Repeated administration of AMPA or a metabotropic glutamate receptor agonist into the rat ventral tegmental area augments the subsequent behavioral hyperactivity induced by cocaine

Psychopharmacology (Berl). 2005 Apr;179(1):172-80. doi: 10.1007/s00213-004-2054-9. Epub 2004 Dec 4.


Rationale: Glutamate receptors and their related second messengers in the ventral tegmental area (VTA) are known to play critical roles in the initiation of behavioral sensitization to cocaine.

Objectives: To evaluate the hypothesis that repeated intra-VTA microinjections of the ionotropic glutamate agonist, AMPA, or the metabotropic glutamate agonist, t-ACPD, augment the behavioral hyperactivity induced by a subsequent challenge injection of cocaine. In addition, the dependency of the t-ACPD effect on activation of the calcium/calmodulin-dependent kinases (CaM-Ks) was assessed.

Methods: Male Sprague-Dawley rats received four once-daily microinjections of saline, AMPA, t-ACPD, or t-ACPD plus the CaM-KII inhibitor KN-93 directly into the VTA; locomotor activity was measured for 120 min after each of the daily treatments. One week after the 4 treatment days, all animals received a challenge injection of cocaine (15 mg/kg, IP) and behavioral activity was monitored for 120 min.

Results: Intra-VTA administration of t-ACPD increased behavioral activity only on the first 2 treatment days, an effect that was blocked by pre-treatment with KN-93. Administration of AMPA into the VTA, in contrast, produced behavioral hyperactivity that sensitized over the 4 treatment days. Following the cocaine challenge injection, there was an augmentation of cocaine-induced behavioral hyperactivity in the groups pretreated with AMPA or t-ACPD but not in the animals administered t-ACPD plus KN-93.

Conclusions: These results indicate that repeated stimulation of AMPA or metabotropic glutamate receptors in the VTA mimics the initiation of behavioral sensitization to cocaine. The present findings also suggest that glutamate agonist-induced activation of CaM-KII in the VTA plays a critical role in the behavioral and neuronal plasticity induced by repeated cocaine injections.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Benzylamines / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology
  • Cocaine / pharmacology*
  • Dioxolanes / pharmacology
  • Drug Synergism
  • Excitatory Amino Acid Agonists / pharmacology*
  • Male
  • Microinjections
  • Purines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / agonists*
  • Sulfonamides / pharmacology
  • Ventral Tegmental Area / drug effects*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology*


  • Benzylamines
  • Dioxolanes
  • Excitatory Amino Acid Agonists
  • Purines
  • Receptors, Metabotropic Glutamate
  • Sulfonamides
  • KN 93
  • 4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolane-2-methanol
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cocaine