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Research ArticleNEUROPHARMACOLOGY

Nicotinic Modulation of Mesoprefrontal Dopamine Neurons: Pharmacologic and Neuroanatomic Characterization

Tony P. George, Christopher D. Verrico, Marina R. Picciotto and Robert H. Roth
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 58-66;
Tony P. George
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Christopher D. Verrico
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Marina R. Picciotto
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Robert H. Roth
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Abstract

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-β-erythroidine (a β2-subunit-selective blocker; 0.0–3.0 mg/kg) and methylycaconitine (an α7-subunit-selective blocker; 0.0–8.4 mg/kg) suggest that both α4β2- and α7-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.

Footnotes

  • Send reprint requests to: Tony P. George, Division of Substance Abuse, Department of Psychiatry, Yale University School of Medicine, Room S-109, Substance Abuse Center, Connecticut Mental Health Center, 34 Park St., New Haven, CT 06519. E-mail: tony.george{at}yale.edu

  • ↵1 This work was supported in part by the Lucille P. Markey Foundation, the National Alliance for Research on Schizophrenia and Depression, and U.S. Public Health Service Grants K12-DA-00167 (to T.P.G.), K02-DA-00436 (to M.R.P.), R37-MH-14092 (to R.H.R.), and P50-DA-84733.

  • Abbreviations:
    nAChR
    nicotinic acetylcholine receptor
    DA
    dopamine
    MEC
    mecamylamine
    VTA
    ventral tegmental area
    mPFC
    medial prefrontal cortex
    MLA
    methylycacontine
    DHBE
    dihydro-β-erythroidine
    DOPAC
    dihydroxyphenylacetic acid
    • Received February 15, 2000.
    • Accepted June 8, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleNEUROPHARMACOLOGY

Nicotinic Modulation of Mesoprefrontal Dopamine Neurons: Pharmacologic and Neuroanatomic Characterization

Tony P. George, Christopher D. Verrico, Marina R. Picciotto and Robert H. Roth
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 58-66;

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Research ArticleNEUROPHARMACOLOGY

Nicotinic Modulation of Mesoprefrontal Dopamine Neurons: Pharmacologic and Neuroanatomic Characterization

Tony P. George, Christopher D. Verrico, Marina R. Picciotto and Robert H. Roth
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 58-66;
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