PHA-568487

Smoking is considered a form of self-medication for psychosis, including nicotine (NIC) dependence, through stimulation of the nicotinic acetylcholine receptors (nAChRs) in the central nervous system of patients with psychiatric disorders. However, the effects of NIC on neuropsychological functions and the underlying molecular mechanisms remain unclear. We investigated the effects of (-)-NIC on emotional behaviors, expression of intracerebral nAChR subunits, and morphological changes in swim-stressed mice. Stressed mice showed social behavior impairments, low phosphorylation levels of Akt, CaMKII, and ERK, and reduced thickness of the pyramidal neuronal layer in the hippocampus. Acute or repeated administration of (-)-NIC (0.3 mg/kg, s.c.) to stressed mice attenuated social behavior impairments. Repeated administration of PHA568487, a selective α7 nAChR agonist, also attenuated these impairments. The attenuating effects of (-)-NIC were blocked by a selective α7 nAChR antagonist, but not by a selective α4β2 nAChR antagonist. Repeated administration of (-)-NIC ameliorated the reduced phosphorylation levels of Akt, CaMKII, and ERK, as well as morphological abnormalities in the hippocampus, without inducing conditioned place preference. Acute administration of (-)-NIC ameliorated the decreased Akt phosphorylation without affecting morphological abnormalities. Our findings suggest that hippocampal α7 nAChR signal pathways play an important role in social behavior impairments in stressed mice, and that abnormal neuronal morphology via these pathways contributes to the development of such impairments. Activation of α7 nAChRs was identified as a key target for new treatment strategies for emotional impairments in stress-related disorders.