Persistent reversal of enhanced amphetamine intake by transient CaMKII inhibition.
Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) α expression in the nucleus accumbens (NAcc) shell and this persistently increases local GluA1 S831 phosphorylation and enhances behavioral responding to the drug. Here we assessed whether transiently interfering with CaMKII signaling using a dominant-negative CaMKIIα mutant delivered to the NAcc shell with herpes simplex viral vectors could reverse these long-lasting biochemical and behavioral effects observed following exposure to amphetamine. As expected, transient expression of CaMKIIα K42M in the NAcc shell produced a corresponding transient increase in CaMKIIα and decrease in pCaMKIIα (T286) protein levels in this site. Remarkably, this transient inhibition of CaMKII activity produced a long-lasting reversal of the increased GluA1 S831 phosphorylation levels in NAcc shell and persistently blocked the enhanced locomotor response to and self-administration of amphetamine normally observed in rats previously exposed to the drug. Together, these results indicate that even transient interference with CaMKII signaling may confer long-lasting benefits in drug-sensitized individuals and point to CaMKII and its downstream pathways as attractive therapeutic targets for the treatment of stimulant addiction.
Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, Illinois 60637, USA.
Jessica A
JA
Loweth
Dongdong
D
Li
James J
JJ
Cortright
Georgia
G
Wilke
Okunola
O
Jeyifous
Rachael L
RL
Neve
K Ulrich
KU
Bayer
Paul
P
Vezina
D000661:Amphetamine / Q000494:pharmacology; D019969:Amphetamine-Related Disorders / Q000378:metabolism*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000697:Central Nervous System Stimulants; D000661:Amphetamine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2