Psychostimulants Lesson 19

Psychostimulants n Cocaine l alkaloid from coca plant n Amphetamines (synthetics) l similar fx & mechanisms l all related to ephedrine (ephedra) l dl-amphetamine: l methamphetamine l MDMA (Ecstasy) ~

Cocaine: Local Anesthetic n Pharmacokinetics l Inject SC n Half-life: 1 hr l Numbing < 2 min l Peak effects: minutes n Pharmacodynamics l Blocks Na+ channels l Constricts blood vessels ~

Cocaine: Psychostimulant n Pharmacokinetics n p.o. l ineffective for cocaine l effective for amphetamine analogs l onset: 30 minutes / peak 2-3 hrs n Intranasal l onset 3-4 minutes l peak effects: minutes ~

Cocaine Pharmacokinetics n Inhalation (smoking) & IV injection l Onset: < 2 min n For both routes l Euphoria  Crash  Craving n Powerful positive RFT l short delay l high magnitude ~

Pharmacokinetics: Metabolism n Cocaine l By cholinesterases l Blood & Liver l Half-life:  1 hr n Amphetamines l In liver, much excreted unchanged l Half-life: 7-30 hrs ~

n Tachyphylaxis l brief & transient tolerance l reuse within minutes - hours n Tolerance l Lower doses n Sensitization l repeated use over days ~ Psychostimulant Pharmacokinetics

Psychostimulant Pharmacology n Indirect agonists: l DA, NE, 5-HT n DA - reinforcing effects l in nucleus accumbens l Euphoria u Rate of change of blood levels n Amphetamine l Primary effects on reuptake l Also  NT &  MAO function ~

Physiological Effects n Sympathomimetic n Heart l Low doses: decrease HR l Moderate:  HR & BP l High: cardiac arrhythmia, failure n Body temperature l Low doses: decrease l moderate & high: increase ~

Physiological Effects n Restlessness n Sleep: interferes with REM n Vomiting n Breathing is facilitated n Depresses cortical activity ~

Psychostimulant Neurotoxicity n DA neurotoxicity;  DA transporters l amphetamine l methamphetamine n 5-HT neurotoxicity l methamphetamine l MDA l MDMA (Ecstasy) n Single high dose ~

Psychotomimetic Effects n Prolonged use n Schizophrenia-like psychosis l Paranoia l Hallucinations: parasitosis l delusions n Methamphetamine l earlier developing l may persist for days, weeks ~

Lethality n Cocaine l Oral: 500 mg l Nasal: mg n Amphetamine/Methamphetamine l toxic effects: 15 mg in novices l lethal mg n Inhalation (smoked): much lower ~

Early Agitation Depression Anorexia High Craving Middle Depression Fatigue Insomnia No craving Late Exhaustion Hypersomnolence Hyperphagia No Craving Phase 1: Crash 9 hrs - 4 days Phase 2: Withdrawal weeks Early Normal sleep Normal mood Low anxiety Low craving Middle & Late Anhedonia Anergia Anxiety High Craving & conditioned cues Phase 3: Extinction indefinite Normal hedonic response Normal mood Episodic craving Conditioned cues trigger craving Abstinence Binge Relapse Cocaine Abstinence Syndrome Gawin & Kleber (1986)

Cocaine Abuse: Animals n Self-administration n Will work hard to get l progressive FR 6400 n Continuous access: l Weight loss l Self-mutilation u parasitosis? l Death within 2 weeks ~