Key concepts and techniques

Key concepts in Agonists, antagonists and partial agonists and antagonists

psychopharmacology at dopamine D2 receptors

Full agonist: dopamine,
apomorphine
David Nutt
Anne Lingford-Hughes

Positive Threshold for

effect = causing psychosis
psychosis
Abstract mania
Drugs are one of the key treatment modalities in psychiatry, so an
Agonist + partial agonist
­understanding of their pharmacology is critical for all people involved in
the treatment of psychiatric disorders. This contribution covers the key
Partial agonist: ariprazole
elements of drug pharmacology. It explains their target proteins, ­either
­receptors or enzymes, and how drugs’ specificity can vary. In ­addition, key
aspects of agonist efficacy and dose–effect responses, partial ­ agonists
and the meaning and effects of antagonists and inverse agonists are
described. Key examples relevant to psychiatry are used.

Antagonist: haloperidol
Keywords agonist; antagonist; dose–response curve; ­ partial agonist;
receptors Dose

Pharmacology is the study of how drugs interact with biologi-

cal processes; psychopharmacology is the study of the effects
of drugs on brain processes such as cognition, mood and other
psychological phenomena. Much psychiatric practice revolves Figure 1
around the appropriate use of drugs’ or medications, and under-
standing the key elements of psychopharmacology can therefore
help optimize treatment. synaptic transmission because of the effect that presynaptic auto-
In psychiatry, drugs are generally small synthetic molecules. receptors may have.
These act in a number of different ways (see Table 1 for details
and examples). Antagonists block the effects of endogenous neurotransmitters
and oppose normal synaptic transmission, although in some
Agonists act to mimic the action of an endogenous neurotrans- cases if they act predominantly on presynaptic receptors they
mitter, though their net action is not necessarily to promote may increase neuronal firing and so increase neurotransmitter
release (see below).

Partial agonists act somewhat like agonists in that they directly

David Nutt FRCP FRCPsych FMedSci is Professor of Psychopharmacology act on receptors, but if used in the presence of an agonist they
and Head of the Department of Community-Based Medicine at the compete for the receptor and so can have partial blocking prop-
University of Bristol, UK. He is a Chair of the Technical Committee of erties; hence they are sometimes called agonist–antagonists. For
the Advisory Council on the Misuse of Drugs, previously a member of example, Figure 1 shows that the maximal effect of the partial
the Committee on Safety of Medicines, adviser to the British National agonist aripirazole is between that of the full agonist dopamine
Formulary, editor of the Journal of Psychopharmacology, past-president and and antagonist (e.g. haloperidol on dopamine D2 receptors).
of the British Association for Psychopharmacology and President of the Once aripirazole has been taken it will occupy brain receptors,
European College of Neuropsychopharmacology. Conflicts of interest: and in brain regions where dopamine is high it will partially block
none declared. the effects of dopamine, so leading to an antipsychotic effect.
However, in brain regions where dopamine levels are lower, then
Anne Lingford-Hughes PhD MRCPsych is Reader in Biological Psychiatry aripirazole will act as an agonist to increase dopamine transmis-
and Addiction at the University of Bristol, UK, and Honorary Consultant sion in these regions. These dual effects of partial agonists means
at the Bristol Area Specialist Alcohol Service. Her research interests that they are sometimes called agonist–antagonists. The weak
include neuroimaging and the neurobiology of addiction. Conflicts of agonist activity of aripirazole means that it never blocks dopa-
interest: she has received honoraria from Sanofi Aventis and Merck mine function as much as an antagonist, which explains why it
Lipha for attending meetings. produces fewer extrapyramidal side effects (EPS). It is thought

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 Key concepts and techniques

Properties of drugs used in psychiatry

Site Agonist Antagonist Partial agonist

Receptors Noradrenaline – clonidine Dopamine D2– neuroleptics Dopamine – aripiprazole

Opiate – morphine Benzodiazepine – flumazenil 5-HT1A – buspirone
Opiate – naltrexone
GABAA – benzodiazepines 5-HT2 – clozapine Opiate – buprenorphine

Enzyme n/a Noradrenaline – MAOIs n/a

Acetylcholinesterase – donepezil
GABA transaminase – vigabatrin

Uptake sites n/a SSRIs – paroxetine n/a

TCAs – imipramine
NARIs – reboxetine
GABA – tiagabine

Ion channels n/a Most anticonvulsants n/a

GABAA, γ-aminobutyric acid A; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; NARI, noradrenaline
reuptake inhibitor.

Table 1

that there is always enough dopamine function from the aripip-

razole to allow normal basal ganglia function. Schematic neuron and synapse

Receptors
Receptors are proteins expressed on the surface of neurons (and Cell
other brain cells) that have specialized peptide conformations body
Cell bodies
which allow the binding of neurotransmitters or hormones. These
specialized binding pockets are called the pharmacophore and
they convey the exquisite selectivity of receptors for substances Axon
such as neurotransmitters and drugs. The avidity (or stickiness) Transporters –
Autoreceptors
with which a neurotransmitter or drug binds to a receptor is (re)uptake site
called its affinity. This is usually measured in nanomolar concen-
trations (nM), as for example the Ki (inhibitory constant), which
gives an indication of the concentration of neurotransmitter or
drug needed to displace half of the binding of a tracer from a
receptor in binding studies. -ve
Receptors can be classified in a number of different ways, such
as their site of localization and the way in which they transmit
information across the cell membrane (Figure 2 and Table 2). Neurotransmitter

Postsynaptic receptors are the typical receptors that mediate the Heteroreceptors Postsynaptic
Neurotransmitter
actions of the released neurotransmitter. These receptors can have receptors in
one of two actions: some are excitatory, which means they pro- terminal regions
duce depolarization of the target postsynaptic neuron, which can
lead to the generation of an action potential that allows the nerve
signal to be transmitted; or they can be inhibitory, ­switching off
the target neuron. It is important to realize that it is the receptor,
not the neurotransmitter, which determines whether excitation
or inhibition occurs. Thus a single neurotransmitter can be both Figure 2

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 Key concepts and techniques

Receptors classified according to location

Location Action Examples in psychiatry Implications

Postsynaptic Stimulatory or inhibitory Ropinirole – D2 dopamine Parkinson’s

Benzodiazepines – GABA-A Anxiety, insomnia
Presynaptic autoreceptor Usually inhibitory Clonidine/lofexidine – α2 adrenoceptor Opiate withdrawal
Low dose amisulpride – dopamine D2/3 Improve cognition?
Presynaptic heteroreceptors Usually inhibitory Clonidine – 5HT neurons May lead to depression

Table 2

excitatory and inhibitory, depending on the receptor subtype it the way in which they pass information into the target cell – the
acts on (see Table 3). second-messenger system they are coupled to. Molecular genetic
studies have shown that there are at least 15 different genes that
Presynaptic autoreceptors are located both on the cell ­bodies/ can produce proteins that look like (i.e. have significant amino-
dendrites of neurons and on the terminal axonal processes. They acid homology with) known 5-HT receptor proteins, and these are
detect neurotransmitter released from the parent neuron (hence now considered the class of 5-HT receptor subtypes. As they all
the term ‘auto’) and, because in general they are ­inhibitory, they bind 5-HT (though with quite different affinities) it is assumed that
act as a ‘brake’ on further release of the neurotransmitter. They 5-HT is the endogenous neurotransmitter for them all. They are
represent important regulating mechanisms to limit excessive classified into families based on their linkage to second-­messenger
release of neurotransmitter into the synapse and have ­ critical systems (see Table 3).
roles in the action of many psychotropic drugs such as the Different receptor families act through different second
­antidepressants and antipsychotics. ­messenger systems because the proteins that make up the binding
site or receptor also act to transmit a signal into the cell after the
Presynaptic heteroreceptors (sometimes called heteroceptors) transmitter binds to the receptor. This transmission of signal can
are located on neurons that release different neurotransmitters be in the form of a change in second messengers, such as cAMP
from those that act on the receptor, hence the term ‘hetero’. Again, or phospholipids catalysed by enzymes that the receptor protein
they are generally inhibitory in nature and, although they are not activates: these are metabotropic receptors. Alternatively, receptor
as well studied as the autoreceptors, there is growing ­ evidence activation by a ligand can result in a change in the conductance of
for their importance as potential new targets for drug treatment. an ion channel that alters ion flux across the cell membrane; these
For example, noradrenaline acting on heteroreceptors of the are ionotropic receptors. Each of these ­processes can either stimu-
α2-adrenoceptor type found on 5-HT (serotonin) neuronal late or inhibit the target cell, depending on whether the metabo-
­terminals inhibits 5-HT release; blockade of these with antagonists tropic or ionotropic processes that are initiated are excitatory or
such as mirtazapine therefore indirectly increases 5-HT release. inhibitory. Some examples that are important in psychiatry are
given in Table 4. In some cases, such as the benzodiazepines, the
Receptor subtypes drug ligand does not directly alter a second messenger process but
Receptors are grouped into families based on several different potentiates the effects of the endogenous transmitter (in this case,
­features, most usually the neurotransmitter that binds to them and γ-aminobutyric acid, or GABA); these are allosteric mechanisms.

The major families of 5-HT receptors

Family Subtypes Second messengers Effect Agonists (other than 5-HT  ) Antagonists

5-HT1 5-HT1A G-proteins Inhibition Buspirone Pindolol, WAY100635

5-HT1B The sartan class of anti-migraine drugs
5-HT1C
5-HT1D

5-HT2 5-HT2A Phospho-inositol (PI) Excitation mCPP Mirtazapine

5-HT2C Many atypical antipsychotics

5-HT3 None Sodium ions Excitation None Ondansetron etc.

(Plus 5-HT4567 subtypes, which at present are little understood in terms of psychiatric disorders and treatments.)

Table 3

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 Key concepts and techniques

Receptor activation

Receptor Effect Receptor type Signal process Antagonists in clinical use

Dopamine D1,5 Excitation Metabotropic Inc. cAMP None

Dopamine D2,3,4 Inhibition Metabotropic Dec. cAMP Haloperidol
GABAA Inhibition Ionotropic Chloride ions None
Benzodiazepine Inhibition Allosteric Flumazenil
Noradrenaline α1 Excitation Metabotropic Inc. cAMP Prazosin
Noradrenaline α2 Inhibition Metabotropic Dec. cAMP Mirtazapine
Noradrenaline β1-3 Inhibition Metabotropic Dec. cAMP Propranolol
Glutamate NMDA Ionotropic Calcium ions Mg++ ions
Glutamate Autoreceptor Metabotropic Dec. cAMP None
Glutamate AMPA Ionotropic Sodium ions None

Inc., increases; Dec., decreases; NMDA, N-methyl-d-aspartate; AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid.

Table 4

Rebound is the worsening of the original condition for which

Effects of chronic drug administration
the drug was used, manifested by an increase in symptoms that
It is rare in medicine for drugs to be given once only so the changes were originally a reason for the prescription of the drug. It can be
that may be seen on repeated drug administration are of impor- considered as the reappearance of the underlying disorder and,
tance. These come in two classes, tolerance and sensitization. if severe enough, may equate to a relapse. A good example of
rebound is seen in epilepsy treatment: suddenly stopping ben-
Tolerance is a state of reduced drug action following repeated zodiazepines such as clonazepam can lead to severe worsening
use. It is generally found with agonist drugs only and reflects of the seizure disorder. In some cases, rebound can result in
homeostatic compensatory mechanisms that can occur in the tar- worse symptoms than those at the outset of drug therapy; this
get neuron or can be due to adaptive changes in neural circuitry.
Tolerance is often associated with a reduction in the number
Phases of withdrawal, with a few possible profiles of
or density of the target receptors (down-regulation). Tolerance
symptomatic change
results in the loss of action of an agonist and is revealed by the
need for higher doses to produce the same effect. There are few
clear examples of therapeutic tolerance in psychiatric treatment, Rebound and
but the loss of side effects seen on repeated use of many drugs overshoot (recoil)
is a form of tolerance (e.g. nausea with the SSRIs, sedation with
antihistamines). In neurology, a good example of drug tolerance
is the need for larger doses of anticonvulsant benzodiazepines
such as clonazepam on chronic use in epilepsy.
Symptoms

Relapse
Sensitization describes the increase in function of a drug when
it is used repeatedly. This is rarely seen in psychiatry but has
been put forward as an explanation of why repeated stimulant Partial
use (e.g. cocaine) may lead to psychotic phenomena. Following recovery
chronic use of antagonists, a form of supersensitivity to agonist
drugs may be seen when they are stopped. This is thought to be
due to an increase in receptor density (up-regulation) and may Full recovery
explain some of the phenomena seen in drug withdrawal. Rebound

Withdrawal
When drug treatment is stopped the person may experience a Treatment After discontinuation
variety of different phenomena which come under the ­ general
term of withdrawal (Figure 3). Withdrawal can be divided Time
into two distinct components, rebound and discontinuation
symptoms (see Table 5). Figure 3

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 Key concepts and techniques

underlying disorder. Thus discontinuation syndromes can be dis-

Withdrawal phenomena tinguished from rebound, and frequently (but not exclusively)
the symptoms do not bear any relation to the known pharmacol-
Rebound Discontinuation ogy of the drug. They can be seen in people who have not had a
therapeutic response to the drug, and have been seen in volun-
Original illness symptoms Yes No teers. Some discontinuation symptoms are quite bizarre, such as
Novel symptoms No Yes electric-shock-like feelings, whereas others are like the original
Symptoms of original drug No Yes side effects of the drugs (e.g. nausea with the SSRIs).
Overshoot? Possible n/a Discontinuation reactions have been reported for a variety
Can occur in absence of tolerance Yes Yes of psychotropic agents, including the neuroleptics, monoamine
oxidase inhibitors and tricyclic antidepressants. Discontinua-
Table 5 tion phenomena are found with many different classes of drugs,
including opiates, caffeine and nicotine. Withdrawal from each
is considered as rebound with overshoot (or recoil). This can be is associated with symptoms that were not originally reasons for
both extremely distressing and even, as in the case of rebound taking the drug, as in the following examples:
seizures, potentially lethal. It is likely that the increased risk of • opiates: nausea/diarrhoea, bone pains, shivering
mania on stopping lithium and the severe psychotic reactions • caffeine: headache
to sudden clozapine withdrawal are other examples of rebound • nicotine: irritability, loss of concentration, low mood.
plus overshoot in psychiatric practice. Discontinuation phenomena are little studied and poorly under-
Rebound can happen without discontinuation phenomena stood, despite their long history and clinical relevance, but presum-
(e.g. in the case of lithium). Rebound can continue even when ably reflect adaptive changes in brain receptor or neurotransmitter
blood levels of the drug are undetectable, so presumably it indi- function as a consequence of chronic drug action. ◆
cates adaptive changes in brain function that are a consequence
of drug use directly, or the physiological changes produced by
the drug, rather than being simply the removal of the drug from
its binding site. Further reading
Anderson IA, Reid IC, eds. Fundamentals of clinical
Discontinuation syndrome is a term that has been used in psychopharmacology, 2nd edn. London: Martin Dunitz, 2004.
recent years in an attempt to clarify the phenomenon of selective Davis KL, Charney D, Coyle JT, Nemeroff C, eds.
serotonin reuptake inhibitors (SSRI) withdrawal symptoms. The Neuropsychopharmacology: the fifth generation of progress.
key feature of a discontinuation syndrome is that it is a reaction Philadelphia: Lippincott, Williams & Wilkins, 2002.
occurring during drug withdrawal (i.e. as plasma/brain levels Shiloh R, Weizman A, Nutt DJ. Atlas of psychiatric pharmacotherapy.
of the drug are falling) whose symptoms are not features of the London: Martin Dunitz, 2006.

PSYCHIATRY 6:7 267 © 2007 Published by Elsevier Ltd.