Inhibition of CaMKII in the nucleus accumbens shell decreases enhanced amphetamine intake in sensitized rats

Neurosci Lett. 2008 Oct 24;444(2):157-60. doi: 10.1016/j.neulet.2008.08.004. Epub 2008 Aug 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amphetamine / administration & dosage
  • Amphetamine / pharmacology*
  • Animals
  • Benzylamines / administration & dosage
  • Benzylamines / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors*
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / pharmacology*
  • Conditioning, Operant
  • Male
  • Microinjections
  • Nucleus Accumbens / enzymology*
  • Rats
  • Rats, Long-Evans
  • Reinforcement Schedule
  • Self Administration
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology

Substances

  • Benzylamines
  • Central Nervous System Stimulants
  • Sulfonamides
  • KN 93
  • Amphetamine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2