Morphine-induced alterations in gene expression of calbindin immunopositive neurons in nucleus accumbens shell and core

Abstract

Chronic opiate administration induces a number of biochemical alterations within the mesolimbic dopamine system that may mediate various aspects of the addictive process. In the present study, rats were administered morphine (1.0 mg/infusion) for 20 days (17.6±3.0 infusions/day) based on infusion histories of self-administering rats. Calbindin-D28K immunoreactive neurons were microdissected from the nucleus accumbens (NAc) shell and core subregions and gene expression was assessed using cDNA macroarrays. Comparison of gene expression between the shell and core subregions of vehicle-treated rats revealed significantly higher relative abundance of GABA-A α1, Gαi2 and post-synaptic density protein 95 transcript (PSD-95) mRNA levels in the shell, whereas Gγ2 and synuclein 1 were more abundant in the core of the NAc. In the NAc shell, morphine administration resulted in upregulation of caspace 9, NF-κB, NF-H, tau, GABA-A δ subunit, FGFR1, Gγ2, synuclein 1, syntaxin 5 and 13, GRK5, and c-fos mRNAs. Caspace 1, D2 dopamine receptor, GABA-A α1 subunit, GRIA 1/3/4, Gαi2, PSD-95 and CREB were down-regulated in the NAc shell with morphine administration. In the core, neuronal apoptotic inhibitory protein (NAIP), GABA-A α1 subunit, GRIN2C, GRIA1, mGluR1, D4 dopamine receptor and PSD-95 were upregulated by morphine administration whereas bax, bcl-x, cox-1 and MAP2 were decreased. These data demonstrate that morphine administration alters gene expression differentially in NAc subregions. Specifically, GABA-A α1 subunit, GRIA1 subunit and PSD-95 mRNAs were decreased in the shell but increased in the core following morphine administration. In addition, these results provide potential targets for further evaluation in models of morphine reinforcement as well as novel mechanisms of action in morphine-induced pathophysiology.