Previous studies have suggested that an abnormality in neuronal nicotinic acetylcholine receptor expression or function may be involved in the neuropathophysiology of schizophrenia. [ 3 H]-nicotine and [ 3 H]-epibatidine binding were compared in postmortem brain from control and schizophrenic subjects with varying smoking histories. In control subjects, increased receptor binding was seen in hippocampus, cortex, and caudate with increasing tobacco use. In contrast, schizophrenic smokers had reduced nicotinic receptor levels in these brain regions compared to control smokers. Chronic haloperidol and nicotine treatment, in the rat, was used to assess neuroleptic effects on receptor up-regulation by nicotine. A significant increase in cortical nicotinic receptors was seen in both nicotine treated as well as haloperidol and nicotine co-treated animals, suggesting that the abnormal regulation of high affinity neuronal nicotinic receptors in schizophrenics followingPrevious studies have shown that high affinity nicotinic receptor numbers increase in the brains of human subjects who smoke (Benwell et al. 1988;Breese et al. 1997a;Court et al. 1998). This increase was shown to be dosedependent, based on the number of cigarettes smoked at death, and was reversible, with binding levels returning to control values in subjects who had quit smoking for at least two months prior to death (Breese et al. 1997a). The up-regulation of receptor numbers does not appear to be under transcriptional regulation (Marks et al. 1992). Rather, the increases may be related to changes in receptor turnover based on receptor desensitization, subunit composition, secondary structural changes in the receptor, or to modification of the receptor by protein kinases (Peng et al. 1994;Baenziger and Chew 1997;Eilers et al. 1997;Flores et al. 1997;Hsu et al. 1997;Xiao et al. 1998;Fenster et al. 1999).In spite of the high degree of nicotine self-administration in schizophrenics (Lohr and Flynn 1992;Ziedonis et al. 1994;de Leon et al. 1995), few studies have examined the effect of smoking or neuroleptic treatment on nicotinic receptor regulation in this disease (Dalack et al. 1998). It has been suggested that nicotine self-administration in schizophrenics may control a neuronal deficit. In this regard, it has been shown that abnormal electro- NO . 4 physiological and eye-tracking deficits can be normalized by cigarette smoking or nicotine administration (Adler et al. 1992(Adler et al. , 1993Olincy et al. 1998). Smoking may also alleviate neuroleptic-induced extrapyramidal side effects (Decina et al. 1990;Goff et al. 1992;Sandyk 1993). Nicotine use increases haloperidol metabolism (Jann et al. 1986;Miller et al. 1990), requiring patients that smoke to take higher doses than non-smoking schizophrenics, often further increasing their smoking behavior (McEvoy et al. 1995). Interestingly, clozapine, which does not induce the motor dysfunctions seen with typical neuroleptics, reduces smoking behavior (George et al. 1995) and normalizes the electrophysiologi...