imipramine. It preferentially inhibits the neuronal reup- High protein binding and relatively high lipid solubility
take of serotonin and noradrenaline (norepinephrine). lead to large volumes of distribution and slow elimina-
The precise mechanism of action of the antipruritic tion rates.
effects of doxepin is unknown but is thought to relate Most TCAs undergo significant metabolism. They are
to its potent H1 antagonist properties. metabolized by the liver by two main routes: demethyl-
ation, followed by glucuronide conjugation. Thus,
alteration of the aliphatic side chain, N-demethylation
(tertiary amines converted to secondary amines, e.g.
Formulations and dose rates amitriptyline to nortriptyline), occurs first. This is fol-
lowed by transformation of the tricyclic nucleus by ring
DOGS
hydroxylation and conjugation to form glucuronides.
Amitriptyline Monodemethylation produces active metabolites, e.g.
• 1–4 mg/kg PO q.12–24 h desipramine and nortriptyline. In humans, the relative
Amitriptyline is extremely bitter, so it can be difficult to administer if
proportion of each metabolite varies between individu-
the tablet is broken.
als. During prolonged treatment the plasma concentra-
Clomipramine tion of active metabolites is likely to be comparable to
• 1–2 mg/kg PO q.12 h 2 weeks, then 3 mg/kg PO q.24 h; may
the parent compound, although individual variation
need up to 4 mg/kg to manage some disorders
Clomipramine is approved for veterinary use in many countries. One
occurs. It appears that the metabolites are more potent
formulation of clomipramine available, Clomicalm®, is meat flavored noradrenaline (norepinephrine) inhibitors, while the
and generally well accepted by cats and dogs. Higher doses appear parent compound is generally more potent in inhibiting
to be necessary to control obsessive-compulsive disorders than serotonin uptake.
anxiety disorders. Renal filtration is generally ineffective in eliminating
Doxepin the parent compounds because they are highly protein
• 3–5 mg/kg PO q.8–12 h (for acral lick dermatitis) bound, very lipophilic and widely dispersed in tissues.
• 0.5–1 mg/kg PO q.12 h (for obsessive-compulsive disorder) Metabolism and inactivation by glucuronide conjuga-
Imipramine tion of the hydroxylated metabolites are required for
• 2.0–4.0 mg/kg PO q.12–24 h significant excretion of glucuronides in urine.
Nortriptyline Up to 2–3 weeks or even longer is required to reach
• 1–2 mg/kg PO q.12–24 h therapeutic blood levels. However, clinical effects are
seen soon after administration.

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 CHAPTER 7 BEHAVIOR-MODIFYING DRUGS

Adverse effects Known drug interactions

It should be noted that, because clomipramine is regis- ● Concurrent MAOI administration should be avoided
tered for use in animals, more is known about its spe- as it may lead to a serotonin syndrome.
cific effects in companion animals than those of other ● TCAs used with antithyroid medications may increase
TCAs. However, the pharmacology of other TCAs the potential risk of agranulocytosis.
in companion animals is expected to be similar to ● As TCAs are strongly bound to plasma protein, their
clomipramine. effects may be temporarily enhanced by drugs that
● The most predictable side effects are short-term leth- compete for protein-binding sites (e.g. aspirin,
argy or sedation, mild and intermittent vomiting phenylbutazone).
which is usually transient and increases or decreases ● As hepatic metabolism is necessary for elimination,
in appetite. drugs such as neuroleptics and some steroids may
● Anticholinergic side effects may be encountered, inhibit metabolism.
often, but not always, at high dose rates. ● Simultaneous administration of clomipramine and
● Other side effects, which usually disappear if the cimetidine (an enzyme inhibitor) may lead to
dose is decreased or the medication is withdrawn, increased plasma levels of clomipramine.
include: ● Plasma levels of certain antiepileptic drugs such as
– Sedation (antihistamine effect) phenytoin and carbamazepine may be increased by
– Dry mouth (antimuscarinic effect) coadministration with clomipramine.
– Constipation (antimuscarinic effect) ● Clomipramine may potentiate the effects of antiar-
– Tachycardia rhythmic drugs, anticholinergic agents and other
– Cardiac arrhythmias CNS-acting drugs (e.g. barbiturates, benzodiaze-
– Ataxia pines, neuroleptics).
– Decreased tear production ● Concurrent use with sympathomimetic drugs may
– Mydriasis increase the risk of cardiac effects (arrhythmias,
– Disturbances of accommodation. hypertension).
● High doses have been associated with increased liver
enzymes, hepatotoxicity and convulsions. Selective serotonin reuptake inhibitors
● A few cases of urine retention have been reported
Currently, there are at least five selective serotonin reup-
in cats after treatment with clomipramine. This
take inhibitors (SSRIs) on the market worldwide for
effect is likely to be the result of decreased
human use. As their collective name implies, they are
bladder muscle tone, which decreases intraluminal
selective for serotonin, lacking the anticholinergic and
pressure and allows collapse of the trigone area,
cardiovascular side effects of TCAs. They do not resem-
obstructing urinary outflow. Hence animals treated
ble TCAs structurally and have minimal autonomic
with clomipramine should be monitored daily for
activity. They have much improved safety and tolerabil-
signs of urine retention or constipation. If urine
ity over the TCAs and MAOIs and wider therapeutic
retention or constipation occurs, drug administra-
indications than depression.
tion should be stopped until normal urination or
defecation is observed, then reinstated at a lower
dose.
EXAMPLES
● Cats are more sensitive to the cardiac effects of Fluoxetine (Prozac®), paroxetine, sertraline, fluvoxamine,
TCAs than dogs and should be monitored closely. citalopram.
● In humans, TCAs may lower the seizure
threshold.
● TCAs should be used with caution in patients with Clinical applications
hyperthyroidism or receiving thyroid supplementa- Apart from the treatment of depression, SSRIs have
tion as there may be an increased risk of cardiac been used successfully in cases of panic disorder, obses-
arrhythmias. sive-compulsive disorder, posttraumatic stress disorder,
chronic pain, social phobias, enuresis and eating disor-
ders in humans.
Contraindications and precautions In cats, fluoxetine and paroxetine have been used to
● Cardiac dysrhythmias treat urine spraying, with the reported success rate of
● Urinary retention fluoxetine being around 80% for urine spraying and
● Concurrent use of hypertensive drugs anxiety-related disorders. Both have also been used to
● Narrow angle glaucoma treat some types of aggression and obsessive-compulsive
● Seizures disorders.

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 ANTIDEPRESSANTS

In dogs, fluoxetine and sertraline have been used in

the treatment of acral lick granulomas. Fluoxetine has Sertraline
• 0.5–1 mg/kg PO q.24 h
also been used to treat obsessive-compulsive disorders,
separation anxiety, generalized anxiety or global fear BIRDS
and dominance aggression. Paroxetine has also been Fluoxetine
used to treat generalized anxiety disorder with 50% of • 2.0–5.0 mg/day
patients showing clinical improvement. Citalopram has
been used to treat acral lick dermatitis with a satisfac- Pharmacokinetics
tory result being seen in about 2 weeks. Until recently, Fluoxetine is well absorbed after oral administration,
their high cost generally prevented SSRIs from being the with peak plasma concentrations in humans achieved in
drug of first choice in companion animal therapy. 4–8 h. In a study in beagles, bioavailability was 70%.
However, fluoxetine is now off patent and the generic The presence of food alters the rate but not extent of
forms are more affordable. They and other SSRIs are a absorption. Fluoxetine is highly protein bound (95%)
valuable therapeutic option if the owner’s financial con- in humans. It has been administered transdermally to
straints do not preclude their use. However, the mint- cats. However, the relative bioavailability by this route
flavored liquid formulation is not readily accepted by was only 10% of that achieved after oral administra-
some cats. tion; the study did not determine the actual oral bio-
availability in cats.
Mechanism of action Fluoxetine and its major metabolite are distributed
Selective serotonin reuptake inhibitors selectively inhibit throughout the body, with highest levels found in lung
serotonin reuptake in presynaptic neurones in the CNS. and liver. CNS concentrations are detected 1 h after
The therapeutic effect of SSRIs in obsessive-compulsive dosing. Fluoxetine is metabolized in the liver to a variety
disorders is thought to be mediated by disinhibition of of metabolites. The demethylated active metabolite,
serotonin neurones in the pathway from the midbrain norfluoxetine, has a half-life of 7–9 d at steady state,
raphe to the basal ganglia. Similarly, the amelioration while the parent drug has a shorter half-life of 2–3 d. In
of panic disorders is thought to occur when disinhibi- humans, there is wide interpatient variation in duration
tion of the pathway to the limbic cortex and hippocam- of action. Liver, but not renal, impairment will increase
pus occurs. However, activation of serotonin receptors clearance times.
can worsen panic or anxiety initially. This has been Sertraline and paroxetine have similar pharmacoki-
observed in both humans and companion animals. netic parameters to the TCAs.

Adverse effects
Formulations and dose rates ● Mild sedation.
● Transient decreased appetite.
DOGS
● Increased anxiety.
Fluoxetine
● Decreased sexual motivation in animals and
• 1–2 mg/kg PO q.24 h
humans.
Fluvoxamine ● Nausea, lethargy, weight loss, tremors and
• 0.5–2 mg/kg PO q.24 h (up to 4 mg/kg q.12 h if necessary,
agitation have been reported in humans.
increased incrementally)
● In humans increased liver enzymes may occur,
Paroxetine although there are no reports of liver pathology
• 1 mg/kg q.24 h
unless the patient had prior liver disease.
Sertraline ● Gastrointestinal disturbances such as vomiting or
• 1–3 mg/kg PO q.24 h diarrhea have been reported in humans.
Citalopram ● Drug-induced rashes have been reported in
• 0.5–1 mg/kg q.24 h humans.
CATS
Fluoxetine Known drug interactions
• 0.5–1 mg/kg PO q. 24 h ● Fluoxetine can increase the half-life of concurrently
Fluvoxamine administered diazepam, although in the short term
• 0.25–0.5 mg/kg PO q.24 h (up to 1–2 mg/kg q.12 h; increase the drug combination is recommended for humans
incrementally) by some psychiatrists.
Paroxetine ● Concomitant MAOI therapy can cause a serotonin
• 0.5–1 mg/kg PO q.24 h syndrome. This is a very serious condition character-
ized by changes in mental status, hyperthermia,

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 CHAPTER 7 BEHAVIOR-MODIFYING DRUGS

agitation, myoclonus and autonomic instability, It may take up to 3 months to see the full behavioral
which may lead to death. At least 2 weeks should be benefits of selegiline, although owners have often
allowed as a wash-out period between SSRI and reported improvement in their dogs within 7–10 days.
MAOI therapy, 5 weeks for fluoxetine.
● Coadministration of TCAs can increase plasma levels Mechanism of action
of the TCA. As the name implies, the MAOIs inhibit the enzyme
● Fluoxetine can enhance the effects of haloperidol monoamine oxidase (MAO). MAO is an intracellular
(increased extrapyramidal effects), lithium (increased enzyme, subclassified into two types, A and B, which
lithium levels), l-tryptophan (CNS stimulation, GI differ in their substrate specificity and tissue distribu-
disturbances), TCAs (increased TCA side effects) and tion. MAO is widely distributed throughout the body
buspirone (increased anxiety). and found in nearly all tissues. MAO-A has a substrate
preference for 5-HT while MAO-B has a substrate pref-
Monoamine oxidase inhibitors erence for phenylethylamine. Both enzymes act on nor-
adrenaline (norepinephrine) and dopamine. In CNS
Monoamine oxidase inhibitors were among the first neurones, MAO plays an important role in the catabo-
drugs to be used as antidepressants. However, they have lism and inactivation of catecholamines, mainly dopa-
been superseded by TCAs, which have fewer side effects. mine, and to a lesser extent noradrenaline and adrenaline
The MAOIs are classified as hydrazides or nonhydra- (epinephrine).
zides depending on whether or not they have the C-N-N Monoamine oxidase inhibitors inhibit one or both
structure. The hydrazides appear to combine irrevers- forms of brain MAO, thus increasing cytosolic stores of
ibly with monoamine oxidase. Older MAOIs are non- noradrenaline, dopamine and 5-HT in nerve terminals.
selective inhibitors of both MAO-A and MAO-B (e.g. MAO-A is primarily responsible for noradrenaline,
phenelzine), while newer types are selective for either serotonin and tyramine metabolism, while MAO-B is
MAO-A and reversible (e.g. moclobemide) or MAO-B more selective for dopamine metabolism.
(e.g. selegiline). Only selegiline has been used in veteri- Selegiline hydrochloride N-[(2R)-1-cyclohexylpropan-
nary medicine. 2-yl]-N-methylprop-2-yn-1-amine is a β-phenylethyl-
amine (PEA) analog that acts as an irreversible inhibitor
EXAMPLE of MAO-B. This is thought to lead to increased synaptic
Selegiline (L-deprenyl).
occupancy of PEA and reduced catabolism of other
monoamines, like dopamine, noradrenaline and tyra-
mine. PEA seems to play a neuromodulation role for
Clinical applications dopamine and noradrenaline.
In humans, selegiline has been used in the treatment of Selegiline is thought to be a selective inhibitor of MAO-
Parkinson’s disease. It has been used in older cats pre- B in the dog. It is believed to also increase synthesis and
senting with anxiety, disturbed sleep/wake cycles and release of dopamine into the synapse as well as interfering
excessive vocalization associated with aging. It has also with dopamine reuptake. The secondary metabolites,
been used to treat generalized anxiety, compulsive including l-amfetamine and l-methamfetamine, both of
licking and several types of aggression, but higher doses which have pharmacological actions of their own, may
seem to be required for cats than dogs. also contribute to the behavioral effects seen; however,
In the USA and Australia the main behavioral use of the extent of this is not known. Selegiline or its metabo-
selegiline is for canine cognitive dysfunction syndrome lites may also enhance the release of other neurotransmit-
in old dogs. It is also useful in some anxiety problems. ters such as noradrenaline. Selegiline also increases the
In Europe, the drug is used for a wider range of behav- action of superoxide dismutase (SOD) and of catalase
ioral problems. It has been advocated in young dogs, enzymes, which are both responsible for the detoxifica-
even as young as 8 weeks, that have been diagnosed tion of free radicals, particularly dopamine metabolites.
with overactivity/hyperactivity, anxiety problems,
phobias, sleep disorders and stereotypies such as tail Formulations and dose rates
chasing. It has also been used in adult dogs with anxiety
Selegiline
disorders that present with signs such as vomiting, diar- DOGS
rhea, salivation, phobias and acral lick dermatitis, as • 0.5 mg/kg PO q.24 h; if no response after 4 weeks, 1.0 mg/kg
well as depressive disorders. It has been reported to be PO q.24 h. It is generally recommended that the drug be
effective in reducing fear aggression but not territorial administered in the morning
aggression. For older dogs (over 7 years of age) it has CATS
been successfully used to treat anxiety and sleep disor- • 0.5–1.0 mg/kg PO q.24 h
ders, as well as cognitive dysfunction.

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 AZASPIRODECANEDIONES – AZAPIRONES

Pharmacokinetics treatment protocol. Buspirone is ineffective when taken

Monoamine oxidase inhibitors are absorbed from the irregularly. It may take 1–2 weeks for any beneficial
gastrointestinal tract. The plasma elimination half-life effects to occur. Maximal effectiveness is achieved after
of selegiline is thought to be 60 min, based on intrave- 4–6 weeks in humans and this time frame appears to be
nous administration to four dogs. Its volume of distribu- similar in companion animals. Consequently, the use of
tion is estimated to be 9.4 L/kg, suggesting that selegiline buspirone in acute anxiety conditions is limited. Buspi-
is extensively distributed to body tissues. The absolute rone does not produce dependence.
bioavailability of an oral solution is less than 10%, sug- Buspirone treatment has been advocated for anxiety-
gesting poor absorption or considerable prehepatic related problems of long standing in cats, including
metabolism. urine marking/spraying and overgrooming. Its success
Inhibition of MAO persists even after the drug is no rate in reducing urine spraying has been reported to be
longer detectable in plasma. about 55%, with a recidivism rate of about 50% after
withdrawal of medication. It has also been used success-
Adverse effects fully for travel sickness in cats.
● Stereotypic behaviors with overdosage. Advantages of buspirone in comparison to benzodi-
● Gastrointestinal effects – vomiting and/or diarrhea. azepines include lack of sedation and a high safety
● Hyperactivity or restlessness. margin. However, the frequency of dosing and cost can
● Pruritus, hypersalivation, anorexia, diminished be problematic.
hearing and listlessness have also been reported Because of its expense, buspirone has not been com-
in dogs. monly used for canine behavior problems. However, it
has been used in the treatment of dominance aggression
Known drug interactions and some stereotypic disorders, with limited success.
Concomitant use of phenylpropanolamine, amitraz (an
MAOI), ephedrine or pethidine (meperidine) or other Mechanism of action
opioids is not recommended. The mechanism of action Buspirone is a potent anxiolytic with a high affinity for
of this drug interaction is not fully understood. However, 5-HT1A receptors. These receptors are abundant in the
it can be fatal. parts of the brain that receive projections from the 5-HT
In humans, severe CNS toxicity, including death, has neurones of the midbrain raphe. It also binds to dopa-
been reported with the combination of TCAs or SSRIs mine receptors, acting as both an agonist and an antago-
and selegiline, although no adverse effects have been nist, but this is not thought to contribute to its anxiolytic
reported in field trials with dogs. It is recommended that effect. It has no direct effects on GABAA receptors and
there be a 2-week wash-out before administration of does not produce sedation; however, it does enhance
selegiline after TCA therapy. A 5-week wash-out is rec- benzodiazepine binding. It does not have anticonvulsant
ommended before administration of selegiline after or muscle-relaxant activity and does not impair motor
fluoxetine, because of the long half-life of fluoxetine and task performance.
its metabolites. The exact mode of action of buspirone is unclear but
it is thought to produce its anxiolytic effect by acting as
a partial agonist at 5-HT1A receptors pre- and postsyn-
AZASPIRODECANEDIONES – AZASPIRONES aptically. Buspirone may act presynaptically and inhibit
5-HT release.

EXAMPLE Formulations and dose rates

Buspirone (Buspar®).
DOGS
• 1.0–2.0 mg/kg PO q.8–24 h
Clinical applications CATS
Buspirone has been used to treat anxiety disorders in • 0.5–1 mg/kg PO q.8–24 h
humans. Its anxiolytic efficacy is believed to be equiva-
lent to the benzodiazepines. However, it has not proved
effective as the sole treatment of panic disorders in Pharmacokinetics
humans. Interestingly, buspirone appears to be least Buspirone is rapidly absorbed orally but undergoes
effective in patients who have taken benzodiazepines extensive first-pass metabolism via hydroxylation and
within the 4 weeks prior to commencing buspirone dealkylation to form several active metabolites, so that
treatment. Whether this is also the case in animals is bioavailability is only 4% in humans. One of its active
unknown but should be considered when devising a metabolites, 1-(2-pyrimidyl)-piperazine, acts via α2-

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 CHAPTER 7 BEHAVIOR-MODIFYING DRUGS

adrenergic receptors to increase the rate of firing of the effects of progestins unacceptable. Currently, synthetic
locus ceruleus, an undesirable effect in anxiety. However, progestins should be considered as drugs of last resort,
it is not known whether this limits buspirone’s efficacy. not only because of their many side effects but also
In humans the half-life of buspirone is 2–4 h. Liver because many other medications are available that
dysfunction decreases its clearance. directly affect the cause of the behavior problem and
are therefore more effective clinically.
Adverse effects Progestins may be the drug of choice for some sexu-
● Bradycardia/tachycardia. ally dimorphic behaviors that do not respond to castra-
● Nervousness. tion. In cats, progestins have been used to successfully
● Gastrointestinal disturbances. treat urine marking, with 42% of cats showing decreased
● Stereotypic behaviors. or cessation of spraying. Males respond significantly
● Restlessness has been reported in humans. better than females. The success rate, therefore, is much
● Caution is needed as treatment can lead to poorer for females treated with progestins compared to
increased aggression as buspirone may decrease the treatment with anxiolytics such as fluoxetine, diazepam
inhibitory effects of fear. or buspirone. However, a similar success rate for pro-
gestin versus anxiolytic therapy is reported for males.
There have been reports of successful use of progestins
HORMONES in the treatment of intermale aggression.
In dogs, progestins have been used to treat ‘domi-
Hormones are chemical messengers produced by endo- nance’ aggression, urine marking, mounting, inter-
crine glands and secreted into the bloodstream, where male aggression (6/8 dogs responded) and
they act on target cells to exert specific effects. Hor- pseudopregnancy.
monal therapy has been used in the treatment of many
behavioral problems but their use is now outdated in Mechanism of action
most circumstances. The most common hormones used The 21-carbon synthetic progestins medroxyprogester-
are the progestins and estrogens. one and megestrol are the most closely related pharma-
cologically and chemically to the natural progestin,
Progestins progesterone, the precursor of estrogens, androgens and
adrenocortical steroids. The physiological effects of the
EXAMPLES synthetic progestins are similar to those of the other
steroid hormones (see Chapter 23).
Medroxyprogesterone acetate (MPA®, Depo-Provera®), Progesterone and its metabolites cause nonspecific
megestrol acetate (Ovarid®, Suppress®). depression of the CNS, act as nonspecific sedatives and
have barbiturate-like activity. They are antiandrogenic
Clinical applications and act mainly in the medial preoptic area and the
Synthetic progestins have been used traditionally in anterior hypothalamus, the areas that control male
veterinary behavioral medicine to treat a variety of sexual behavior and urine marking. Progesterone also
problems. It has been claimed that they are effective interferes with synthesis of estrogen receptors and sup-
in the treatment of problems ranging from roaming, presses the production of testosterone in the reproduc-
sexual perversion, raucous behavior, obsessive barking, tive tract of intact animals. However, progestins also
destructiveness, hole digging, car chasing, excessive suppress male-like behavior in castrated cats.
timidity and poultry killing to urine spraying and The behavioral and physiological effects of progestins
aggression. were initially thought to be due to inhibition of 5α-
The rationale for treatment was based on the fact that steroid reductase. However, their effects are now
some behaviors are directly affected by male hormones thought to be mediated in a number of other ways,
and hence treatment with synthetic progestins may including actions on GABAA receptors to produce effects
counteract these effects. Additionally, the sedating similar to those of the benzodiazepines.
effects of the progestins may also have been considered
useful. However, this treatment approach does not take Formulations and dose rates
into account the underlying cause of many of the behav-
iors treated. It should also be noted that the addition of DOGS
female hormone may not necessarily mimic the removal Megestrol acetate
of male hormone, so the effect of progestins is not neces- • 1.1–2.2 mg/kg PO q.24 h for 2 weeks, then one-half dose for
sarily due to suppression or counteraction of male next 2 weeks then one-quarter dose for last 3 weeks
hormone. Treatment failure is common and the adverse

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 α-ADRENERGIC AGONISTS

been used as an adjunct in the treatment of urination

Medroxyprogesterone acetate (MPA-50) associated with excitement, submissive urination and
• 5–11 mg/kg SC or IM, maximum 3 times per year
nocturnal urination in combination with behavior
CATS modification.
Megestrol acetate In humans, ephedrine is used as a nasal decongestant
• 2.5–10 mg PO q.24 h for 1 week, then reduce dose to and in the management of stress incontinence in
minimum effective dose women.
Medroxyprogesterone acetate (MPA-50)
• 50 mg (females) 100 mg (males) SC or IM, maximum 3 times Mechanism of action
per year Ephedrine is structurally related to noradrenaline (nor-
epinephrine) and acts primarily through the release of
catecholamines. It also has direct effects on α- and β-
Pharmacokinetics adrenoreceptors and inhibits MAO. It is a mild CNS
Medroxyprogesterone acetate has a duration of activity
stimulant. Ephedrine is nonselective and mimics the
of at least 30 days in cats. Megestrol is well absorbed
affects of adrenaline (epinephrine).
from the gastrointestinal tract, is metabolized in the
Ephedrine and phenylpropanolamine decrease urinary
liver and has a half-life of 8 days in the dog. It is
incontinence by increasing urethral sphincter tone in
excreted mainly in urine.
cases of urethral incompetence.
Adverse effects
Multiple side effects have been reported and include the Formulations and dose rates
following.
● Increased appetite Ephedrine
● Weight gain Ephedrine is available in over-the-counter nasal decongestant
● Depression/lethargy
preparations.
DOGS: 15–50 mg PO q.12 h or 5–15 mg q.8 h
● Mammary gland hyperplasia and carcinoma
CATS: 2–4 mg/cat PO q.8–12 h
● Diabetes mellitus
● Bone marrow suppression
Phenylpropanolamine
Phenylpropanolamine is available in over-the-counter weight reduc-
● Endometrial hyperplasia
tion preparations.
● Pyometria
DOGS: 1.1–4.4 mg/kg PO q.8–12 h
● Adrenocortical suppression
CATS: 12.5 mg PO q.8 h
● Thinning and increased fragility of the skin

Contraindications and precautions

● Progestins should not be used in intact females, Pharmacokinetics
breeding animals and in animals with diabetes
In humans a substantial amount of ephedrine is excreted
mellitus (increases insulin resistance).
unchanged in urine.
● Concurrent corticosteroid use is contraindicated.
Adverse effects
a-ADRENERGIC AGONISTS ● Bronchodilation
● Restlessness, excitability, irritability and anxiety
Sympathomimetic amines produce vasoconstriction by ● Hypertension
activation of α1-adrenoreceptors, exerting a powerful ● Panting
effect on skin, mucous membranes, splanchnic, hepatic ● Anorexia
and renal circulation, with little effect on cerebral and ● Tremors
coronary blood flow. ● Cardiac arrhythmias

Contraindications and precautions

EXAMPLES ● Concurrent MAOI therapy
Phenylpropanolamine, ephedrine. ● Glaucoma
● Prostatic hypertrophy
● Hyperthyroidism
Clinical applications ● Diabetes mellitus
Adrenergic drugs are primarily used in the treatment of ● Cardiovascular disease
urinary incontinence (see Chapter 4). They have also ● Hypertension

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 CHAPTER 7 BEHAVIOR-MODIFYING DRUGS

a-ADRENERGIC ANTAGONISTS tant in learning. This effect is more consistent with

long-term use.

EXAMPLE Formulations and dose rates

Nicergoline (Fitergol®). DOGS
• 0.25–0.5 mg/kg PO q.24 h to be given in the morning for at
least 30 days. Repeat monthly or as needed
Clinical applications
Currently one α-adrenergic antagonist, nicergoline, is CATS
• 0.25–0.5 mg/kg PO q.24 h in the morning. Repeat monthly or
marketed for use in companion animals. At present it is
as needed
only registered for use in dogs. It is used in humans for
the prevention and treatment of cerebrovascular disor-
ders and arteriosclerotic diseases. Pharmacokinetics
Although not registered for use in cats, nicergoline Nicergoline is rapidly absorbed after oral administra-
has been reported to be beneficial for cats that present tion, with peak plasma levels in dogs attained in 1 h. It
with behavioral problems associated with aging, such is partially metabolized on first pass through the liver
as excessive vocalization and restlessness, especially at and plasma levels appear to stabilize 12–15 d after com-
night. mencement of treatment in rats.
Nicergoline has been recommended for dogs showing
signs consistent with aging-related behavioral disorders Adverse effects
(canine cognitive dysfunction syndrome – CCDS) and No definite adverse effects have been reported in any
cerebral insufficiency of vascular origin. These include clinical trials to date. However, there is a single case
alteration in sleep/wake cycles and loss of learned report of diarrhea, vomiting and tremors in one dog.
behaviors such as housetraining. It has also been advo- However, it was not known if this was due to the drug
cated in the treatment of aggression associated with or coincidental.
aging. In the author’s experience, nicergoline has allevi-
ated these clinical signs in 70% of cases. In addition, Known drug interactions
the author has successfully used nicergoline in one 12- ● Nicergoline can be expected to have an additive
year-old dog that exhibited behavioral changes, possibly effect if used concurrently with other vasodilators.
analogous to depression in humans, after the death of ● Treatment should be stopped 24 h before induction
its companion dog. of anesthesia with xylazine. Because it is an α-
antagonist, nicergoline may interfere with the activ-
Mechanism of action ity of xylazine, reducing or negating its sedative
Nicergoline belongs to the ergoline group of compounds effects. Alternatively, xylazine may reduce the effec-
and has a core structure analogous to that of natural tiveness of nicergoline.
ergot alkaloids. It is an α1-adrenergic antagonist. In
vitro studies demonstrate that it has high affinity for PHEROMONES
α1-adrenergic receptors and only minimal affinity for
α2-adrenergic or β-adrenergic receptors. Pheromones are volatile chemical messengers that are
Nicergoline has a neuroprotective effect (in rat fetuses) produced in exocrine glands. They are released into the
by blocking the toxic effects and neuronal damage environment by animals to communicate with and alter
induced by the vasoconstrictive effects of catecholamines the behavior of other members of (usually) the same
during ischemic episodes. It increases the oxygen supply species. Recently, synthetic analogs of pheromones have
to the brain by causing vasodilation. Nicergoline also been used in the treatment of behavior problems in cats
increases oxygen and glucose uptake of brain cells, and dogs. Pheromones for other species are in develop-
increases cerebral blood flow, especially in ischemic epi- ment. Cats are believed to use facial pheromones to
sodes, stimulates memory and learning and has anti- familiarize themselves with their environment.
thrombotic effects (inhibits platelet aggregation and
platelet adhesion to endothelium). Restoration of EXAMPLES
learned conditioned responses after an hypoxic episode
has been demonstrated. Feliway®, Dog Appeasement Pheromone® (DAP).
Other reported effects include increased dopamine
turnover. Studies have also indicated that nicergoline Clinical applications
stimulates the turnover of secondary messengers such as Feliway® has been advocated for use in cases of urine
inositol triphosphate, which is purported to be impor- spraying or anxiety in domestic cats and cheetahs. It has

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 ERGOT ALKALOIDS

been reported to be help decrease intercat aggression in bitch secretes in the first few days after birth which helps
multicat households (one of the major causes of urine the attachment process of mother to pups.
spraying). It can be used alone or concurrently with
anxiolytic medication. It has been reported to success- Formulations and dose rates
fully reduce urine spraying in over 90% of cases. As it
does not involve actually medicating the cat (rather, it Feliway®
Spray and diffuser are now available.
is applied to the environment), it has proved to be a
Spray: for scratching/urine marking, spray daily at a height of
useful and convenient tool for behavioral modification. 20 cm (cat nose level) in 6–8 prominent locations per room, including
The author recommends its use in most cases of anxiety- areas that have been marked with urine. Needs to be used continu-
related problems in cats and where owners are unable ously for 21 d for scratching, 30 d for urine marking, 45 d for older
to medicate their pet. cats; for travel: spray cat carrier 15 min prior to introducing the
Feliway is also recommended to help cats tolerate cat.
clinical examinations during a veterinary consultation. Diffuser: needs to be plugged in the room where the cat spends
Over 70% of veterinarians surveyed in France reported most of its time. One diffuser covers around 50 sq m and lasts
that it was helpful in these circumstances. The author approximately 1 month. In multistory houses diffusers need to be
has had considerable success using Feliway in the con- placed on each level. The product should be used continuously for
1–3 months initially depending on the problem.
sultation room, on the examination table and on per-
sonnel involved in handling cats, to calm fractious DAP®
cats. Spray, diffuser and collar are now available.
Spray (e.g. for for car travel): spray 8–10 pumps of DAP 15 min
Other uses include calming cats prior to travel by
before effect is required and before introducing the dog into the car
spraying the cat-carrier prior to placing the cat inside, or crate. It can also be sprayed onto a bandana and tied around the
helping cats to become familiar with a new house and dog’s neck if the DAP collar is not available.
in the introduction of a new cat to the household. Addi- Diffuser: should be placed in the room where the dog spends most
tionally, it appears to be useful in stimulating appetite of its time. It should not be placed behind furniture or areas that the
in hospitalized cats. It has also been reported to help to dog cannot access as many dogs prefer to lie close to the diffuser. It
control undesirable scratching behavior. should not be placed under tables as this will prevent circulation
It has also been used successfully in catteries, board- through the room. One diffuser covers approximately 50–70 sq m and
ing establishments and veterinary hospitals to decrease lasts around 30 days. In multistory houses a diffuser should be placed
anxiety and assist cats to familiarize themselves with the on each level. The diffuser should be plugged in continuously for at
least 30 days..
novel environment.
Collar: the collar should be fitted firmly on the dog’s neck (one
Dog Appeasement Pheromone® has been used in finger between collar and neck). Each collars lasts about 1 month.
dogs in the treatment of noise phobias (fireworks and
thunderstorms), separation anxiety, motion sickness
and helping puppies settle in to their new home. It has Adverse effects
also been used as an adjunct to treatment with other ● None have been reported, although some clients
anxiety disorders. claim that the alcohol vehicle is irritating.
It has also been used successfully in boarding estab- ● Caution should be exercised if there are birds in
lishments and veterinary hospitals to help decrease the environment as they are likely to investigate
anxiety, facilitate handling of dogs and assist dogs to anything new in the environment by sniffing.
familiarize themselves with the novel environment.
ERGOT ALKALOIDS
Mechanism of action
To date, five functional fractions of facial secretions of
EXAMPLE
cats have been identified. The F3 fraction of facial phero-
mone is thought to inhibit urine marking, enhance Bromocriptine.
feeding in an unknown situation and enhance explor-
atory behavior in unfamiliar surroundings. The F4 frac- Clinical applications
tion is said to be an allomarking pheromone, hence Bromocriptine has been used for urine spraying in cats,
familiarizing and calming the cat. with a success rate of 85% in treated males and 40%
Feliway® contains a synthetic analog of the F3 frac- in females. It has also been used for the treatment of
tion of feline facial pheromone, along with a cat attrac- pseudocyesis in dogs.
tant (the alcoholic extract of the plant Valeriana
officinalis). Mechanism of action
Dog Appeasement Pheromone® is believed to be the Ergot alkaloids are dopamine agonists and inhibit pro-
synthetic analog of the appeasing pheromone that the lactin release from the anterior pituitary gland. However,

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 CHAPTER 7 BEHAVIOR-MODIFYING DRUGS

the mechanism by which bromocriptine reduces urine messenger systems, by interfering with either cAMP
spraying in some cats is unknown. formation or inisitol triphosphate formation. Its effects
on neurotransmitters are complex but it is thought
Formulations and dose rates to enhance serotonin transmission and may also
affect dopamine, noradrenaline (norepinephrine) and
DOGS acetylcholine.
• 0.01–0.10 mg/kg once PO or divided twice per 24 h
CATS Formulations and dose rates
• 2–4 mg/cat SC; repeat after 2–4 weeks
However, the injectable formulation is no longer available. Oral dose Lithium carbonate
rates have not been determined. DOGS
• 3–12 mg/kg q.12–24 h
Titrate dose by measuring plasma concentration (range
0.8–1.2 mEq/L).
Pharmacokinetics
Bromocriptine is a dopamine agonist that acts at D1-
receptor sites, particularly in the CNS. It is absorbed Pharmacokinetics
from the gastrointestinal tract, reaching a peak plasma Lithium is excreted via the kidneys in two phases, with
level 1–2 h after dosing in humans. It is metabolized in about half excreted within 12 h and the rest over the
the liver into two main metabolites and excreted in bile next 1–2 weeks in humans. It therefore has a long
and feces. After a single oral dose in humans, mean plasma half-life and narrow therapeutic window. Plasma
elimination half-life varied from 2 to 8 h for the parent concentration monitoring is essential.
compound and from 50 to 73 h for the metabolites.
In dogs peak plasma levels are reached 3–5 h after Adverse effects
subcutaneous injection and after 10–21 days similar ● Adverse effects are common and include nausea,
levels are still seen, with total clearance after 60 days vomiting and diarrhea, tremor, polyuria leading to
post injection. Phenothiazines can counteract the effect polydipsia, thyroid enlargement and weight gain in
of bromocriptine. humans.
● Acute overdose causes confusion, convulsions,
Adverse effects cardiac arrhythmias and death.
● Bromocriptine can cause vomiting and diarrhea, ● Renal disease and sodium depletion increase the
hypotension, sedation and fatigue in dogs. likelihood of lithium toxicity.
● In cats bromocriptine can cause prolapse of the
third eyelid and inappetence for the first 2 days of Known drug interactions
treatment. Diuretics enhance lithium’s action and increase the like-
lihood of toxicity.

LITHIUM
XANTHINE DERIVATIVE GLIAL
Clinical applications CELL MODULATORS
Lithium is a monovalent cation that is used, particularly
for acute mania in humans, as an antidepressant and an
antipsychotic. It is used to control the mood swings of
EXAMPLE
bipolar manic depression in humans. Lithium has been Propentofylline (Vivitonin®, Karsivan®).
used to treat some cases of unpredictable, severe aggres-
sion in dogs. However, it has a narrow therapeutic Clinical applications
window, so a complete blood count and biochemistry Propentofylline is a neuroprotective glial cell modulator
panel, electrocardiogram and thyroid function test that has proved effective in clinical trials in patients with
should be run prior to commencing treatment. Addi- vascular dementia and those with dementia of the
tionally, regular monitoring of its plasma concentration Alzheimer type. Some of the pathological process of
is required. Lithium is not considered a drug of first Alzheimer’s disease, including glial cell activation and
choice for these reasons. increased production of cytokines, free radicals and
glutamate, have been shown to be modulated by
Mechanism of action propentofylline.
Lithium’s mechanism of action is not understood. Propentofylline has been demonstrated to improve
However, it is thought that it may act on the second learning and memory deficits induced by β-amyloid

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 FURTHER READING

protein deposition. In clinical studies in humans it cerebral blood flow and inhibition of adenosine uptake.
improved cognitive functions as well as global func- It is thought to increase oxygen supply to the brain,
tions. It improves the ability of patients suffering from inhibit platelet aggregation and make red blood cells
Alzheimer’s disease and vascular dementia to cope with more pliable. It also acts as an antiarrhythmic, periph-
the routine tasks of daily life. eral vasodilator and diuretic.
Similar neuropathological changes are found in the
brains of senile dogs and in human patients suffering
from Alzheimer’s disease. In senile dogs a distinctive Formulations and dose rates
correlation exists between the quantity of β-amyloid
DOGS
accumulation and the degree of dementia. Propentofyl-
• 6–11 mg/kg divided and administered in two equal doses PO
line is recommended to improve dullness, lethargy and
Administer 1 h before feeding for at least 30 days, then continue
overall demeanor in old dogs. It is claimed to increase indefinitely.
exercise and activity and decrease sleeplessness in
dogs.

Mechanism of action Pharmacokinetics

Propentofylline is a xanthine derivative. It is a selective The mean half-life of propentofylline in humans is
inhibitor of adenosine uptake and phosphodiesterase 0.74 h, with peak concentration after oral administra-
that has been shown to be neuroprotective in focal tion at about 2.2 h, and it is rapidly metabolized.
ischemia. It is thought to directly interfere with the Although the drug is registered for animal use in some
neurodegenerative process and reduce the extent of countries, the author was unable to obtain pharmaco-
damage to brain structures. In experimental models of kinetic information about propentofylline in companion
vascular dementia and/or Alzheimer’s disease it improved animals.
cognitive functions, inhibited inflammatory processes
and inhibited excessive activation of microglia, forma- Adverse effects
tion of free radicals, cytokines and abnormal amyloid In humans adverse effects are mostly minor and tran-
precursor proteins (APP). Its effects are thought to be sient and affect the digestive and nervous systems. No
exerted via stimulation of nerve growth factor, increased significant effects were seen on laboratory findings.

FURTHER READING

Crowell-Davis S L, Murray T 2006 Veterinary psychopharmacology. Overall KL 1997 Clinical behavioral medicine for small animals. Mosby,
Blackwell, Ames, IA St Louis, MO
Katzung BG 1998 Basic and clinical pharmacology. Appleton and Rang HP, Dale MM, Ritter JM, Gardner P 1995 Pharmacology.
Lange, Stanford, CT Churchill Livingstone, New York
Landsberg G, Hunthausen W, Ackerman L 2003 Handbook of
behaviour problems of the dog and cat. Butterworth-Heinemann,
Oxford

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