Roles of hippocampal N-methyl-D-aspartate receptors and calcium/calmodulin-dependent protein kinase II in amphetamine-produced conditioned place preference in rats

Behav Pharmacol. 2007 Sep;18(5-6):497-506. doi: 10.1097/FBP.0b013e3282ee7b62.


This study investigates the roles of hippocampal N-methyl-D-aspartate (NMDA) glutamate receptors and CaMKII (calcium/calmodulin-dependent protein kinase II) in amphetamine-produced conditioned place preference (AMPH-CPP) in rats. An earlier report showed that AMPH-CPP resulted in the enhancement of hippocampal CaMKII activity. In this study, AMPH-CPP significantly increased hippocampal GluR1 receptors, though AMPH-CPP was impaired by either blockade of NMDA receptors (AP5) or inhibition of CaMKII (KN-93) during conditioning. These treatments also impaired CPP if administered before testing, but CPP recovered during the next testing session. Therefore, these treatments had no effect on the extinction of CPP. If the conditioned rats were, however, reexposed to AMPH-CPP after a hippocampal-infusion of AP5 or KN-93, the extinction of the original CPP was greater than that seen in the controls. The hippocampal-infusion of D-cycloserine before CPP testing enhanced the extinction of CPP. These results, taken together, indicate that NMDA receptor activation and CaMKII activity are essential for the AMPH-CPP. AMPH-CPP reexposure is similar to the memory reconsolidation process, being disrupted by either a blockade of the NMDA receptor or an inhibition of CaMKII. Furthermore, the extinction of CPP resembles new learning, which is an active process and is facilitated by a partial NMDA agonist.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Amphetamine / pharmacology*
  • Animals
  • Behavior, Animal / drug effects
  • Benzylamines / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / drug effects*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Central Nervous System Stimulants / pharmacology*
  • Conditioning, Operant / drug effects*
  • Cycloserine / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Immunoblotting
  • Male
  • Motor Activity / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Sulfonamides / pharmacology


  • Benzylamines
  • Central Nervous System Stimulants
  • Excitatory Amino Acid Agonists
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Sulfonamides
  • KN 93
  • 2-Amino-5-phosphonovalerate
  • Cycloserine
  • Amphetamine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • glutamate receptor ionotropic, AMPA 1