Alpha7 Nicotinic Acetylcholine Receptors Modulate Motivation to Self-Administer Nicotine: Implications for Smoking and Schizophrenia

Individuals diagnosed with schizophrenia have an exceptionally high risk for tobacco dependence. Postmortem studies show that these individuals have significant reductions in alpha 7 nicotinic acetylcholine receptors (nAChRs) in several brain areas. Decreased alpha 7-mediated function might not only be linked to schizophrenia but also to increased tobacco consumption. The purpose of this study was to determine whether pharmacological blockade of alpha 7 nAChRs would increase motivation of rats to intravenously self-administer nicotine (NIC) during a progressive ratio schedule of reinforcement (PR). Before PR, rats received local infusions of 0, 10, or 20 pmol of a selective alpha 7 nAChR antagonist, alpha-conotoxin ArIB [V11L,V16D] (ArIB) into the nucleus accumbens (NAc) shell or the anterior cingulate cortex, brain areas that contribute to motivation for drug reward. We additionally sought to determine whether local infusion of 0, 10, or 40 nmol of a selective alpha 7 nAChR agonist, PNU 282987, into these brain areas would decrease motivation for NIC use. Infusion of ArIB into the NAc shell and anterior cingulate cortex resulted in a significant increase in active lever pressing, breakpoints, and NIC intake, suggesting that a decrease in alpha 7 nAChR function increases motivation to work for NIC. In contrast, PNU 282987 infusion resulted in reductions in these measures when administered into the NAc shell, but had no effect after administration into the anterior cingulate cortex. These data identify reduction of alpha 7 nAChR function as a potential mechanism for elevated tobacco use in schizophrenia and also identify activation of alpha 7 nAChRs as a potential strategy for tobacco cessation therapy. Neuropsychopharmacology (2012) 37, 1134-1143; doi:10.1038/npp.2011.299; published online 14 December 2011