Nicotine dependence: studies with a laboratory model.

Simple, rapid preclinical models of nicotine physical dependence and abstinence syndrome are needed to identify underlying neurobiological mechanisms and screen potential therapies. One such model induces dependence by 7 days of continuous subcutaneous nicotine infusion in the rat. Abstinence is initiated through termination of infusion or injection of nicotinic antagonist drugs. The result is an abstinence syndrome involving a pattern of behaviors somewhat resembling opiate abstinence in the rat as well as weight gain and depressed locomotor activity. The model has met a number of validity criteria and its essential features have been replicated in several laboratories. Several research groups have modified or extended the model by measuring emotional/motivational changes associated with nicotine abstinence such as conditioned aversion, intracranial self-stimulation (ICSS) thresholds and the startle response. Dependence models have been used to identify neurobiological systems that contribute to nicotine dependence, particularly endogenous opiate systems and the mesolimbic dopamine pathway. It is hypothesized that these different systems contribute to different behavioral aspects of nicotine abstinence syndrome. Increasingly used as a preclinical screening tool, the model has proved sensitive to various abstinence-alleviating therapeutic approaches, including some with already demonstrated clinical effectiveness.