title: 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+)/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 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.
authors.affiliation: 1] Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA [2] Department of Physiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Brianna
authors.initials: B
authors.lastname: Wilkinson
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan, China.
authors.forename: Jinshun
authors.initials: J
authors.lastname: Qi
authors.affiliation: 1] Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA [2] Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Olsen
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: K Ulrich
authors.initials: KU
authors.lastname: Bayer
authors.affiliation: 1] Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA [2] Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Qing-song
authors.initials: QS
authors.lastname: Liu
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000201:enzymology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003042:Cocaine