Transient overexpression of alpha-Ca2+/calmodulin-dependent protein kinase II in the nucleus accumbens shell enhances behavioral responding to amphetamine.
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is known to contribute to the expression of psychostimulant sensitization by regulating dopamine (DA) overflow from DA neuron terminals in the nucleus accumbens (NAcc). The present experiments explored the contribution of CaMKII in NAcc neurons postsynaptic to these terminals where it is known to participate in a number of signaling pathways that regulate responding to psychostimulant drugs. Exposure to amphetamine transiently increased alphaCaMKII levels in the shell but not the core of the NAcc. Thus, HSV (herpes simplex viral) vectors were used to transiently overexpress alphaCaMKII in NAcc neurons in drug-naive rats, and behavioral responding to amphetamine was assessed. Transiently overexpressing alphaCaMKII in the NAcc shell led to long-lasting enhancement of amphetamine-induced locomotion and self-administration manifested when alphaCaMKII levels were elevated and persisting long after they had returned to baseline. Enhanced locomotion was not observed after infection in the NAcc core or sites adjacent to the NAcc. Transient elevation of NAcc shell alphaCaMKII levels also enhanced locomotor responding to NAcc AMPA and increased phosphorylation levels of GluR1 (Ser831), a CaMKII site, both soon and long after infection. Similar increases in pGluR1 (Ser831) were observed both soon and long after exposure to amphetamine. These results indicate that the transient increase in alphaCaMKII observed in neurons of the NAcc shell after viral-mediated gene transfer and likely exposure to amphetamine leads to neuroadaptations in AMPA receptor signaling in this site that may contribute to the long-lasting maintenance of behavioral and incentive sensitization by psychostimulant drugs like amphetamine.
Loweth
Jessica A
JA
Committee on Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.
Singer
Bryan F
BF
Baker
Lorinda K
LK
Wilke
Georgia
G
Inamine
Hidetoshi
H
Bubula
Nancy
N
Alexander
John K
JK
Carlezon
William A
WA
Neve
Rachael L
RL
Vezina
Paul
P
D000662:Amphetamines / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects*; D050882:CREB-Binding Protein / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D012646:Self Administration / Q000379:methods; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000235:genetics; D013997:Time Factors
D000662:Amphetamines; D001224:Aspartic Acid; D050882:CREB-Binding Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000697:Central Nervous System Stimulants; D018091:Receptors, AMPA; D012694:Serine; D013912:Threonine