Elsevier

Brain Research

Volume 643, Issues 1–2, 18 April 1994, Pages 1-9
Brain Research

Clozapine attenuates the discriminative stimulus properties of (−)-nicotine

https://doi.org/10.1016/0006-8993(94)90002-7Get rights and content

Abstract

Rats were trained to discriminate 1.9 μmol/kg (−)-nicotine (0.3 mg/kg) from saline in a standard two-bar operant conditioning paradigm with food reinforcement. The effect of neuronal nicotinic acetylcholine receptor (nAChR) agonists and antagonists were verified, and the participation of dopaminergic receptors subtypes in the expression of the (−)-nicotine cue was investigated with cis-flupentixol (D1-D2 antagonist), haloperidol (D2 antagonist) and clozapine (D4 antagonist). The stereoselectivity of the behavioral response was indicated by the 10-fold less sensitivity to (+)-nicotine in (−)-nicotine-trained rats. (±)-Anabasine and (−)-cytisine exhibited partial agonist profiles at the 1.9 μmol/kg dose while (−)-lobeline was devoid of any effect in doses up to 19 μmol/kg. (−)-Lobeline did not show antagonist properties in this paradigm. The nicotinic channel blockers mecamylamine, chlorisondamine and hexamethonium were inactive on their own but mecamylamine and chlorisondamine were able to block the effect of (−)-nicotine. Clozapine attenuated the (−)-nicotine cue while cis-flupentixol and haloperidol were ineffective. Similar doses of cis-flupentixol significantly blocked the locomotr stimulant effect of (−)-nicotine in rats indicating that blockade of dopaminergic receptors was achieved at the doses used in the drug discrimination studies. These data suggest that the discriminative stimulus properties of (−)-nicotine are mediated through neuronal nAChRs and involves the activation of dopaminergic receptors of the D4 subtype.

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