Vol. 295, Issue 1, 58-66, October 2000

Nicotinic Modulation of Mesoprefrontal Dopamine Neurons: Pharmacologic and Neuroanatomic Characterization¹

Tony P. George , Christopher D. Verrico, Marina R. Picciotto and Robert H. Roth

Division of Substance Abuse (T.P.G.), Department of Psychiatry (T.P.G., M.R.P., R.H.R.), and Departments of Pharmacology (C.D.V., M.R.P., R.H.R.) and Neurobiology (M.R.P.), Yale University School of Medicine, New Haven, Connecticut

Schizophrenics have cortical dysfunction that may involve mesoprefrontal dopamine (DA) systems. Rates of nicotine dependence approach 90% in schizophrenia, and nicotine administration through cigarette smoking may ameliorate cognitive dysfunction, which may be related to cortical DA dysregulation. We have shown that repeated, but not acute, nicotine pretreatment (0.15 mg/kg daily s.c.) reduces footshock stress-induced mesoprefrontal DA metabolism and immobility responses. This effect of repeated nicotine is dependent on mecamylamine (MEC)-sensitive nicotinic acetylcholine receptor (nAChR) stimulation and endogenous opioid peptides. In the present study, we have further characterized these effects of repeated nicotine on the stress reactivity of mesoprefrontal DA neurons by using the following: 1) local infusion of MEC into cell bodies (ventral tegmental area) and terminal fields (medial prefrontal cortex) to determine the site of action of nicotine; and 2) systemic administration of selective nAChR antagonists. Results of bilateral local infusions of MEC (0.1-1.0 µg/side) into ventral tegmental area or medial prefrontal cortex in saline- and nicotine-pretreated rats suggests a modulatory role for somatodendritic versus terminal field nAChRs on mesoprefrontal DA neurons under stress-induced states. Experiments with dihydro--erythroidine (a 2-subunit-selective blocker; 0.0-3.0 mg/kg) and methylycaconitine (an 7-subunit-selective blocker; 0.0-8.4 mg/kg) suggest that both 42- and 7-containing nAChRs modulate mesoprefrontal DA neurons. Thus, complex regulation of mesoprefrontal DA neurons by nAChRs is suggested, which may have relevance to prefrontal cortical DA dysfunction and the high comorbid rates of nicotine dependence in schizophrenia.