Inhibitory modulation of CART peptides in accumbal neuron through decreasing interaction of CaMKIIα with dopamine D3 receptors.

Abstract

Previous studies in rats have shown that microinjections of cocaine- and amphetamine-regulated transcript (CART) peptide into the nucleus accumbens (NAc; the area of the brain that mediates drug reward and reinforcement) attenuate the locomotor effects of psychostimulants. CART peptide has also been shown to induce decreased intracellular concentrations of calcium (Ca(2+)) in primary cultures of hippocampus neurons. The purpose of this study was to characterize the interaction of Ca(2+)/calmodulin-dependent kinases (CaMKIIα) with dopamine D3 (D3) receptors (R) in primary cultures of accumbal neurons. This interaction is involved in inhibitory modulation of CART peptides. In vitro, CART (55-102) peptide (0.1, 0.5 or 1μM) was found to dose-dependently inhibit K(+) depolarization-elicited Ca(2+) influx and CaMKIIα phosphorylation in accumbal neurons. Moreover, CART peptides were also found to block cocaine (1μM)-induced Ca(2+) influx, CaMKIIα phosphorylation, CaMKIIα-D3R interaction, and CREB phosphorylation. In vivo, repeated microinjections of CART (55-102) peptide (2μg/1μl/side) into the NAc over a 5-day period had no effect on behavioral activity but blocked cocaine-induced locomotor activity. These results indicate that D3R function in accumbal neurons is a target of CART (55-102) peptide and suggest that CART peptide by dephosphorylating limbic D3Rs may have potential as a treatment for cocaine abuse.

• Authors: Zhenyu Cai, Dalei Zhang, Ying Ying, Min Yan, Jianhua Yang, Fangyun Xu, Kiwan Oh, Zhenzhen Hu
• Journal: Brain research (Brain Res) Vol. 1557 Pg. 101-10 (Apr 04 2014) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 24560901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Calcium-Binding Proteins
• Camk2n1 protein, rat
• Carrier Proteins
• Cyclic AMP Response Element-Binding Protein
• Dopamine Uptake Inhibitors
• Nerve Tissue Proteins
• Peptide Fragments
• Receptors, Dopamine D3
• cocaine- and amphetamine-regulated transcript protein (55-102)
• Cocaine
• Potassium
• Calcium

Topics

• Akathisia, Drug-Induced (metabolism)
• Animals
• Calcium (metabolism)
• Calcium-Binding Proteins
• Carrier Proteins (metabolism)
• Cells, Cultured
• Cocaine (pharmacology)
• Cocaine-Related Disorders (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Dopamine Uptake Inhibitors (pharmacology)
• Male
• Membrane Potentials (drug effects, physiology)
• Nerve Tissue Proteins (metabolism)
• Neurons (drug effects, physiology)
• Nucleus Accumbens (drug effects, physiology)
• Peptide Fragments (metabolism)
• Phosphorylation
• Potassium (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Dopamine D3 (metabolism)