CaMKII Activity in the Ventral Tegmental Area Gates Cocaine-Induced Synaptic Plasticity in the Nucleus Accumbens.

1] Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA [2] Department of Physiology, Shanxi Medical University, Taiyuan, China.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.83). 10/2013; DOI: 10.1038/npp.2013.299
Source: PubMed

ABSTRACT Addictive drugs such as cocaine induce synaptic plasticity in discrete regions of the reward circuit. The goal of the present study is to investigate whether cocaine-evoked synaptic plasticity in the ventral tegmental area (VTA) and nucleus accumbens (NAc) is causally linked. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of long-term synaptic plasticity, learning and drug addiction. We examined whether blocking CaMKII activity in the VTA affected cocaine conditioned place preference (CPP) and cocaine-evoked synaptic plasticity in its target brain region, the NAc. TatCN21 is a CaMKII inhibitory peptide that blocks both stimulated and autonomous CaMKII activity with high selectivity. We report that intra-VTA microinjections of tatCN21 prior to cocaine conditioning blocked the acquisition of cocaine CPP, whereas intra-VTA microinjections of tatCN21 prior to saline conditioning did not significantly affect cocaine CPP, suggesting that the CaMKII inhibitor blocks cocaine CPP through selective disruption of cocaine-cue associated learning. Intra-VTA tatCN21 prior to cocaine conditioning blocked cocaine-evoked depression of excitatory synaptic transmission in the shell of the NAc slices ex vivo. In contrast, intra-VTA microinjection of tatCN21 just prior to the CPP test did not affect the expression of cocaine CPP and cocaine-induced synaptic plasticity in the NAc shell. These results suggest that CaMKII activity in the VTA governs cocaine-evoked synaptic plasticity in the NAc during the time window of cocaine conditioning.Neuropsychopharmacology accepted article preview online, 24 October 2013; doi:10.1038/npp.2013.299.

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