Nicotine and some related compounds: effects on schedule-controlled behaviour and discriminative properties in rats

Abstract

Behavioural effects of d- and l-nicotine, d- and l-nornicotine and l-cotinine were studied in two paradigms. In experiment 1, rats responded under a multiple fixed-interval (FI) 5 min, fixed-ratio (FR) 20 schedule of food presentation. Aside from differences in potency and time course, l-nicotine and the stereoisomers of nornicotine produced qualitatively similar effects on rates of responding. With increasing doses of drugs, FI response rates first increased and then decreased, while FR response rates only decreased. In contrast, d-nicotine did not significantly increase FI response rates at lower doses, and only decreased FI and FR response rates at higher doses. At doses up to 100 mg/kg, cotinine produced only dose-dependent increases in FI response rates and had no effect on FR response rates. Rate-increasing effects of cotinine were not blocked by mecamylamine. In experiment 2, rats were trained to discriminate between l-nicotine (0.1 mg/kg SC) and saline (0.1 mg/kg SC) in a two-bar, operant conditioning procedure under a tandem variable-interval (VI) 1 min, FR 10 schedule of food presentation. Full generalization was obtained to d-nicotine and to l- and d-nornicotine. Generalization to cotinine occurred only with large doses that contained significant amounts of nicotine present as an impurity. There was no generalization to non-nicotinic drugs (morphine and clenbuterol), even at doses that reduced response rates. The rank order of potency for nicotine and its analogues was similar in experiments 1 and 2: l-nicotine was 10–20 times more potent than d-nicotine and the stereoisomers of nornicotine (which did not show stereoselectivity in the rat). Cotinine was at least several hundred times less potent than nicotine. Behavioural potencies correlated with previously reported concentrations of the analogues needed to reduce binding of tritiated nicotine to rat brain membranes