Biochemistry Of Ligand Gated Ion Channels Important To D

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Nicotinic acetylcholine receptors, the ligand gated ion channels at which nicotine acts, play an important role in nicotine abuse and understanding its neurobiology may be central to developing more rational approaches for nicotine abuse treatments. The in vitro characterization of the receptor-ligand interaction is an important step in understanding the action of a ligand in vivo (i.e., for interpretation of the results from the functional studies of receptors). Less upregulation of nicotinic acetylcholine receptors is found in studies of brain tissue from patients with schizophrenia who smoke than in brain tissue from mentally healthy smokers. As schizophrenic patients often take typical or atypical neuroleptics chronically, the impact of these drugs on the upregulation of alpha4beta2* nicotinic receptors by nicotine was tested in rats. Literature reports suggest that the typical neuroleptic, haloperidol, has no effect. We tested the effect of the atypical neuroleptics, risperidone and olanzapine on the upregulation of these receptors by nicotine in the thalamus, striatum and hippocampus of rats using in vitro assays with 5-[I-125]iodo-A-85380. Neither drug attenuated the effect of nicotine, which increased the density of the receptors in these areas by 50, 80 and 90%, respectively; however, risperidone given without nicotine produced a modest increase (25%) in the density of the nicotinic receptors in the striatum. Substantial anecdotal evidence suggests that nicotine may function as a gateway drug to illicit drug use. It has been established, using an animal behavorial model of drug rewards, conditioned place preference (CPP) that nicotine produces cross sensitization to opioids. We utilized CPP to test the hypothesis that nicotine produces behavioral cross sensitization to a different class of abused drugs, specifically stimulants. These experiments in rats demonstrated that nicotine pretreatment enhances the rewarding effects of amphetamine for at least 3 to 5 days following the cessation of nicotine, with this effect dissipating within 19 days. The underlying mechanism involves alpha4beta2 nicotinic acetylcholine receptors as the competitive alpha4beta2 antagonist dihydro beta erythroidine effectively blocked the development of nicotine-induced cross sensitization. Interestingly, the alpha7 nicotinic antagonist methyllycaconitine also antagonized cross-sensitization at doses that do not block nicotine self-administration in rats. This study and published report have clearly demonstrated that nicotine produces cross-sensitization to the rewarding effects of both opiates and psychostimulants measured with CPP. The development of cross-sensitization to the rewarding effects of these drugs involves the interaction of nicotine with alpha4beta2 and probably alpha7 nicotinic acetylcholine receptors, differing from niccotine self-administration, which is primarily mediated by alpha4beta2 receptors.