Lecture 13 Neuropharmacology BSC 343 March 4, 2008 Exam 2, Thurs. March 6 @ 2pm Homework #2, due Thurs. March 6 @ 2pm Exam 2 lectures: LECT 8, Feb. 14 (Dr. Garris #1, synapse I) LECT 9, Feb. 19 (presynaptic proteins) LECT 10, Feb. 21 (neurotransmitters) LECT 11, Feb. 26 (Dr. Garris #2, receptors and effects I) LECT 12, Feb. 28 (receptors and effects II) LECT 13, March 4 (neuropharmacology) Steward and Worley, 2001 The arc (activity-regulated cyotskeleton- associated protein) gene encodes a protein associated with the cytoskeleton. Outline CNS Depressants Psychostimultants Opioid Analgesics Psychedelic Drugs Marijuana ? Sedative-euphoriant-psychedelic Drug Date Rape Drugs Guide For the major classes of drugs discussed in class, know general effects, general mechanism of action, and specific examples of each CNS Depressants Definition: a group of drugs that depresses CNS functioning in such a way that produces calming (anxiolysis), drowsiness and sleep Sedative, tranquilizer, anxiolytic and hypnotic applies to all CNS depressants Continuum of Behavior Effects CNS Depressants Types: barbiturates, alcohol, volatile anesthetics, antiepileptics and benzodiazepines General Characteristics: potentiate other depressants (supra-additive) non-specific antagonism between depressants and stimulants Barbiturates Examples pentobarbital amobarbital Mechanism of Barbiturates Ionotropic GABA(A) Receptor increases affinity for GABA channel opening is easier and more prolonged enhancement of inhibition Inhalation Anesthetics Anesthetic produces sedation, depression, analgesia and amnesia Examples isoflurane halthane nitrous oxide* Inhalation Anesthetics: Site of Action Very lipid soluble Alteration of physiochemical processes of nerve membranes Antiepileptic Drugs Epilepsy CNS disorders characterized by relatively brief, but chronically recurring seizures that have a rapid onset Examples carbamazepine, valproic acid Antiepileptic Drugs: Site of Action 1. Limit repetitive firing by blocking sodium channels 2. Enhance GABA neurotransmission Benzodiazepines Anxiolytics treat anxiety Examples valium librium paxipam Mechanism of Benzodiazepines Ionotropic GABA(A) Receptor distinct site from barbiturates channel opening is easier and more prolonged enhancement of inhibition amygdala is key region Psychostimultants Definition: a group of drugs that evokes an alerting, arousing or behavior-activating response similar to the normal reaction to an emergency or stress Mimics adrenalin: increase in blood pressure and heart rate, pupils dilate, etc. Psychostimultants Examples amphetamine cocaine Positive Effects: elevate mood, induce euphoria, increase alertness, reduce fatigue Negative Effects: anxiety, insomnia and irritability Mechanism of Action Cocaine Uptake inhibitor (DA, NE, 5-HT) Amphetamine Uptake inhibitor (DA and NE) - MAO - inhibitor - Releaser (DA and NE) AMPHETAMINE AND BEHAVIOR IN RATS Saline treated rat (0 mg/kg AMPH) AMPHETAMINE AND BEHAVIOR IN RATS Low dose (1 mg/kg AMPH) AMPHETAMINE AND BEHAVIOR IN RATS High dose (8 mg/kg AMPH) Opioid Analgesics Analgesic control pain Opioid compound with morphine like activity endogenous: endorphins, enkephalins and dynorphins natural: morphine and heroin synthetic: codeine, meperidine Pain Pathway: Peripheral Central Pain Pathway: Opioid peptides act at several levels Block release or action of Sub P Opioids: Mechanism of Action Opioid Receptors mu, delta and kappa distinct distribution and pharmacology Drugs of Abuse: Common Site of Action Activation of dopamine neurons Opioids Activate Dopamine Neurons ?Disinhibition? Treatment for Opioid Addiction Methadone pure agonist Buprenorphine partial agonist (low efficacy) Naltrexone antagonist Psychedelic Drugs Definition induce visual and auditory hallucinations, separating people from reality Catecholamine-like Psychedelic Drugs additional methyl groups mescaline (from peyote) designer drugs (ecstasy) 5-HT releases (similar to amphetamine) 5-HT-like Psychedelic Drugs 5-HT agonists LSD (lysergic acid diethylamide) psilocybin and psilocin (mushroom) DMT (South American snuff) bufotenine (from genus Bufo toads) Phencyclidine (PCP) binding site of NMDA receptor (blocks ion flux ? antagonist) Marijuana ? Sedative-euphoriant-psychedelic Drug Active Ingredient delta-p-tetrahydrcannabinol (THC) Endogenous Cannabinoid anandamide 2-arachidonylglycerol (2-AG) Marijuana ? Mechanism of Action Anandamide G-protein Coupled Receptor activates potassium channel inhibits calcium channel inhibit neurotransmitter release Date Rape Drugs Ketamine cat Valiums, K, Special K, vitamin K similar to PCP veterinary anesthetic Rohypnol Roofies, rophies, Roche, Forget-me Pill benzodiazepine Gamma-hydroxbutryate (GHB) G, Georgia home boy, grievous bodily harm, liquid ecstasy CNS depressant (anesthetic) OVERVIEW OF CHEMICAL SYNAPTIC TRANSMISSION KEY STEPS 1. Action potential invasion 2. Ca2+ influx 3. Vesicle fusion 4. Transmitter diffusion 5. Receptor binding 6. Channel opening 7. Postsynaptic potential 8. Transmitter clearance 9. Vesicular retrieval FROG NEUROMUSCULAR JUNCTION: MODEL SYNAPSE motor end plate - terminals - postjunctional folds - postsynaptic receptors - postjunctional folds - active zones - degradative enzymes NMJ: CLOSE UP EPSP: Excitatory PostSynaptic Potential (End Plate Potential) - large (60 mV vs 1 mV at neuron synapse) - invariably leads to action potential - reduced by curare Acetylcholinesterase breaks down acetylcholine to acetate and choline located in cleft very fast and very plentiful Buffered Diffusion diffusion of ACh hindered by binding to receptors and folds prevents efflux from cleft RELEASE OF NEUROTRANSMITTER MEPP: miniature end plate potentials spontaneous 1 mV similar to evoked EPP in low Ca2+ QUANTAL HYPOTHESIS OF RELEASE transmitter release occurs in packets called quanta one quantum = one MEPP one quantum = 10,000 molecules (100 mM) many quantum (200) = one EPP *** neurons: one quantum = one PSP CH. 6
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