Alterations in PKCγ in the mouse hippocampus after prenatal exposure to heroin: a link from cell signaling to behavioral outcome

Abstract

Administration of heroin to pregnant mice evokes neurochemical and behavioral deficits consequent to disruption of septohippocampal cholinergic innervation, notably involving desensitization of the ability of cholinergic receptors to activate PKC activity. The present study further evaluates whether desensitization occurs specifically for the PKCγ isoform, the behaviorally relevant subtype, as compared to PKCα. Mice were exposed transplacentally to heroin on gestational days (GD) 9–18 via s.c. maternal injections (10 mg/kg per day). In young adulthood (50 days old), control offspring showed an increase in hippocampal cell membrane PKCγ after incubation with the muscarinic cholinergic receptor agonist, carbachol, indicative of translocation from the cytosol. Prenatal exposure to heroin eliminated this response, whereas basal PKCγ levels were unchanged. In contrast, PKCα, which is not related to heroin-induced behavioral deficits, did not show a loss of response. The present findings strongly point to abnormalities in the responsiveness of PKCγ as a mechanism underlying the neurobehavioral teratogenicity of heroin.