COCAINE AND SELECTIVE MONOAMINE UPTAKE BLOCKERS (SERTRALINE, NISOXETINE, AND GBR-12935) PREVENT THE D-FENFLURAMINE-INDUCED HEAD-TWITCH RESPONSE IN MICE

Serotonin release subsequent to 5-HT precursor loading mainly occurs v ia exocytosis. Acute cocaine or sertraline administration promote the ability of 5-HT precursors (e.,a. L-tryptophan) to induce the 5-HT2A r eceptor-mediated head-twitch response (HTR) in rodents. The 5-HT relea ser, d-fenfluramine, at behaviorally active doses, can induce the head -twitch response in rodents by releasing cytoplasmic 5-HT via the sero tonin uptake carrier working in reverse. The purpose of the present st udy was to utilize the d-fenfluramine-induced HTR to determine the ser otonergic and nonserotonergic components of cocaine's actions on the d -fenfluramine-sensitive pool of cytoplasmic 5-HT. Because a dramatic d ifferential potentiation in HTR frequency is obtained when cocaine is administered prior relative to after L-tryptophan injection, the effec ts of varying doses of cocaine and the selective serotonin (sertraline ), dopamine (DA) (GBR 12935), and norepinephrine (NE) (nisoxetine) upt ake blockers were investigated on the d-fenfluramine-induced behavior in two experimental protocols. Thus, each uptake inhibitor was adminis tered either 10 min following (protocol 1) or 10 min prior to (protoco l 2) d-fenfluramine injection. All the tested uptake inhibitors attenu ated the d-fenfluramine-induced HTR in a dose-dependent manner in both experimental protocols. However, their order of potency in either pro tocol 1 (nisoxetine > GBR 12935 > cocaine > sertraline) or protocol 2 (cocaine > GBR 12935 > nisoxetine = sertraline) does not agree with in vitro affinity of these drugs for the 5-HT transporter. In addition, the potency order for cocaine and nisoxetine in protocol 1 was signifi cantly reversed in protocol 2. The inhibitory effects of the cited dru gs on the d-fenfluramine-induced HTR are discussed in terms of: 1) hig h doses of selective monoamine uptake blockers may not exhibit as much selectivity for their target uptake sites as indicated by in vitro te sts; and 2) possible pharmacokinetic interactions between d-fenflurami ne and the monoamine uptake blockers. (C) 1998 Elsevier Science Inc.