title: Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys.
abstract: Monoamine releasers with varying selectivity for dopamine (DA)/norepinephrine and serotonin (5-HT) release are potential treatment medications for cocaine abuse. Although DA-selective monoamine releasers effectively reduce cocaine abuse, their clinical usefulness is limited by abuse liability. It is hypothesized that increasing 5-HT neurotransmission may reduce the abuse-related effects of DA releasers, but the optimal DA:5-HT release ratio remains to be determined. This study in rhesus monkeys compared the effects of two compounds with differing potency for 5-HT release. Methcathinone and 3-Cl-methcathinone (PAL-434) have equal potency for DA release, but PAL-434 has 10-fold higher potency for 5-HT release. In drug discrimination studies, monkeys were trained to discriminate cocaine (0.4 mg/kg i.m.) from saline in a two-key, food-reinforced procedure. In drug self-administration studies, a separate group of monkeys was trained to respond for cocaine [0.01 mg/kg/injection (inj)] and food (1 g pellets) under a second order schedule of reinforcement [FR2(VR16:S)]. When responding was stable, methcathinone (0.1–0.56 mg/kg.h i.v.) or PAL-434 (0.32–1.8 mg/kg.h i.v.) was administered chronically (one injection every 20 min for 23 h/d) for 7–10 d. In discrimination studies, both compounds dose-dependently increased cocaine-like responding but with different potencies (cocaine=methcathinone >PAL-434). Chronic treatment with methcathinone or PAL-434 dose-dependently and selectively reduced cocaine self-administration. PAL-434 was about 4-fold and methcathinone about 1.6-fold more potent at decreasing cocaine- over food-maintained responding. These data suggest that compounds with moderate selectivity for DA vs. 5-HT release (8–15-fold) may be effective for the treatment of cocaine dependence.
authors.affiliation: Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kohut
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fivel
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Mello
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D004192:Discrimination, Psychological / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D008253:Macaca mulatta; D008297:Male; D011427:Propiophenones / Q000494:pharmacology*; D012054:Reinforcement, Psychology; D012646:Self Administration; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D011427:Propiophenones; D012701:Serotonin; C047806:monomethylpropion; D003042:Cocaine; D004298:Dopamine