DISCRIMINATIVE STIMULUS PROPERTIES OF THE NICOTINIC AGONIST CYTISINE

Cytisine binds with high affinity and specificity to neuronal nicotini c receptors but its physiological and behavioural effects are complex and differ from those of nicotine. The present study explores the beha vioural aspects further by comparing the discriminative stimulus effec ts of cytisine with those of nicotine. Two groups of rats were trained to discriminate cytisine (2 mg/kg SC) or nicotine (0.2 mg/kg SC) from saline in a two-lever operant conditioning procedure with food reinfo rcers presented on a tandem VI FR schedule. A third group of rats was trained to discriminate cytisine (3 mg/kg SC). Rats acquired these dis criminations within 50 training sessions. The stimulus effects of both cytisine and nicotine appeared within 4 min of SC injection. fn gener alization tests, rats trained with either cytisine or nicotine showed steep dose-response curves (generalization gradients) for their respec tive training drug. However, rats trained with cytisine showed full do se-related, generalization to nicotine (93%), whereas rats trained wit h nicotine exhibited only partial generalization to cytisine (54%). Ra ts trained with either cytisine or nicotine exhibited similar, partial generalization (76-77%) to (+)-amphetamine. The nicotine antagonist m ecamylamine blocked the discriminative stimulus effects of both cytisi ne and nicotine; it was confirmed that the block of nicotine (0.2 mg/k g) was complete, whereas the block of cytisine (2 and 3 mg/kg) was inc omplete in two separate experiments. Overall, the results showed that cytisine, like nicotine, can serve as a robust discriminative stimulus but, in contrast to its relatively high affinity in binding experimen ts, cytisine was much less potent than nicotine in the behavioural stu dies. Although the stimulus effects of the two drugs were very similar , there were some subtle differences such as the asymmetrical cross-ge neralizations between them and possible small differences in susceptib ility to antagonism by mecamylamine. These effects were interpreted ei ther in terms of a putative partial agonist effect of cytisine, or by assuming that nicotine produces a compound stimulus. Such a stimulus w ould be mediated through two or more subtypes of nicotinic receptor, a nd cytisine would act at some, but not all, of these receptor subtypes .