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NEUROCHEMICAL EFFECTS OF STIMULANTS:

NEUROCHEMICAL EFFECTS OF STIMULANTS:. Relation to their motor effects. DA terminal. . Amphetamines and Ritalin stimulate Release of monamines Including DA. . . . . . . Synaptic cleft. . . Postsynaptic cell. DA terminal.

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NEUROCHEMICAL EFFECTS OF STIMULANTS:

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  1. NEUROCHEMICAL EFFECTS OF STIMULANTS: Relation to their motor effects

  2. DA terminal . Amphetamines and Ritalin stimulate Release of monamines Including DA . . . . . . Synaptic cleft . . Postsynaptic cell

  3. DA terminal 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 . . . Synaptic cleft Postsynaptic cell

  4. DA terminal Postsynaptic Action. transmitter binds to postsynaptic receptors; apomorphine is a DA agonist that binds to DA receptors . Synaptic cleft . . . . . . . . DA Receptor proteins Postsynaptic cell

  5. DA terminal Postsynaptic Action. apomorphine is a DA agonist that also induces the same signal transduction effects as DA . . Synaptic cleft . Physiological and biochemical effects (EPSPs or IPSPs) Postsynaptic cell

  6. Caudate/ Putamen neocortex Cingulate cortex Prefrontal cortex hippocampus Nucleus accumbens Basal forebrain cerebellum Locus ceruleus thalamus hypothalamus Raphe Substantia Nigra (SNc) Ventral Tegmental Area (VTA) Brain Anatomy: DA amygdala

  7. Presynaptic DA terminals: Amphetamines, cocaine, Ritalin Act Here Dopamine (DA) neuron DA terminals axons Postsynaptic cells with DA receptors: Apomorphine acts Here Cell body (point of origin)

  8. Dopamine (DA) neuron DA terminals axons Postsynaptic cells with DA receptors Cell body (point of origin) 6-OHDA kills DA terminals, but not the postsynaptic cells, so it destroys the substrate of action for amphetamine, cocaine & ritalin, but not apomorphine.

  9. Dopamine (DA) neuron Postsynaptic cells with DA receptors Cell body (point of origin) After DA depletion, postsynaptic cells make more DA receptors (i.e., receptor supersensitivity)

  10. Rotation Model Nucleus accumbens Caudate/putamen (neostriatum or “striatum”) SNc (substantia nigra pars compacta) VTA (ventral tegmental area)

  11. Rotation Model Nucleus accumbens Caudate/putamen (neostriatum or “striatum”) Unilateral DA Depletion (inject 6-OHDA) SNc (substantia Nigra pars compacta) VTA (ventral tegmental area)

  12. Rotation Model In which direction do the rats rotate? Nucleus accumbens Caudate/putamen (neostriatum or “striatum”) Unilateral DA Depletion (inject 6-OHDA) SNc (substantia Nigra pars compacta) VTA (ventral tegmental area)

  13. Amphetamine-induced Rotation Nucleus accumbens Caudate/putamen (neostriatum or “striatum”) Unilateral DA Depletion (inject 6-OHDA) Amphetamine- Rats rotate towards the DA depletion. SNc (substantia Nigra pars compacta) VTA (ventral tegmental area)

  14. Apomorphine-induced Rotation Nucleus accumbens Caudate/putamen (neostriatum or “striatum”) Unilateral DA Depletion (inject 6-OHDA) Apomorphine- Rats rotate away from the DA depletion. SNc (substantia Nigra pars compacta) VTA (ventral tegmental area)

  15. Caudate/ putamen neocortex Cingulate cortex Prefrontal cortex hippocampus Nucleus accumbens Basal forebrain cerebellum Locus ceruleus thalamus hypothalamus Raphe Substantia nigra Ventral Tegmental area Brain Anatomy: ACh amygdala

  16. Caudate/ putamen neocortex Cingulate cortex Prefrontal cortex hippocampus Nucleus accumbens Basal forebrain cerebellum Locus ceruleus thalamus hypothalamus Raphe Substantia nigra Ventral Tegmental area Brain Anatomy: Adenosine A2A receptors amygdala pons medulla

  17. Schizophrenia Pictures by Louis Wain (1860-1939)

  18. Schizophrenics show lower prefrontal cortex activity at rest Schizophrenics show lower task-stimulated prefrontal cortex activity

  19. NEUROCHEMICAL EFFECTS OF ANTIPSYCHOTIC DRUGS: Antipsychotic drugs are DA antagonists

  20. DA terminal Postsynaptic Action: Antipsychotic drugs act As DA antagonists; they bind to DA receptors, and have no signal transduction effects. . . Synaptic cleft . Physiological and biochemical effects (EPSPs or IPSPs) Postsynaptic cell

  21. 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).

  22. Radioactive ligand for D2 receptors binds in the brain ANTIPSYCHOTIC DOSE OF HALOPERIDOL CONTROL Haloperidol occupies DA receptors, reduces binding of radioactive ligand

  23. PET IMAGES: D2 RECEPTOR BINDING Clozapine occupies 5-HT as well as DA receptors ANTIPSYCHOTIC DOSE OF HALOPERIDOL CONTROL ANTIPSYCHOTIC DOSE OF CLOZAPINE

  24. NEUROCHEMICAL EFFECTS OF ANTIDEPRESSANT DRUGS: Antidepressant drugs generally interfere with the inactivation of monamines by: Blocking the enzyme MAO, or Blocking monoamine uptake

  25. Caudate/ putamen neocortex Cingulate cortex Prefrontal cortex hippocampus Nucleus accumbens Basal forebrain cerebellum Locus ceruleus thalamus hypothalamus Raphe Substantia nigra Ventral Tegmental area Brain Anatomy amygdala pons medulla

  26. MA terminal Inactivation: Transmitter is broken down (i.e. “metabolized”) by enzymes. Many antidepressant drugs block the enzyme MAO. . Synaptic cleft MAO . Postsynaptic cell

  27. MA terminal Inactivation: Transmitter is transported back into presynaptic terminal by protein transporter (i.e., uptake or “reuptake”). Several antidepressants block the uptake of monoamines. . . . Synaptic cleft Postsynaptic cell

  28. NEUROCHEMICAL EFFECTS OF DRUGS USED TO TREAT ANXIETY: Benzodiazepines such as Valium and Xanax facilitate GABA-mediated inhibition.

  29. Test Used to Assess Benzodiazepines in Rats: The Elevated Plus Maze

  30. Caudate/ putamen neocortex Cingulate cortex Prefrontal cortex hippocampus Nucleus accumbens Basal forebrain cerebellum Locus coeruleus thalamus hypothalamus Raphe Substantia nigra Ventral Tegmental area Brain Anatomy: Amygdala AMYGDALA pons medulla

  31. LIGAND BINDING TO A RECEPTOR outside inside 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

  32. LIGAND BINDING TO A RECEPTOR 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 outside inside RECEPTOR + BENZODIAZEPINE (e.g. Valium) V GABA Signal transduction Mechanism: Cl- Channel GABA BINDING SITE BENZODIAZEPINE BINDING SITE membrane

  33. LIGAND BINDING TO A RECEPTOR 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 outside inside RECEPTOR + BENZODIAZEPINE INVERSE AGONIST (e.g. FG7142) V GABA Signal transduction Mechanism: Cl- Channel GABA BINDING SITE BENZODIAZEPINE BINDING SITE membrane

  34. NEUROCHEMICAL EFFECTS OF DRUGS USED TO TREAT ADHD: Stimulant drugs stimulate release or block uptake of catecholamines.

  35. DA terminal . Amphetamines and Ritalin stimulate release of monamines including DA . . . . . . Synaptic cleft . . Postsynaptic cell

  36. 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).

  37. ACH terminal Inactivation: Transmitter is broken down (i.e. “metabolized”) by enzymes. Many drugs used to treat Alzheimer’s disease block the enzyme acetylcholinesterase. . Synaptic cleft . ACHesterase Postsynaptic cell

  38. NEUROCHEMICAL EFFECTS OF VARIOUS DRUGS OF ABUSE: Drugs of abuse have many distinct neurochemical actions.

  39. nerve terminal 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. . . Synaptic cleft . Nicotinic receptors Postsynaptic cell

  40. Caffeine and other methylxanthines • Caffeine • Theophylline • Theobromine • From coffee, tea, sodas, yerba mate • Act as adenosine antagonists bombilla Yerba mate gourd from Argentina

  41. nerve terminal 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. . . Synaptic cleft . Adenosine receptors Postsynaptic cell

  42. nerve terminal 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. . . Synaptic cleft . Adenosine Receptors Physiological and biochemical effects (EPSPs or IPSPs) Postsynaptic cell

  43. H H H C C H H O H ETHANOL MOLECULE Lipophilic/Hydrophobic Lipophobic/ Hydrophilic CH3CH2OH

  44. Endogenous Cannabinoids & CB1 Agonists THC and synthetic CB1 agonists act on pre and postsynaptic CB1 receptors. . . . . Presynaptic CB1 stimulation decreases release Synaptic cleft . . . . . . . . . CB1 Receptor proteins Postsynaptic cell

  45. Endogenous Opiate terminal Postsynaptic Action. transmitter binds to postsynaptic receptors; morphine, codeine, heroin and synthetic opiates are agonists at these receptors . Synaptic cleft . . . . . . . . Opiate Receptor proteins Postsynaptic cell

  46. Glutamate terminal 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. . . Synaptic cleft . NMDA receptor proteins Postsynaptic cell

  47. SOURCES OF HALLUCINOGENS Peyote Cactus Ayahuasaca Psilocybe Mushroom Atropa Belladona

  48. Caudate/ putamen neocortex Cingulate cortex Prefrontal cortex hippocampus Nucleus accumbens amygdala Basal forebrain cerebellum Locus ceruleus thalamus hypothalamus Raphe Substantia nigra Ventral Tegmental area Brain Anatomy: Serotonin (5-HT)

  49. Brain Anatomy: DA Caudate/ putamen neocortex Cingulate cortex Prefrontal cortex hippocampus Nucleus accumbens Basal forebrain cerebellum Locus ceruleus thalamus hypothalamus Raphe Substantia Nigra (SNc) Ventral Tegmental Area (VTA) amygdala

  50. “LIKING”vs. “WANTING” Hedonic Reaction to Drug i.e., pleasure, “high” Intake; Tendency to Consume; Propensity to obtain i.e., reinforcer seeking, effort in working for drug

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