UC San Diego

Nicotine is the primary psychoactive substance in tobacco and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the alpha4beta2-nAChR, endogenously modulates neuronal excitability and, thereby, modifies certain normal, as well as nicotine-induced, behaviors. Although alpha4- containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addition, mental illness and movement control in humans. This work generated a unique model system to examine the role of alpha4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the alpha4 subunit from dopaminergic neurons in mice. Selective deletion was confirmed by loss of alpha4 mRNA and alpha4beta2-nAChRs from dopaminergic neurons, as well as selective loss of alpha4beta2-nAChR function from dopaminergic but not GABAergic neurons. Mice without alpha4-containing nAChRs had no gross impairments in learning or locomotor activity and were examined in two behaviors central to nicotine dependence, reward and anxiety relief. alpha4-nAChRs on dopaminergic neurons were found to be necessary for nicotine reward as measured by nicotine place preference, but not for reward from another drug of abuse, cocaine. Studies using the elevated plus maze as a measure of anxiety indicated that alpha4beta2- nAChRs are necessary for the anxiolytic effects of nicotine and that elimination of alpha4beta2-nAChRs specifically from dopaminergic neurons decreased the sensitivity to the anxiolytic effects of nicotine. In further characterizing the role of alpha4-nAChRs on dopaminergic neurons in nicotine behaviors, studies showed that deletion of these receptors also increased sensitivity to nicotine-induced locomotor depression, however these receptors were not involved in nicotine induced hypothermia. This was the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine behaviors