Psychopharmacology

 The study of the effects of exogenous drugs on

the nervous system and on behavior.
 Can be used to generate and test hypotheses
about the effects of endogenous substances on
the nervous system and on behavior.

Drug Effects (how it works)

Site of Action (where it works)
Pharmacokinetics (how it gets used)
What does a drug have to do to
affect you?
 It must get inside you
 It must get to the site of action
 It must bind to a receptor
Routes of Administration
 Injection
Intravenous (i.v.)
Intraperitoneal (i.p.)
Intramuscular (i.m.)
Subcutaneous (s.c.)
 Oral
 Sublingual
 Rectal
 Inhalation
 Topical
Routes of Administration
 Intracerebral
 Intracerebroventricular (i.c.v.)
Effect of Route of Administration
Dose-Response Curve
Margin of Safety/Therapeutic Index
The synapse
NEUROTRANSMITTER PRESYNAPTIC GLIAL CELL
CRITERIA TERMINAL

1. In terminal
2. Ca2+-dependent release
Neurotransmitter

Autoreceptors

Postsynaptic Postsynaptic
receptor receptor
(ionotropic) (metabotropic)
POSTSYNAPTIC CELL
Receptors
 Ionotropic receptors
 Metabotropic
receptors
Ligand-gated ion channel G-protein coupled receptor
(ionotropic receptor) (metabotropic receptor)
 Metabotropic
receptor

G protein subunits
Gs and Gi mediated (cAMP) pathways

Receptor

G-protein

Adenylyl cyclase

cAMP

PKA
Gs and Gi mediated (cAMP) pathways

Receptor

G-protein

Adenylyl cyclase

cAMP

PKA
Gs and Gi mediated pathways
Affinity
 How well two molecules join together.
Psychopharmacology
 Precursor: a substance from which
another substance is formed

 Agonist: drugs that facilitate

postsynaptic effects

 Antagonist: drugs that block

postsynaptic effects
Agonists
 Direct Agonist

 Indirect Agonist

 Competitive Binding

 Non-competitive Binding
Antagonists
 Direct Antagonist - receptor blocker

 Indirect Antagonist

 Competitive Binding

 Non-competitive Binding
Drug Action
Competitive vs. Non-
competitive binding
 Competitive binding: drug and
neurotransmitter compete for the same
binding site

 Non-competitive binding: drug and

neurotransmitter do not compete for the
same binding site, although the drug can
affect the receptor activity
The Neurotransmitters
Neurotransmitters
 Monoamines
 Amino acids
 Peptides
 Acetylcholine
Monoamines
 Catecholamines
DA
NE
E

 Indolamines
5-HT
Dopamine
 EPSPs and IPSPs

 Movement, attention, learning, drugs of

abuse, reward system

 From dietary tyrosine

CATECHOLAMINES
COOH
CH2 CH2 NH2

HO
TYROSINE

rate- tyrosine
limiting 5-hydroxylase
step

COOH
HO
CH2 CH2 NH2

HO
DOPA

aromatic amino
acid decarboxylase

HO
CH2 CH2 NH2

HO
DOPAMINE
CATECHOLAMINES
HO
CH2 CH2 NH2

HO
DOPAMINE

dopamine-
β-hydroxylase

OH
HO
CH2 CH2 NH2

HO
NOREPINEPHRINE

phenylethanolamine-
N-methyl transferase

OH CH3
HO
CH2 CH2 NH

HO
EPINEPHRINE
Dopamine Systems
 Nigrostriatal: Substantia Nigra → Striatum

 Mesolimbic: VTA → Ncl. Accumbens

 Mesocortical: VTA → Prefrontal Cortex

 Tubero-infundibular: Hypothalamus →
Pituitary gland
Brain Dopaminergic
Pathways
Brain Dopaminergic Pathways
Dopamine Receptors
 Many subtypes

 Confer biological specificity of DA action

Parkinson‘s disease
 Nigrostriatal dopamine system affected: substantia
nigra → striatum (basal ganglia)

 Decrease of dopamine release

 Symptoms: tremor, rigidity, difficulties initiating

movement

 Treatment: L-Dopa, MAO inhibitor

 Side effects: halluzinations are possible

Schizophrenia
 Overactivity of dopamine

 Symptoms: halluzinations, delusions,

difficulties thinking

 Treatment: dopamine antagonists e.g.

Chlorpromazine (blocks D2 receptors)

 Side effects: tremor, movement difficulties

Mesolimbic DA system
 Mesolimbic: VTA → Ncl. Accumbens

 Reward, addiction, pleasure

 Self-administration in rats

 Dopamine agonists: cocaine,

amphetamine,…
Norepinephrine
 Brain and autonomic nervous system

 Produced in locus coeruleus

 Projects to almost every brain region

Norepinephrine + Epinephrine
(Noradrenaline + Adrenaline)
 locus coeruleus: cell bodies

 β1 and β2 adrenergic, α1 and α2

adrenergic receptors

 NE + E bind to the same receptors

 all metabotropic
NE + E
 NE: role in mood, drive reduction, sleep,
arousal, cognition, implicated in some
disorders: depression

 E: present very low in the brain,

produced in adrenal medulla

 Both increase heart rate, respiration

rate, sweating, and pupil dilation
Monoamines
 Catecholamines
DA
NE
E

 Indolamines
5-HT
 SEROTONIN
COOH
CH2 CH2 NH2

N
H
TRYPTOPHAN

rate- tryptophan
limiting 5-hydroxylase
step

COOH
HO
CH2 CH2 NH2

N
H
5-HYDROXYTRYPTOPHAN
(5-HTP)

aromatic amino
acid decarboxylase

HO
CH2 CH2 NH2

N
H
5-HYDROXYTRYPTAMINE
(5-HT a.k.a. SEROTONIN)
Serotonin (5-HT)
Tryptophan
↓
5-hydroxytryptophan (5-HTP)
↓
5-hydroxytryptamine (5-HT or Serotonin)
Serotonin
 Cell bodies: in the Raphe nuclei

 Project to the cerebral cortex, innervate

basal ganglia, dentate gyrus
(hippocampus)

 Regulation in mood (depression), control

of eating, sleep, arousal, regulation of
pain
Brain Serotonin Pathways
 Serotonin Function

Basal ganglia
Hippocampus/fornix
Neocortex Thalamus

Hypothalamus
Temporal lobe

Cerebellum
Raphe nuclei
To spinal cord
Serotonin
 5-HT1 receptor: anxiety, aggression,
depression

 5-HT2 receptor: appetite, motor control

 5-HT3 receptor: nausea, vomiting,

anxiety, schizophrenia
Depression
 Decrease in Serotonin
 Treatment:
SSRI – selective serotonin reuptake inhibitor
(fluoxetine)
Tricyclic antidepressant: block reuptake of
serotonin, norepinephrine, and dopamine
 Monoamines and depression
5-HT transporter (SERT)

Monoamine oxidase

Serotoninergic
neuron
PRESYNAPTIC NEURON POSTSYNAPTIC NEURON
Tryp 5-HTP 5-HT
trypOHase AADC
Serotonin
 LSD (lyseric acid diethylamide)
distortion of visual perception

 MDMA (“ecstacy”)
(methylenedioxymethamphetaminne)
 noradrenergic and serotonergic agonist,
excitatory and hallucinogenic effects: short-
term feeling of euphoria and well-being
Acetylcholine
 2 components: choline and acetate

 all muscular movement accomplished by

the release of Ach (outside the CNS)

 3 systems in the brain:

Origin: dorsolateral pons: REM sleep
Origin: basal forebrain: perceptual learning
Origin: medial septum: memory
Acetylcholine
 Muscarinic receptors:
In the PNS: parasympathetic responses
In the CNS: learning, memory, arousal
Metabotropic receptor
Muscarinic antagonist: atropine
Acetylcholine
 Nicotinic receptors:
CNS: cognitive processes, reduction of
anxiety
PNS: neuromuscular junction (motor
neurons)
Ionotropic receptor
Nicotine: nicotinic agonist
Distribution of cholinergic neurons in the rat brain

Laterodorsal and
pedunculopontine Dorsal
tegmental nuclei
(dorsolateral pons)
Neocortex

Cingulate
cortex
Tectum
Hippocampus Olfactory
bulb
Deep Medial
cerebellar habenula
nuclei

Thalamus

Substantia
Locus nigra
Vestibular coeruleus Amygdala Medial
nuclei Lateral septum
hypothalamus
Medullary
reticular Pontine
formation Reticular
Raphe formation
nuclei Caudate nucleus,
Nucleus basalis putamen, and
(basal forebrain) nucleus accumbens
(contains interneurons)
SOME CNS FUNCTIONS
Memory
Learning
Aggression
Grand Mal seizures
Sensory Perception
Behavioral Arousal
Attention
Energy Conservation
Mood
Motor Coordination
REM sleep
Acetylcholine is broken down (inactivated) by Acetylcholinesterase (AChE)
Acetylcholine
 Choline acetyltransferase: synthesis of
Ach from choline and Acetyl coenzyme
A

 Acetylcholinesterase: enzymatic
deactivation of Ach
Acetylcholine
 Curare

 Tetanus
Amino Acids
 Glutamate

 GABA (gamma amino-butyric acid)

Glutamate
 Main excitatory neurotransmitter

 Receptors
NMDA - ionotropic Ca++ channel, 6 different
binding sites
AMPA - ionotropic Na+ channel
others

 General excitation of the brain, LEARNING

Modulation of NMDA receptor
A coincidence detector

Glutamate
NMDA Receptor
GABA
 Inhibitory

 2 receptors:
GABAA (ionotropic, controls Cl channels), 5
different binding sites
GABAB (metabotropic, controls K channels)
GABA
 Benzodiazepines - Diazepam/ Valium,
anxiolytic (indirect agonist)

 Barbiturates (indirect agonist)

 Steroids (general anethesia)

GABA
Peptides
 Amino acids linked together
 Destroyed by enzymes, no reuptake
mechanism
Endogenous opioids
 Effects of endogenous opioids are
mimicked by drugs such as opium and
heroin

 Opiates (drugs as morphine) bind to

opiate receptors, reduce pain
(analgesia)

 Enkephalins: endogenous opioids

Opioids
 At least 3 different opiate receptors: μ, δ,
κ

 pain, reward, species-typical defensive

responses

 Agonist: heroin (dihydromorphine)

 Antagonist: naloxone
Peptides
 Angiotensin II (water retention, thirst)

 CCK: transmits signals about satiety

after a meal
Psychopharmacology
 Tolerance: decrease in the effectiveness
of a drug, compensation for the effect of
the drug

 Sensitization: increase in the

effectiveness of a drug

 Withdrawal symptoms: opposite effects

of the drug
Ethanol
 binds to a specific site on the GABAA
receptor, GABA agonist

 Blocks NMDA receptors

 Increases dopamine activity

Ethanol
 Acute

 Chronic

 Withdrawal
Ethanol
 Anxiety-reducing

 Korsakoff syndrome: cognitive

dysfunction, memory loss
Nicotine
 binds to the nicotinic receptor

 Nicotinic agonist

 Improves cognitive processing, increase of

cerebral blood flow, decreases anxiety

 induces release of dopamine in the ncl

accumbens
Brain Dopaminergic
Pathways
Cocaine
 blocks the reuptake of the other
monoamines

 Agonist of the monoamines

 Euphoria
Marihuana/ THC
 THC (tetrahydrocannabinoid): stimulates
cannabioid receptors (in cerebellum,
globus pallidus, hippocampus, substantia
nigra)

 anandamide: first natural ligand for THC

discovered

 interference of functioning of 5-HT3

receptor (involved in vomiting)
Marihuana/ THC
 analgesia
 sedation
 stimulates appetite
 reduces nausea
 reduces symptoms of motor disorders
 interferes with memory + concentration,
alters visual and auditory perception
Gases as
Neurotransmitters
 Nitric Oxide (NO)

 Produced in several regions of the neuron

and released as soon as it is produced

 Does not bind to receptors, but enters the

cell and activates second messenger

 Control of muscles in the wall of the

intestines
 Learning