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 via exocytosis. Acute cocaine or sertraline administration promote the ability of 5-HT precursors (e.g. L-tryptophan) to induce the 5-HT2A receptor-mediated head-twitch response (HTR) in rodents. The 5-HT releaser, d-fenfluramine, at behaviorally active doses, can induce the head-twitch response in rodents by releasing cytoplasmic 5-HT via the serotonin uptake carrier working in reverse. The purpose of the present study was to utilize the d-fenfluramine-induced HTR to determine the serotonergic and nonserotonergic components of cocaine's actions on the d-fenfluramine-sensitive pool of cytoplasmic 5-HT. Because a dramatic differential potentiation in HTR frequency is obtained when cocaine is administered prior relative to after L-tryptophan injection, the effects of varying doses of cocaine and the selective serotonin (sertraline), dopamine (DA) (GBR 12935), and norepinephrine (NE) (nisoxetine) uptake blockers were investigated on the d-fenfluramine-induced behavior in two experimental protocols. Thus, each uptake inhibitor was administered either 10 min following (protocol 1) or 10 min prior to (protocol 2) d-fenfluramine injection. All the tested uptake inhibitors attenuated the d-fenfluramine-induced HTR in a dose-dependent manner in both experimental protocols. However, their order of potency in either protocol 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 significantly reversed in protocol 2. The inhibitory effects of the cited drugs on the d-fenfluramine-induced HTR are discussed in terms of: 1) high doses of selective monoamine uptake blockers may not exhibit as much selectivity for their target uptake sites as indicated by in vitro tests; and 2) possible pharmacokinetic interactions between d-fenfluramine and the monoamine uptake blockers.
Darmani
N A
NA
Department of Pharmacology, Kirksville College of Osteopathic Medicine, MO 63501, USA.
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D005277:Fenfluramine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D020280:Sertraline
D015057:1-Naphthylamine; D003042:Cocaine; D005277:Fenfluramine; D005473:Fluoxetine; D008996:Monoamine Oxidase Inhibitors; D010879:Piperazines; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; C011386:nisoxetine; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine