AKT2 modulates astrocytic nicotine responsesin vivo

Abstract

A better understanding of nicotine neurobiology is needed to reduce or prevent chronic addiction, ameliorate the detrimental effects of nicotine withdrawal, and increase successful cessation of use. Nicotine binds and activates two astrocyte-expressed nicotinic acetylcholine receptors (nAChRs), α4β2 and α7. We recently found thatProtein kinase B-β (Pkb-β orAkt2) expression is restricted to astrocytes in mice and humans. To determine if AKT2 plays a role in astrocytic nicotinic responses, we generated astrocyte-specificAkt2conditional knockout (cKO) and fullAkt2KO mice forin vivoandin vitroexperiments. Forin vivostudies, we examined mice exposed to chronic nicotine for two weeks in drinking water (200 μg/mL) and following acute nicotine challenge (0.09, 0.2 mg/kg) after 24 hrs. Ourin vitrostudies used cultured mouse astrocytes to measure nicotine-dependent astrocytic responses. We validated our approaches using lipopolysaccharide (LPS) exposure inducing astrogliosis. Sholl analysis was used to measure glial fibrillary acidic protein responses in astrocytes. Our data show that wild-type (WT) mice exhibit increased astrocyte morphological complexity during acute nicotine exposure, with decreasing complexity during chronic nicotine use, whereasAkt2cKO mice showed increased astrocyte morphology complexity. In culture, we found that 100μM nicotine was sufficient for morphological changes and blocking α7 or α4β2 nAChRs prevented observed morphologic changes. Finally, we performed conditioned place preference (CPP) inAkt2cKO mice and found that astrocytic AKT2 deficiency reduced nicotine preference compared to controls. These findings show the importance of nAChRs andAkt2signaling in the astrocytic response to nicotine.Main PointsNicotine regulates astrogliosisin vivo: acute exposure boosts complexity; chronic exposure diminishes it.AKT2, expressed in astroglia, modulates morphological changes in response to nicotine and nicotine-dependent conditioned place preference.