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NEUROPHARMACOLOGY

Stimulation of Serotonin_2C Receptors Blocks the Hyperactivation of Midbrain Dopamine Neurons Induced by Nicotine Administration

Istituto di Ricerche Farmacologiche "Mario Negri", Consorzio "Mario Negri" Sud, Santa Maria Imbaro, Chieti, Italy

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 µg/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 µg/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 µg/kg i.v. (S)-2-(chloro-5-fluoro-indo-l-yl)-l-methylethylamine 1:1 C₄H₄O₄ (RO 60-0175) prevented the enhancement in DA neuronal firing rate elicited by acute nicotine (25–400 µg/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 µg/kg i.v. RO 60-0175 significantly reduced the stimulatory effect of VTA DA neurons induced by acute challenge with nicotine (25–400 µg/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.

Address correspondence to: Dr. Ennio Esposito, Istituto di Ricerche Farmacologiche "Mario Negri", Consorzio "Mario Negri" Sud, 66030 Santa Maria Imbaro, Chieti, Italy. E-mail: esposito{at}negrisud.it