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

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

3. DA terminal Postsynaptic cell 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...

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

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

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

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

8. Dopamine (DA) neuron Cell body (point of origin) DA terminals axons 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.

9. 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)

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

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

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

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

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

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

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

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

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

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

24. 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

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

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

27. MA terminal Postsynaptic cell 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....

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

31. LIGAND BINDING TO A RECEPTOR RECEPTOR GABA membrane + V WHEN GABA IS BOUND TO IT SITE ON THE GABA A RECEPTOR, IT CAUSES THE CHLORIDE CHANNEL TO OPEN, ALLOWING Cl- IONS TO ENTER THE CELL, AND THUS INHIBITING THE CELL Signal transduction Mechanism: Cl- Channel outside inside GABA BINDING SITE

32. LIGAND BINDING TO A RECEPTOR GABA RECEPTOR BENZODIAZEPINE (e.g. Valium) membrane + V WHEN A BENZODIAZEPINE IS BOUND TO ITS BINDING SITE ON THE GABA A RECEPTOR, IT CAUSES THE GABA SITE TO HAVE A HIGHER AFFINITY FOR GABA; THIS ENHANCES GABA-MEDIATED INHIBITION Signal transduction Mechanism: Cl- Channel outside inside BENZODIAZEPINE BINDING SITE GABA BINDING SITE

33. 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 GABA A RECEPTOR, IT CAUSES THE GABA SITE TO HAVE A LOWER AFFINITY FOR GABA; THIS REDUCES GABA-MEDIATED INHIBITION Signal transduction Mechanism: Cl- Channel outside inside BENZODIAZEPINE BINDING SITE GABA BINDING SITE GABA

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

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

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

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

39. nerve terminal Postsynaptic cell Synaptic cleft 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

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

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

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

43. ETHANOL MOLECULE C H H H C H H O H Lipophilic/Hydrophobic Lipophobic/ Hydrophilic CH 3 CH 2 OH

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

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

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

47. SOURCES OF HALLUCINOGENS Peyote CactusAyahuasaca Psilocybe Mushroom Atropa Belladona

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

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

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

51. Opponent Process Model