GET73 increases rat extracellular hippocampal CA1 GABA levels through a possible involvement of local mGlu5 receptor

Synapse. 2013 Oct;67(10):678-91. doi: 10.1002/syn.21672. Epub 2013 May 21.


N-[(4-trifluoromethyl) benzyl] 4-methoxybutyramide (GET73) is a newly synthesized compound displaying anti-alcohol and anxiolytic properties. In light of the importance of the hippocampal CA1 subregion in alcohol addiction and anxiety-like behaviors-this in vivo microdialysis study characterized the effect of GET73 on extracellular GABA levels in the hippocampal CA1 region of the freely moving rat-including a possible role for mGlu5 receptor in mediating this effect. Both intraperitoneal administration (2-10 mg/kg) and local intra-hippocampal CA1 perfusion with GET73 (50-1000 nM) were associated with a transient, step-wise increase in dialysate hippocampal CA1 GABA levels. The GET73 (10 mg/kg)-induced increase in GABA levels was not affected by intra-CA1 perfusion with either the GABA reuptake inhibitor SKF89976A (0.5 mM) or by local GABAA (bicuculline; 1μM) and GABAB (CGP35348; 500 μM) receptor antagonists. On the contrary, the GET73-induced increase in GABA levels was partially counteracted by the intra-CA1 perfusion with the mGlu5 receptor negative allosteric modulator MPEP (300 µM). Interestingly, GET73 at the lowest (2 mg/kg) dose tested, by itself ineffective, fully counteracted the increase in GABA levels induced by the mGlu5 receptor agonist CHPG (1000 µM). Taken together, these findings suggest that the GET73-induced increase in hippocampal CA1 GABA levels operates independently of local GABA reuptake and/or GABAA or GABAB receptors. Furthermore, the present data lead to hypothesize a possible interaction between GET73 and mGluR5-mediated regulation of hippocampal CA1 GABA transmission, an effect which may be relevant to the ability of GET73 to reduce alcohol intake in an alcohol-preferring rat strain.

Keywords: GABA receptors; GABA uptake; microdialysis; negative allosteric modulator; positive allosteric modulator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / administration & dosage
  • Anilides / pharmacology*
  • Animals
  • Anti-Anxiety Agents / administration & dosage
  • Anti-Anxiety Agents / pharmacology*
  • CA1 Region, Hippocampal / drug effects*
  • CA1 Region, Hippocampal / metabolism
  • Extracellular Space / metabolism*
  • GABA Uptake Inhibitors / pharmacology
  • GABA-A Receptor Antagonists / pharmacology
  • GABA-B Receptor Antagonists / pharmacology
  • Injections, Intraperitoneal
  • Injections, Intraventricular
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • gamma-Aminobutyric Acid / metabolism*


  • Anilides
  • Anti-Anxiety Agents
  • GABA Uptake Inhibitors
  • GABA-A Receptor Antagonists
  • GABA-B Receptor Antagonists
  • N-(4-trifluoromethylbenzyl)-4-methoxybutanamide
  • Receptor, Metabotropic Glutamate 5
  • gamma-Aminobutyric Acid