Transient viral-mediated overexpression of alpha-calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell leads to long-lasting functional upregulation of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors: dopamine type-1 receptor and protein kinase A dependence

Eur J Neurosci. 2010 Apr;31(7):1243-51. doi: 10.1111/j.1460-9568.2010.07155.x. Epub 2010 Mar 19.

Abstract

Calcium/calmodulin-dependent protein kinase II (CaMKII) activity is necessary for the long-lasting expression of locomotor sensitization and enhanced drug-taking observed in rats previously exposed to psychostimulants. Exposure to these drugs also transiently increases alphaCaMKII levels in the nucleus accumbens (NAcc), an effect that, when mimicked by transient viral-mediated overexpression of alphaCaMKII in NAcc shell neurons, leads to long-lasting enhancement in locomotor responding to amphetamine and NAcc alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA). The present experiments characterized the dopamine (DA) dependence of the functional AMPA receptor upregulation observed long after transient overexpression of alphaCaMKII. Rats infected with herpes simplex virus-alphaCaMKII in the NAcc shell showed a transient increase in alphaCaMKII levels that peaked at 4 days post-infection and returned to baseline 8 days later. When challenged with AMPA (0.8 nmol/side) in the NAcc shell at 20 days post-infection, these rats showed enhanced locomotion compared with controls. This sensitized locomotor response was blocked when AMPA was coinfused with either the DA type-1 receptor antagonist SCH23390 (0.8 nmol/side) or the protein kinase A inhibitor Rp-cAMPS (80 nmol/side). Neither SCH23390 nor Rp-cAMPS produced locomotor effects when infused by itself into the NAcc shell. Furthermore, these antagonists did not block the acute non-sensitized locomotor response to AMPA observed in control rats. These findings show that transient viral-mediated overexpression of alphaCaMKII in neurons of the NAcc shell leads to long-lasting functional upregulation of AMPA receptors that is DA type-1 receptor and protein kinase A dependent. Thus, transient increases in levels of alphaCaMKII in the NAcc shell produce long-lasting changes in the way that DA and glutamate interact in this site to generate locomotor behavior.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzazepines / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Gene Transfer Techniques
  • Microinjections / methods
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism*
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / metabolism*
  • Simplexvirus / physiology
  • Thionucleotides / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology

Substances

  • Benzazepines
  • Protein Kinase Inhibitors
  • Receptors, AMPA
  • Receptors, Dopamine D1
  • SCH 23390
  • Thionucleotides
  • adenosine-3',5'-cyclic phosphorothioate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2