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

Abstract

Addictive drugs such as cocaine induce synaptic plasticity in discrete regions of the reward circuit. The aim 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 þ /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 cocaineevoked 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 before cocaine conditioning blocked the acquisition of cocaine CPP, whereas intra-VTA microinjections of tatCN21 before 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 before 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 before 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.

Autophosphorylation of alpha isoform of calcium/calmodulin‐dependent kinase II regulates alcohol addiction‐related behaviors

“…Previously, it was shown that inhibition of CaMKII activity in the hippocampus with KN93 abolishes the acquisition of morphine‐induced place preference (Fan et al , 1999), while a blockade of αCaMKII activity in the ventral tegmental area with the inhibitory peptide Tat‐CN1 impairs cocaine place preference (Liu et al ). Furthermore, αCaMKII autophosphorylation‐deficient mutant mice are impaired in cocaine‐induced place preference (Easton et al ), but surprisingly, the same line of mice was shown to develop alcohol‐induced place preference faster than WT mice (Easton et al ).…”

Calmodulin kinases: essential regulators in health and disease

“…Reduced CREB phosphorylation and c-Fos expression, impaired hippocampal L-LTP and long-term spatial memory Saneyoshi et al, (2008) shell and drug-related behavior was also suggested, as pharmacological inhibition of CaMKII activity in the NAc shell decreased the drug-related behaviors (Loweth et al 2008;Liu et al 2014), while virus-mediated over-expression of CaMKIIa in the NAc shell enhanced them (Loweth et al 2010). Importantly, experimental transient CaMKII inhibition in the NAc shell by herpes-virus mediated expression of dominant-negative CaMKIIa reversed drug-related behaviors, indicating CaMKII and its downstream pathways are potential therapeutic targets for the treatment of addiction (Loweth et al 2013).…”

“…; Liu et al . ), while virus‐mediated over‐expression of CaMKIIα in the NAc shell enhanced them (Loweth et al . ).…”

Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine‐induced addictive behavior

“…It is also essential to clarify the causal relationship between neuroplasticity and behavioral changes. Nevertheless, a limited number of studies have addressed this issue previously (Moussawi et al ., ; Gipson et al ., ; Kreple et al ., ; Liu et al ., ; Pascoli et al ., ).…”