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

Authors

  • Sarah Beggiato,

    1. Department of Medical Sciences, University of Ferrara, Italy
    2. IRET Foundation, Ozzano Emilia, Bologna
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  • William Thomas O'Connor,

    1. Graduate Entry Medical School and Materials and Surface Science Institute, University of Limerick, Limerick, Ireland
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  • Maria Cristina Tomasini,

    1. IRET Foundation, Ozzano Emilia, Bologna
    2. Department of Life Sciences and Biotechnology, University of Ferrara, Italy
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  • Tiziana Antonelli,

    1. Department of Medical Sciences, University of Ferrara, Italy
    2. IRET Foundation, Ozzano Emilia, Bologna
    3. Laboratory for the Technology of Advanced Therapies (LTTA Centre), University of Ferrara, Italy
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  • Antonella Loche,

    1. Laboratorio Farmaceutico CT, Sanremo, Italy
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  • Sergio Tanganelli,

    1. Department of Medical Sciences, University of Ferrara, Italy
    2. IRET Foundation, Ozzano Emilia, Bologna
    3. Laboratory for the Technology of Advanced Therapies (LTTA Centre), University of Ferrara, Italy
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  • Roberto Cacciaglia,

    1. Laboratorio Farmaceutico CT, Sanremo, Italy
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  • Luca Ferraro

    Corresponding author
    1. IRET Foundation, Ozzano Emilia, Bologna
    2. Department of Life Sciences and Biotechnology, University of Ferrara, Italy
    3. Laboratory for the Technology of Advanced Therapies (LTTA Centre), University of Ferrara, Italy
    • Department of Medical Sciences, University of Ferrara, Italy
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  • Antonella Loche and Roberto Cacciaglia are employees of Laboratorio Farmaceutico CT, Sanremo, Italy. The other authors declare no conflicts of interest.

Correspondence to: Luca Ferraro, Department of Life Sciences and Biotechnology, c/o Pharmacology, University of Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy. E-mail: frl@unife.it

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. Synapse 67:678–691, 2013. © 2013 Wiley Periodicals, Inc.

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