Inhibition of CaMKII in the nucleus accumbens shell decreases enhanced amphetamine intake in sensitized rats.
Microinjection of the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 into the nucleus accumbens (NAcc) shell impairs expression of the sensitized locomotion and NAcc dopamine (DA) overflow normally observed in psychostimulant-exposed rats. Based on these results, we investigated the effect of NAcc shell KN-93 on the enhanced amphetamine (AMPH) intake normally observed in AMPH- relative to saline-exposed rats. Rats were administered five injections of either AMPH (1.5mg/kg, i.p.) or saline, one injection every 2-3 days. Fourteen days following the last injection, they were trained to self-administer AMPH (200 microg/kg/infusion, i.v.) first on fixed ratio schedules (FR) and then on a progressive ratio schedule of reinforcement (PR). As expected, AMPH-exposed rats worked harder and obtained significantly more drug infusions than saline-exposed rats on the PR schedule. After 4 days of stable responding, all rats were bilaterally microinjected with KN-93 (1 or 10 nmol/0.5 microl/side) into the NAcc shell, 2 min prior to the beginning of the self-administration session. Inhibiting CaMKII in this site reduced the enhanced drug intake observed in AMPH-exposed rats to levels no longer significantly different from those of saline-exposed rats. Responding in these latter controls was not affected by KN-93 nor did KN-93 affect responding in AMPH-exposed rats when it was infused into the NAcc core. Thus, in a manner similar to what has been reported for sensitized locomotion and NAcc DA overflow, these results suggest that inhibiting CaMKII in the NAcc shell attenuates the enhanced motivation to obtain a drug reinforcer that is normally displayed in AMPH-exposed rats.
Loweth
Jessica A
JA
Committee on Neurobiology, The University of Chicago, Chicago, IL 60637, United States. jloweth@uchicago.edu
Baker
Lorinda K
LK
Guptaa
Tarra
T
Guillory
Anitra M
AM
Vezina
Paul
P
D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant; D008297:Male; D008845:Microinjections; D009714:Nucleus Accumbens / Q000201:enzymology*; D051381:Rats; D020318:Rats, Long-Evans; D012055:Reinforcement Schedule; D012646:Self Administration; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000661:Amphetamine; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000697:Central Nervous System Stimulants; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides