Role of ventral hippocampal GABA(A) and NMDA receptors in the anxiolytic effect of carbamazepine in rats using the elevated plus maze test

Pharmacology. 2009;84(6):356-66. doi: 10.1159/000256666. Epub 2009 Nov 11.


Background: The successful use of antiepileptic drugs to treat a wide range of nonepileptic disorders led us to evaluate the potential efficacy of carbamazepine (CBZ) in anxiety disorders. Anxiety may be related to the imbalance between gamma-aminobutyric acid (GABA) and glutamate neurotransmitters, systems that are also involved in the CBZ effects. We investigated the role of these systems in the ventral hippocampus (VH) and their interactions with the CBZ effect on anxiety-like behavior in rats using the elevated plus maze.

Methods: Animals received GABAergic and NMDA agents in a volume of 1 microl/rat, which was injected into the VH (0.5 microl for each side) 60 min after receiving systemic administration of CBZ. The test sessions took place 10 min later.

Results: The systemic administration of CBZ increased the percentage of open arm time (%OAT) at the dose of 40 mg/kg, which is representative of an anxiolytic response. Intra-VH injection of the GABA(A) receptor agonist muscimol (0.25-1 microg/rat) in the absence or presence of an ineffective dose of CBZ (30 mg/kg) did not show any significant changes in the parameters of anxiety-like behavior. The administration of GABA(A) receptor antagonist bicuculline by itself decreased %OAT at a dose of 1 microg/rat, indicating possible anxiogenic effect. The antagonist (0.75 and 1 microg/rat) also decreased CBZ response. A microinjection of NMDA (0.125 and 0.25 microg/rat) decreased %OAT, which was reversed by the administration of CBZ (40 mg/kg). This indicates interaction between the two drugs. However, the NMDA receptor antagonist DAP-5 (1 microg/rat) significantly increased %OAT, but combined with the lower dose of CBZ (30 mg/kg), it did not trigger any response on anxiety-like parameters.

Conclusion: Both GABAergic and NMDA systems in the VH play a role in modulation of anxiety-like behavior of rats. The anxiolytic-like effects of CBZ seem to be mediated, at least in part, through an interaction with GABA(A) and NMDA systems in the VH.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Anti-Anxiety Agents / therapeutic use
  • Anxiety / drug therapy*
  • Anxiety / metabolism
  • Anxiety / physiopathology
  • Carbamazepine / pharmacology*
  • Carbamazepine / therapeutic use
  • Disease Models, Animal
  • GABA Agonists / pharmacology
  • GABA Antagonists / pharmacology
  • GABA-A Receptor Agonists
  • GABA-A Receptor Antagonists
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Male
  • Maze Learning / drug effects*
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / physiology*
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / physiology*


  • Anti-Anxiety Agents
  • GABA Agonists
  • GABA Antagonists
  • GABA-A Receptor Agonists
  • GABA-A Receptor Antagonists
  • Receptors, GABA-A
  • Receptors, N-Methyl-D-Aspartate
  • Carbamazepine