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Psych 181: Dr. Anagnostaras Lec 11: PCP and Hallucinogens

Psych 181: Dr. Anagnostaras Lec 11: PCP and Hallucinogens. Phencyclidine. Dissociative anaesthetic Parke Davis in 1950 (Serylan®) withdrawn from human use in 1965 related to ketamine (“K” Ketalar, Ketaset®) Illicit use 1967 in San Francisco (PeaCe Pill)

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Psych 181: Dr. Anagnostaras Lec 11: PCP and Hallucinogens

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  1. Psych 181: Dr. AnagnostarasLec 11: PCP and Hallucinogens

  2. Phencyclidine Dissociative anaesthetic • Parke Davis in 1950 (Serylan®) • withdrawn from human use in 1965 • related to ketamine (“K” Ketalar, Ketaset®) Illicit use • 1967 in San Francisco (PeaCe Pill) • Widespread in late 1970,’s, early 1980’s • (1980 - 22% of kids in grades 11-12 in N.Y.) • Cheap, mostly distributed by the Crips nowadays

  3. Street names • PCP, angel dust, crystal, horse tranquilizer “sherm” “embalming fluid” on cigarettes or marijuana • sold under many names and preparations • very often sold as ∆9-THC • take orally, intranasal or i.v.; or smoke

  4. Effects Low dose (1-5 mg) • alcohol-like effect (giddy drunken-like state, disinhibition) Moderate dose (5-10 mg) • distortion of space & time, psychotic reactions (panic, agitation, depression, catatonia, paranoia) • “anaesthetic” and analgesic effects • blank stare, amnesia, mutism

  5. Toxic psychosis High dose (> 10 mg) • model of acute schizophrenia, including true hallucinations • (can last up to 1-7 days with high doses) • sometimes violent, abusive behavior Overdose • Respiratory depression/seizures

  6. Self-administration Reinforcing effects • Readily self-administered in animals • to point of intoxication • modest tolerance • addiction and withdrawal

  7. Mechanisms of action Two distinct binding sites • Sigma site - generalizes with benzomorphans • PCP site (“PCP receptor”) PCP site • part of the NMDA glutamate receptor

  8. Glutamate (glutamic acid) Ubiqutious excitatory transmitter • Depolarizes virtually all cells • Primary transmitter for fast excitatory signalling

  9. Glutamate receptors Ionotropic subtypes Non-NDMA Types • AMPA • Kainate NMDA • Selectively binds N-Methyl-D-aspartate Metabotropic subtypes

  10. Glutamate receptors 10.2

  11. PCP/NMDA interactions Noncompetative antagonist at NMDA receptor • site inside channel - blocks it • not antagonizeAMPA/kainateeffects 10.10

  12. Other actions Effects on many transmitter systems • Action at sigma site • Enhances DA release Locomotor activity 17.20

  13. Neuropathology • Multiple vacuoles form in cytoplasm of some neurons and mitochondria disappear 2-4 hrs after treatment • Increasingly obvious 4-12 hrs after drug • Disappear within 24 hrs • Only certain parts of cortex • Related to acute toxic psychosis?

  14. Neuropathology Eight day old rats treated once with PCP or MK-801 and brains examined 24 hours later. + Sustained activation of NMDA receptors at crit- ical stages in develop- ment activates program- ed cell death. See with PCP, ketamine (special K) and ethanol _

  15. Control Drug Degenerating neurons PCP

  16. Excitotoxicity • Glutamateexcitotoxicity • MK-801 10.14

  17. Hallucinogens Common features Hallucinogen • the ability to evoke hallucinationspseudohallucinations; illusions Psychotomimetic • ability to mimic endogenous psychosis Phantasicum, Psychedelic • “mind-expanding” change in perception of reality

  18. Major classes The LSD ‘Family’ • indole type hallucinogens • structural similarity to 5-HT (serotonin) • LSD (lysergic acid diethylamide)

  19. Major classes The Phenylethylamines • structural similarity to CA’s • mixed hallucinogenic and stimulant effects • mescaline

  20. LSD type hallucinogens LSD (lysergic acid diethylamide) • acid, blotters, windowpane, etc.

  21. LSD type hallucinogens LSD (lysergic acid diethylamide, LSD-25) • Hofman (1938) • led to Imitrex& Zomig

  22. LSD type hallucinogens LSD (lysergic acid diethylamide) • ergot

  23. LSD • Absorption and metabolism • Tolerance

  24. LSD type hallucinogens Psilocybin and Psilocin • magic mushroom • Psilocybe genus

  25. LSD type hallucinogens DMT (Dimethyltryptamine) • naturally-occuring LSD-like substance in plants; e.g. Piptadina peregrina (bean plant) Morning Glory Seeds • lysergic acid amide (LSA) Bufotenin (5-hydroxy-DMT) Harmine and Harmaline

  26. The phenylethylamines • structural similarity to CA’s • mixed hallucinogenic and stimulant effects • mescaline

  27. Mescaline • in peyote cactus (Lophophora Williamsii) • mescal button

  28. The phenylethylamines Methoxyamphetamines • synthetic derivatives of mescaline • many are so-called “designer drugs”

  29. Methoxyamphetamines DOM (dimethoxymethylamphetamine) • Called STP often TMA (trimethoxyamphetamine) • Similar to mescaline, but more potent MDA and MDMA • Methylenedioxyamphetamine and methylenedioxymethamphetamine

  30. Major effects (LSD) Sensory-Perceptual • pseudohallucinations • illusions • synesthesias, etc. Psychic Experiences Somatic Effects

  31. Adverse effects • Bad ‘trips’ • Flashbacks

  32. Mechanisms of action • Common action for hallucinogenic effects sensory-perceptual effects and psychedelic effects • Only short-term tolerance to LSD, no withdrawal, dependence or addiction • LSD not lethal at very high doses • Cross tolerance for hallucinogenic effect • Focus on 5-HT systems (structural similarity)

  33. Serotonin (5-hydroxytryptamine) Synthesis & storage Receptors 5-HT 1, 2….. (14 subtypes Known) Inactivation & degradation Raphe 9.1

  34. Mechanisms of action • Initial prevailing view from peripheral tissues - block action of 5-HT (antagonist?) • Second view: agonist at inhibitory autoreceptors • increases 5HT content and 5HIAA down turnover down? • inhibits firing of 5HT neurons • discredited by presynaptic lesion studies

  35. Current Postsynaptic hypothesis Binding to 5-HT receptors (over 14 subtypes) • LSD is fairly promiscuous(5-HT1/2/5/6/7 types) • Mescaline not to 5-HT1/5/7 • All have affinity for 5-HT2 family • 5-HT2A shows greatest expression in neocortex Hypothesis:LSD and other hallucinogens are 5-HT2A postsynaptic receptor agonists

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