title: In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat.
abstract: Evidence suggests that elevations in extracellular serotonin (5-HT) in the brain can diminish stimulant effects of dopamine (DA). To assess this proposal, we evaluated the pharmacology of amphetamine analogs (m-fluoroamphetamine, p-fluoroamphetamine, m-methylamphetamine, p-methylamphetamine), which display similar in vitro potency as DA releasers (EC(50) = 24-52 nM) but differ in potency as 5-HT releasers (EC(50) = 53-1937 nM). In vivo microdialysis was used to assess the effects of drugs on extracellular DA and 5-HT in rat nucleus accumbens, while simultaneously measuring ambulation (i.e., forward locomotion) and stereotypy (i.e., repetitive movements). Rats received two intravenous injections of drug, 1 mg/kg at time 0 followed by 3 mg/kg 60 min later. All analogs produced dose-related increases in dialysate DA and 5-HT, but the effects on DA did not agree with in vitro predictions. Maximal elevation of dialysate DA ranged from 5- to 14-fold above baseline and varied inversely with 5-HT response, which ranged from 6- to 24-fold above baseline. All analogs increased ambulation and stereotypy, but drugs causing greater 5-HT release (e.g., p-methylamphetamine) were associated with significantly less forward locomotion. The magnitude of ambulation was positively correlated with extracellular DA (p < 0.001) and less so with the ratio of DA release to 5-HT release (i.e., percentage DA increase divided by percentage 5-HT increase) (p < 0.029). Collectively, our findings are consistent with the hypothesis that 5-HT release dampens stimulant effects of amphetamine-type drugs, but further studies are required to address the precise mechanisms underlying this phenomenon.
authors.affiliation: Translational Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.forename: Robert D
authors.initials: RD
authors.lastname: Clark
authors.forename: William L
authors.initials: WL
authors.lastname: Woolverton
authors.forename: Sunmee
authors.initials: S
authors.lastname: Wee
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
mesh_terms: D000661:Amphetamine / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D012701:Serotonin; D000661:Amphetamine; D004298:Dopamine