Stimulation of serotonin2C receptors blocks the hyperactivation of midbrain dopamine neurons induced by nicotine administration.
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.
Pierucci
Massimo
M
Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Chieti, Italy.
Di Matteo
Vincenzo
V
Esposito
Ennio
E
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*
D005021:Ethylamines; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; C103848:Ro 60-0175; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D009538:Nicotine; D004298:Dopamine