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Effect of ?FosB overexpression on opioid and cannabinoid receptor-mediated signaling in the nucleus accumbens.

ABSTRACT: The stable transcription factor ?FosB is induced in the nucleus accumbens (NAc) by chronic exposure to several drugs of abuse, and transgenic expression of ?FosB in the striatum enhances the rewarding properties of morphine and cocaine. However, the mechanistic basis for these observations is incompletely understood. We used a bitransgenic mouse model with inducible expression of ?FosB in dopamine D(1) receptor/dynorphin-containing striatal neurons to determine the effect of ?FosB expression on opioid and cannabinoid receptor signaling in the NAc. Results showed that mu opioid-mediated G-protein activity and inhibition of adenylyl cyclase were enhanced in the NAc of mice that expressed ?FosB. Similarly, kappa opioid inhibition of adenylyl cyclase was enhanced in the ?FosB expressing mice. In contrast, cannabinoid receptor-mediated signaling did not differ between mice overexpressing ?FosB and control mice. These findings suggest that opioid and cannabinoid receptor signaling are differentially modulated by expression of ?FosB, and indicate that ?FosB expression might produce some of its effects via enhanced mu and kappa opioid receptor signaling in the NAc.

SUBMITTER: Sim-Selley LJ

PROVIDER: S-EPMC3261795 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Effect of ΔFosB overexpression on opioid and cannabinoid receptor-mediated signaling in the nucleus accumbens.

Sim-Selley Laura J LJ Cassidy Michael P MP Sparta Antonino A Zachariou Venetia V Nestler Eric J EJ Selley Dana E DE

Neuropharmacology 20110903 8

The stable transcription factor ΔFosB is induced in the nucleus accumbens (NAc) by chronic exposure to several drugs of abuse, and transgenic expression of ΔFosB in the striatum enhances the rewarding properties of morphine and cocaine. However, the mechanistic basis for these observations is incompletely understood. We used a bitransgenic mouse model with inducible expression of ΔFosB in dopamine D(1) receptor/dynorphin-containing striatal neurons to determine the effect of ΔFosB expression on ...[more]

PMID: 21907220

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Project description:The pharmacological effects of opioid- and adenosine-receptor agonists on neural signalling were investigated by measuring drug actions on barium current flowing through calcium channels in acutely-dissociated neurons of the rat nucleus accumbens (NAc). Under whole-cell voltage clamp, opioids acted via mu, but not delta or kappa, receptors to partially inhibit barium current. Mean inhibition was 35+/-2% (+/-s.e.mean, n = 33) for methionine-enkephalin and 37+/-1% (n = 65) for the selective mu receptor agonist DAMGO, both measured at saturating agonist concentrations in neurons with diameter > or = 20 microm. EC(50) for DAMGO was 100 nM. Perfusion of naloxone reversed the current inhibition by DAMGO. Adenosine also partially inhibited barium current in these neurons. Mean inhibition was 28+/-2% (n = 29) for adenosine and 33+/-3% (n = 27) for the selective A1 receptor agonist N(6)CPA, both at saturating concentrations in neurons with diameter > or = 20 microm. EC(50) for N(6)CPA was 34 nM. Adenosine inhibition was reversed by perfusion of an A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine, while the selective A2A receptor agonist, CGS 21680, had no effect. Inhibition by opioids and adenosine was mutually occlusive, suggesting a converging pathway onto calcium channels. These actions involved a G-protein-coupled mechanism, as demonstrated by the partial relief of inhibition by strong depolarization and by the application of N-ethylmaleimide or GTP-gamma-S. Inhibition of barium current by opioids had their greatest effect in large neurons, that is, in presumed interneurons. In contrast, opioid inhibition in neurons with diameter < or = 15 microm was 11+/-2% (n = 26) for methionine-enkephalin and 11+/-4% (n = 17) for DAMGO, both measured at saturating agonist concentrations. Adenosine inhibition in neurons with diameter < or = 15 microm was 22+/-5% (n = 9). These results implicate the interneurons as a locus for the modulation of the excitability of projection neurons in the NAc during the processes of addiction and withdrawal.

Dataset Information

Effect of ?FosB overexpression on opioid and cannabinoid receptor-mediated signaling in the nucleus accumbens.

Publications

Effect of ΔFosB overexpression on opioid and cannabinoid receptor-mediated signaling in the nucleus accumbens.

Similar Datasets

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