Effects of isoarecolone, a nicotinic receptor agonist in rodent models of nicotine dependence

Abstract

Rationale

The nicotinic receptor agonist, isoarecolone, has ‘nicotine-like’ subjective properties as detected by rats in a discrimination paradigm. However, isoarecolone lacks the intra-accumbens dopamine-releasing effects, a feature akin to most abused substances. In the five-choice serial reaction time task, isoarecolone can enhance attention and thus may be developed as a cognitive enhancer.

Objective

The present experiments assess the dependence profile of isoarecolone in rodent models of nicotine dependence.

Method and results

Tests for cross-substitution in which isoarecolone is substituted for nicotine [0.3 mg/kg/infusion (inf)] self-administration suggest isoarecolone to have nominal reinforcing properties (0.3 or 1.0 mg/kg/inf); intake of isoarecolone declined over three test sessions in which responding was no different from saline extinction, and behaviour was reinstated by re-presenting nicotine. In a model of nicotine-seeking behaviour, rats having been extinguished by removal of nicotine (0.03 mg/kg/inf) and associated cues, the presentation of priming doses of nicotine (0.1–0.4 mg/kg s.c.) with the cues robustly reinstated responding of nicotine-seeking behaviour. Tests with priming doses of isoarecolone (1–20 mg/kg s.c.) shown previously to generalise to nicotine in discrimination tests produced significant levels of reinstatement but the responses were significantly less compared to nicotine-induced reinstatement.

Conclusion

Overall, these results suggest that isoarecolone with its unique profile of behavioural activity should be further examined for treating chronic diseases that are characterised by attentional dysfunction.