title: Stimulation of serotonin2C receptors blocks the hyperactivation of midbrain dopamine neurons induced by nicotine administration.
abstract: In vivo electrophysiological techniques were used to study the effect of nicotine on the basal activity of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) of chloral hydrate-anesthetized rats. Acute i.v. injections of nicotine (25-400 microg/kg) caused a dose-dependent increase of the firing rate and the bursting activity of DA neurons both in the SNc and the VTA. Repeated daily injection of nicotine (1 mg/kg i.p.) for 10 consecutive days did not cause any significant change in the basal activity of DA neurons in the SNc and the VTA. Acute challenge with nicotine (25-400 microg/kg i.v.) in animals treated repeatedly with this drug caused a dose-related excitation of DA neurons in both areas. To test the hypothesis that stimulation of 5-hydroxytryptamine (5-HT, serotonin)(2C) receptors could affect nicotine-induced stimulation of DA neuronal activity, the selective 5-HT(2C) receptor agonist RO 60-0175 was used. Pretreatment with 100 microg/kg i.v. (S)-2-(chloro-5-fluoro-indo-l-yl)-l-methylethylamine 1:1 C(4)H(4)O(4) (RO 60-0175) prevented the enhancement in DA neuronal firing rate elicited by acute nicotine (25-400 microg/kg i.v.) in the SNc of both drug naive and chronically treated rats but was devoid of any significant effect in the VTA. Moreover, the dose of 300 microg/kg i.v. RO 60-0175 significantly reduced the stimulatory effect of VTA DA neurons induced by acute challenge with nicotine (25-400 microg/kg i.v.) both in drug naive and chronically treated rats. It is concluded that selective activation of 5-HT(2C) receptors can block the stimulatory action of nicotine on midbrain DA neuronal activity.
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Chieti, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pierucci
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Matteo
authors.forename: Ennio
authors.initials: E
authors.lastname: Esposito
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D005021:Ethylamines / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008636:Mesencephalon; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013378:Substantia Nigra / Q000166:cytology*; D017557:Ventral Tegmental Area / Q000166:cytology*
chemical_list: D005021:Ethylamines; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; C103848:Ro 60-0175; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D009538:Nicotine; D004298:Dopamine