neurochemical effects of stimulants: relation to their motor effects
TRANSCRIPT
NEUROCHEMICAL EFFECTS OF STIMULANTS:
Relation to their motor effects
DA terminal
Postsynaptic cell
Synapticcleft
.. ... . Amphetamines
and Ritalin stimulateRelease of monaminesIncluding DA
...
DA terminal
Postsynaptic cell
Synapticcleft
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
...
DA terminal
Postsynaptic cell
Synapticcleft
. . . .. .
Postsynaptic Action.transmitter bindsto postsynapticreceptors; apomorphineis a DA agonist thatbinds to DA receptors
DA Receptor proteins
...
DA terminal
Postsynaptic cell
Synapticcleft
Physiological and biochemical effects (EPSPs
or IPSPs)
Postsynaptic Action.apomorphine is a DAagonist that also induces the same signaltransduction effects as DA.
..
Brain Anatomy: DA
hippocampus
cerebellum
neocortex
Prefrontalcortex
Cingulatecortex
Caudate/Putamen
Nucleusaccumbens
Basalforebrain
hypothalamus
SubstantiaNigra(SNc)
VentralTegmentalArea(VTA)
Raphe
Locusceruleusthalamus
amygdala
Dopamine (DA) neuron
Cell body(point of origin)
DA terminals
axons
Postsynaptic cells withDA receptors: Apomorphineacts Here
Presynaptic DA terminals:Amphetamines, cocaine,Ritalin Act Here
Dopamine (DA) neuron
Cell body(point of origin)
DA terminals
axons
Postsynaptic cells withDA receptors
6-OHDA kills DA terminals, but not the postsynaptic cells, soit destroys the substrate of actionfor amphetamine, cocaine & ritalin,but not apomorphine.
Dopamine (DA) neuron
Cell body(point of origin)
Postsynaptic cells withDA receptors
After DA depletion, postsynaptic cells make more DA receptors (i.e.,receptor supersensitivity)
Rotation Model
SNc (substantianigra pars compacta)
VTA(ventral tegmentalarea)
Nucleus accumbens
Caudate/putamen(neostriatum or“striatum”)
Rotation Model
SNc (substantiaNigra pars compacta)
VTA(ventral tegmentalarea)
Nucleus accumbens
Caudate/putamen(neostriatum or“striatum”)
UnilateralDA Depletion(inject 6-OHDA)
Rotation Model
SNc (substantiaNigra pars compacta)
VTA(ventral tegmentalarea)
Nucleus accumbens
Caudate/putamen(neostriatum or“striatum”)
UnilateralDA Depletion(inject 6-OHDA)
In which directiondo the rats rotate?
Amphetamine-induced Rotation
SNc (substantiaNigra pars compacta)
VTA(ventral tegmentalarea)
Nucleus accumbens
Caudate/putamen(neostriatum or“striatum”)
UnilateralDA Depletion(inject 6-OHDA)
Amphetamine-Rats rotatetowards theDA depletion.
Apomorphine-induced Rotation
SNc (substantiaNigra pars compacta)
VTA(ventral tegmentalarea)
Nucleus accumbens
Caudate/putamen(neostriatum or“striatum”)
UnilateralDA Depletion(inject 6-OHDA)
Apomorphine-Rats rotateaway from theDA depletion.
Brain Anatomy: ACh
hippocampus
cerebellum
neocortex
Prefrontalcortex
Cingulatecortex
Caudate/putamen
Nucleusaccumbens
Basalforebrain
hypothalamus
Substantianigra Ventral
Tegmentalarea
Raphe
Locusceruleusthalamus
amygdala
Brain Anatomy: Adenosine A2A receptors
hippocampus
cerebellum
neocortex
Prefrontalcortex
Cingulatecortex
Caudate/putamen
Nucleusaccumbens
Basalforebrain
hypothalamus
Substantianigra Ventral
Tegmentalarea
Raphe
Locusceruleusthalamus pons
medulla
amygdala
Schizophrenia
Pictures by Louis Wain (1860-1939)
Schizophrenics showlower prefrontal cortexactivity at rest
Schizophrenics showlower task-stimulatedprefrontal cortexactivity
NEUROCHEMICAL EFFECTS OF ANTIPSYCHOTIC DRUGS:
Antipsychotic drugs are DA antagonists
DA terminal
Postsynaptic cell
Synapticcleft
Physiological and biochemical effects (EPSPs
or IPSPs)
Postsynaptic Action:Antipsychotic drugs actAs DA antagonists; theybind to DA receptors, andhave no signaltransduction effects..
..
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 DAreceptors (i.e., the Kd value).
CONTROL ANTIPSYCHOTICDOSE OF HALOPERIDOL
Haloperidol occupies DA receptors, reduces binding of radioactive ligand
Radioactive ligand for D2 receptors binds in the brain
CONTROL ANTIPSYCHOTICDOSE OF HALOPERIDOL
PET IMAGES: D2 RECEPTOR BINDING
ANTIPSYCHOTICDOSE OF CLOZAPINE
Clozapineoccupies 5-HTas well as DAreceptors
NEUROCHEMICAL EFFECTS OF ANTIDEPRESSANT DRUGS:
Antidepressant drugs generally interfere with the inactivation of monamines by:1. Blocking the enzyme MAO, or2. Blocking monoamine uptake
Brain Anatomy
hippocampus
cerebellum
neocortex
Prefrontalcortex
Cingulatecortex
Caudate/putamen
Nucleusaccumbens
Basalforebrain
hypothalamus
Substantianigra Ventral
Tegmentalarea
Raphe
Locusceruleusthalamus pons
medulla
amygdala
MA terminal
Postsynaptic cell
Synapticcleft
Inactivation:Transmitter is brokendown (i.e.
“metabolized”)by enzymes. Many
antidepressant drugs block the enzyme MAO.
..
MAO
MA terminal
Postsynaptic cell
Synapticcleft
Inactivation: Transmitter is transported back into presynaptic terminal
by protein transporter (i.e.,
uptake or “reuptake”).
Several antidepressants block the uptake of monoamines.
...
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
hippocampus
cerebellum
neocortex
Prefrontalcortex
Cingulatecortex
Caudate/putamen
Nucleusaccumbens
Basalforebrain
hypothalamus
Substantianigra Ventral
Tegmentalarea
Raphe
Locuscoeruleusthalamus pons
medulla
AMYGDALA
LIGAND BINDING TO A RECEPTOR
RECEPTOR
GABA
membrane
+
V
WHEN GABA IS BOUND TO IT SITE ONTHE GABAA RECEPTOR, IT CAUSESTHE CHLORIDE CHANNEL TO OPEN,ALLOWING Cl- IONS TO ENTER THE CELL, AND THUS INHIBITING THE CELL
SignaltransductionMechanism:Cl- Channel
outsideinside
GABA BINDINGSITE
LIGAND BINDING TO A RECEPTOR
GABA
RECEPTOR
BENZODIAZEPINE (e.g. Valium)
membrane
+
V
WHEN A BENZODIAZEPINE IS BOUNDTO ITS BINDING SITE ON THE GABAA RECEPTOR, IT CAUSESTHE GABA SITE TO HAVE A HIGHERAFFINITY FOR GABA; THIS ENHANCESGABA-MEDIATED INHIBITION
SignaltransductionMechanism:Cl- Channel
outsideinside
BENZODIAZEPINE BINDINGSITE
GABABINDING
SITE
LIGAND BINDING TO A RECEPTOR
RECEPTOR
BENZODIAZEPINE INVERSE AGONIST (e.g. FG7142)
membrane
+
V
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
SignaltransductionMechanism:Cl- Channel
outsideinside
BENZODIAZEPINE BINDINGSITE
GABABINDING
SITE
GABA
NEUROCHEMICAL EFFECTS OF DRUGS USED TO TREAT
ADHD:Stimulant drugs stimulate release or
block uptake of catecholamines.
DA terminal
Postsynaptic cell
Synapticcleft
.. ... . Amphetamines
and Ritalin stimulaterelease of monaminesincluding DA
...
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
Postsynaptic cell
Synapticcleft
Inactivation:Transmitter is brokendown (i.e.
“metabolized”)by enzymes. Many
drugs used to treat Alzheimer’s disease block the enzyme acetylcholinesterase.
..ACHesterase
NEUROCHEMICAL EFFECTS OF VARIOUS DRUGS OF
ABUSE:
Drugs of abuse have many distinct neurochemical actions.
nerve terminal
Postsynaptic cell
Synapticcleft
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.
.
. .Nicotinic receptors
Caffeine and other methylxanthines
• Caffeine• Theophylline• Theobromine• From coffee, tea, sodas,
yerba mate• Act as adenosine antagonists
Yerba mate gourd from Argentina
bombilla
nerve terminal
Postsynaptic cell
Synapticcleft
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.
.
. .Adenosinereceptors
nerve terminal
Postsynaptic cell
Synapticcleft
Physiological and biochemical effects (EPSPs
or IPSPs)
Postsynaptic action:caffeine and similar compounds also actpostsynaptically as adenosineantagonists. Selective adenosine A2A antagonists also have stimulant effects, and are being studied as possible antiparkinsonian drugs.
.
..
AdenosineReceptors
ETHANOL MOLECULE
C
H
H
H
CH
HO
H
Lipophilic/Hydrophobic
Lipophobic/Hydrophilic
CH3CH2OH
Endogenous Cannabinoids & CB1 Agonists
Postsynaptic cell
Synapticcleft
. . . .. .
THC and synthetic CB1 agonistsact on pre and postsynaptic CB1receptors.
CB1 Receptor proteins
....
.
..PresynapticCB1 stimulationdecreasesrelease
PresynapticCB1 stimulationdecreasesrelease
Endogenous Opiate terminal
Postsynaptic cell
Synapticcleft
. . . .. .
Postsynaptic Action.transmitter bindsto postsynapticreceptors; morphine, codeine, heroin and synthetic opiates are agonists at these receptors
Opiate Receptor proteins
...
Glutamate terminal
Postsynaptic cell
Synapticcleft
NMDA receptor proteins
Postsynaptic Action:Dissociative anestheticsSuch as PCP and ketamineare NMDA receptorantagonists; theybind to NMDA receptors, and have no signaltransduction effects,blocking the effects of thetransmitter.
.
..
SOURCES OF HALLUCINOGENS
Peyote Cactus Ayahuasaca PsilocybeMushroom
AtropaBelladona
Brain Anatomy: Serotonin (5-HT)
hippocampus
cerebellum
neocortex
Prefrontalcortex
Cingulatecortex
Caudate/putamen
Nucleusaccumbens
Basalforebrain
hypothalamus
Substantianigra Ventral
Tegmentalarea
Raphe
Locusceruleusthalamus
amygdala
Brain Anatomy: DA
hippocampus
cerebellum
neocortex
Prefrontalcortex
Cingulatecortex
Caudate/putamen
Nucleusaccumbens
Basalforebrain
hypothalamus
SubstantiaNigra(SNc)
VentralTegmentalArea(VTA)
Raphe
Locusceruleusthalamus
amygdala
“LIKING”
vs.
“WANTING”Intake; Tendency to Consume;Propensity to obtain i.e., reinforcer seeking, effort in working for drug
Hedonic Reaction to Drugi.e., pleasure, “high”
Opponent Process Model