NEUROCHEMICAL
EFFECTS OF STIMULANTS:
Relation to their motor effects
DA terminal
Synaptic
cleft
.. ..
.... .
Amphetamines
and Ritalin stimulate
Release of monamines
Including DA
Postsynaptic cell
DA terminal
Synaptic
cleft
.
..
Inactivation: Transmitter is
transported back into
presynaptic terminal
by protein transporter (i.e.,
uptake or “reuptake”).
Amphetamines, Ritalin,
Cocaine all block CA
uptake, including DA
Postsynaptic cell
DA terminal
Synaptic
cleft
. .
.
.
.
.
.
Postsynaptic Action.
transmitter binds
to postsynaptic
receptors; apomorphine
is a DA agonist that
binds to DA receptors
.
DA Receptor proteins
Postsynaptic cell
.
DA terminal
Synaptic
cleft
..
.
Postsynaptic Action.
apomorphine is a DA
agonist that also induces
the same signal
transduction effects as DA
Physiological and biochemical
effects (EPSPs or IPSPs)
Postsynaptic cell
Brain Anatomy: DA
Cingulate
cortex
Caudate/
Putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus
hypothalamus
Locus
ceruleus
Raphe
Substantia
Nigra
Ventral
(SNc)
Tegmental
Area
(VTA)
cerebellum
Dopamine (DA) neuron
axons
Cell body
(point of origin)
Presynaptic DA terminals:
Amphetamines, cocaine,
Ritalin Act Here
DA
terminals
Postsynaptic cells with
DA receptors: Apomorphine
acts Here
Dopamine (DA) neuron
axons
Cell body
(point of origin)
DA
terminals
Postsynaptic cells with
DA receptors
6-OHDA kills DA terminals, but
not the postsynaptic cells, so
it destroys the substrate of action
for amphetamine, cocaine & ritalin,
but not apomorphine.
Dopamine (DA) neuron
Cell body
(point of origin)
Postsynaptic cells with
DA receptors
After DA depletion, postsynaptic
cells make more DA receptors (i.e.,
receptor supersensitivity)
Rotation Model
Nucleus accumbens
Caudate/putamen
(neostriatum or
“striatum”)
SNc (substantia
nigra pars compacta)
VTA
(ventral tegmental
area)
Rotation Model
Nucleus accumbens
Caudate/putamen
(neostriatum or
“striatum”)
Unilateral
DA
Depletion
(inject 6-OHDA)
SNc (substantia
Nigra pars compacta)
VTA
(ventral tegmental
area)
Rotation Model
Nucleus accumbens
In which direction
do the rats rotate?
Caudate/putamen
(neostriatum or
“striatum”)
Unilateral
DA
Depletion
(inject 6-OHDA)
SNc (substantia
Nigra pars compacta)
VTA
(ventral tegmental
area)
Amphetamine-induced Rotation
Nucleus accumbens
Caudate/putamen
(neostriatum or
“striatum”)
AmphetamineRats rotate
towards the
DA depletion.
SNc (substantia
Nigra pars compacta)
VTA
(ventral tegmental
area)
Unilateral
DA
Depletion
(inject 6-OHDA)
Apomorphine-induced Rotation
Nucleus accumbens
Caudate/putamen
(neostriatum or
“striatum”)
ApomorphineRats rotate
away from the
DA depletion.
SNc (substantia
Nigra pars compacta)
VTA
(ventral tegmental
area)
Unilateral
DA
Depletion
(inject 6-OHDA)
Brain Anatomy: ACh
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus
hypothalamus
Locus
ceruleus
Raphe
Substantia
nigra
Ventral
Tegmental
area
cerebellum
Brain Anatomy: Adenosine A2A receptors
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus pons
hypothalamus
Locus
ceruleus
Raphe
Substantia
nigra
Ventral
Tegmental
area
cerebellum
medulla
Schizophrenia
Pictures by Louis Wain (1860-1939)
Schizophrenics show
lower prefrontal cortex
activity at rest
Schizophrenics show
lower task-stimulated
prefrontal cortex
activity
NEUROCHEMICAL EFFECTS
OF ANTIPSYCHOTIC DRUGS:
Antipsychotic drugs are DA
antagonists
DA terminal
Synaptic
cleft
..
.
Postsynaptic Action:
Antipsychotic drugs act
As DA antagonists; they
bind to DA receptors, and
have no signal
transduction effects.
Physiological and biochemical
effects (EPSPs or IPSPs)
Postsynaptic cell
Antipsychotic drugs- correlation between clinical
potency and binding affinity for DA receptors
Across a large number of
antipsychotic drugs, the clinical
potency (i.e., the dose needed to
obtain a clinical effect) is highly
related to the affinity for DA
receptors (i.e., the Kd value).
Radioactive ligand for D2 receptors binds in the brain
CONTROL
ANTIPSYCHOTIC
DOSE OF HALOPERIDOL
Haloperidol occupies DA receptors, reduces binding of radioactive ligand
PET IMAGES: D2 RECEPTOR BINDING
Clozapine
occupies 5-HT
as well as DA
receptors
ANTIPSYCHOTIC
CONTROL
DOSE OF HALOPERIDOL
ANTIPSYCHOTIC
DOSE OF CLOZAPINE
NEUROCHEMICAL EFFECTS
OF ANTIDEPRESSANT DRUGS:
Antidepressant drugs generally interfere
with the inactivation of monamines by:
1. Blocking the enzyme MAO, or
2. Blocking monoamine uptake
Brain Anatomy
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus pons
hypothalamus
Locus
ceruleus
Raphe
Substantia
nigra
Ventral
Tegmental
area
cerebellum
medulla
MA terminal
Synaptic
cleft
MAO
.
.
Inactivation:
Transmitter is broken
down (i.e. “metabolized”)
by enzymes. Many
antidepressant drugs
block the enzyme MAO.
Postsynaptic cell
MA terminal
Synaptic
cleft
.
..
Inactivation: Transmitter is
transported back into
presynaptic terminal
by protein transporter (i.e.,
uptake or “reuptake”).
Several antidepressants
block the uptake of
monoamines.
Postsynaptic cell
NEUROCHEMICAL EFFECTS
OF DRUGS USED TO TREAT
ANXIETY:
Benzodiazepines such as Valium and
Xanax facilitate GABA-mediated
inhibition.
Test Used to Assess Benzodiazepines
in Rats: The Elevated Plus Maze
Brain Anatomy: Amygdala
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
AMYGDALA
Basal
forebrain
thalamus pons
hypothalamus
cerebellum
Locus
coeruleus
Raphe
Substantia
nigra
Ventral
Tegmental
area
medulla
LIGAND BINDING TO A RECEPTOR
inside
outside
WHEN GABA IS BOUND TO IT SITE ON
THE GABAA RECEPTOR, IT CAUSES
THE CHLORIDE CHANNEL TO OPEN,
ALLOWING Cl- IONS TO ENTER THE
CELL, AND THUS INHIBITING THE CELL
RECEPTOR
+
V
Signal
transduction
Mechanism:
Cl- Channel
GABA
GABA BINDING
SITE
membrane
LIGAND BINDING TO A RECEPTOR
inside
RECEPTOR
outside WHEN A BENZODIAZEPINE IS BOUND
TO ITS BINDING SITE ON THE
GABAA RECEPTOR, IT CAUSES
THE GABA SITE TO HAVE A HIGHER
AFFINITY FOR GABA; THIS ENHANCES
GABA-MEDIATED INHIBITION
+
BENZODIAZEPINE (e.g. Valium)
V
Signal
transduction
Mechanism:
Cl- Channel
GABA
GABA
BINDING
SITE
BENZODIAZEPINE BINDING
SITE
membrane
LIGAND BINDING TO A RECEPTOR
inside
outside
RECEPTOR
+
V
Signal
transduction
Mechanism:
Cl- Channel
GABA
WHEN A BENZODIAZEPINE INVERSE
AGONIST IS BOUND TO ITS BINDING
SITE ON THE GABAA RECEPTOR, IT
CAUSES THE GABA SITE TO HAVE A
LOWER AFFINITY FOR GABA; THIS
REDUCES GABA-MEDIATED
INHIBITION
BENZODIAZEPINE
INVERSE AGONIST (e.g.
FG7142)
GABA
BINDING
SITE
BENZODIAZEPINE BINDING
SITE
membrane
NEUROCHEMICAL EFFECTS
OF DRUGS USED TO TREAT
ADHD:
Stimulant drugs stimulate release or
block uptake of catecholamines.
DA terminal
Synaptic
cleft
.. ..
.... .
Amphetamines
and Ritalin stimulate
release of monamines
including DA
Postsynaptic cell
NEUROCHEMICAL EFFECTS
OF DRUGS USED TO TREAT
ALHEMER’S DISEASE:
Most of the currently available drugs stimulate
acetylcholine transmission, typically by
blocking acetylcholesterase (the enzyme that
breaks down acetylcholine).
ACH terminal
Synaptic
cleft
ACHesterase
.
.
Inactivation:
Transmitter is broken
down (i.e. “metabolized”)
by enzymes. Many drugs
used to treat
Alzheimer’s disease
block the enzyme
acetylcholinesterase.
Postsynaptic cell
NEUROCHEMICAL EFFECTS
OF VARIOUS DRUGS OF
ABUSE:
Drugs of abuse have many distinct
neurochemical actions.
nerve terminal
.
Synaptic
cleft
Nicotinic receptors
.
.
Transmitter release can be
modulated by
presynaptic receptors.
Some of these presynaptic
receptors are nicotinic
ACH. ACH increases
release of other
transmitters by acting on
these receptors. Nicotine
mimics the actions of
ACH, and stimulates
release. Nicotine also has
postsynaptic actions.
Postsynaptic cell
Caffeine and other methylxanthines
•
•
•
•
bombilla
Caffeine
Theophylline
Theobromine
From coffee, tea, sodas,
yerba mate
• Act as adenosine antagonists
Yerba mate gourd from
Argentina
nerve terminal
.
Synaptic
cleft
Adenosine
receptors
Transmitter release can be
modulated by presynaptic
receptors.
Some of these presynaptic
receptors are adenosine
receptors. Adenosine
decreases release of other
transmitters by acting on
these receptors. Caffeine
and other methylxanthines
block the actions of
adenosine, and thus they
stimulate release.
.
.
Postsynaptic cell
nerve terminal
Synaptic
cleft
..
.
Postsynaptic action:
caffeine and similar
compounds also act
postsynaptically as
adenosine
antagonists. Selective
adenosine A2A
antagonists also have
stimulant effects, and are
being studied as possible
antiparkinsonian drugs.
Physiological and biochemical
effects (EPSPs or IPSPs)
Postsynaptic cell
Adenosine
Receptors
ETHANOL MOLECULE
Lipophilic/Hydrophobic H
H
H
C
C
H
H
O
CH3CH2OH
H
Lipophobic/
Hydrophilic
Endogenous Cannabinoids & CB1 Agonists
Synaptic
cleft
THC and
synthetic CB1 agonists
act on pre and
postsynaptic CB1
receptors.
.
. . .
Presynaptic
CB1 stimulation
.
decreases
. .
release
.
. . . .
CB1 Receptor proteins
Postsynaptic cell
.
Endogenous Opiate terminal
Synaptic
cleft
. .
.
.
.
.
Postsynaptic Action.
transmitter binds
to postsynaptic
receptors; morphine,
codeine, heroin and
synthetic opiates are
agonists at these
receptors
.
.
Opiate Receptor proteins
Postsynaptic cell
.
Glutamate terminal
Synaptic
cleft
..
.
Postsynaptic Action:
Dissociative anesthetics
Such as PCP and ketamine
are NMDA receptor
antagonists; they
bind to NMDA receptors,
and have no signal
transduction effects,
blocking the effects of the
transmitter.
NMDA receptor proteins
Postsynaptic cell
SOURCES OF HALLUCINOGENS
Peyote Cactus
Ayahuasaca
Psilocybe
Mushroom
Atropa
Belladona
Brain Anatomy: Serotonin (5-HT)
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus
hypothalamus
Locus
ceruleus
Raphe
Substantia
nigra
Ventral
Tegmental
area
cerebellum
Brain Anatomy: DA
Cingulate
cortex
Caudate/
putamen
neocortex
Prefrontal
cortex
hippocampus
Nucleus
accumbens
amygdala
Basal
forebrain
thalamus
hypothalamus
Locus
ceruleus
Raphe
Substantia
Nigra
Ventral
(SNc)
Tegmental
Area
(VTA)
cerebellum
“LIKING”
Hedonic Reaction to Drug
i.e., pleasure, “high”
vs.
“WANTING”
Intake; Tendency to Consume;
Propensity to obtain i.e., reinforcer
seeking, effort in working for drug
Opponent Process Model