title: GET73 increases rat extracellular hippocampal CA1 GABA levels through a possible involvement of local mGlu5 receptor.
abstract: 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.
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Beggiato
authors.forename: William Thomas
authors.initials: WT
authors.lastname: O'Connor
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Tomasini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Antonelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Loche
authors.forename: Sergio
authors.initials: S
authors.lastname: Tanganelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Cacciaglia
authors.forename: Luca
authors.initials: L
authors.lastname: Ferraro
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D058805:GABA Uptake Inhibitors / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000813:Anilides; D014151:Anti-Anxiety Agents; D058805:GABA Uptake Inhibitors; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; C522244:N-(4-trifluoromethylbenzyl)-4-methoxybutanamide; D064529:Receptor, Metabotropic Glutamate 5; D005680:gamma-Aminobutyric Acid
keywords: GABA receptors; GABA uptake; microdialysis; negative allosteric modulator; positive allosteric modulator