Microinjection of baclofen and CGP7930 into the ventral tegmental area suppresses alcohol self-administration in alcohol-preferring rats

Paola Maccioni; Irene Lorrai; Andrea Contini; Kimberly Leite-Morris; Giancarlo Colombo

doi:10.1016/j.neuropharm.2017.10.012

Microinjection of baclofen and CGP7930 into the ventral tegmental area suppresses alcohol self-administration in alcohol-preferring rats

Neuropharmacology. 2018 Jul 1;136(Pt A):146-158. doi: 10.1016/j.neuropharm.2017.10.012. Epub 2017 Oct 16.

Authors

Paola Maccioni¹, Irene Lorrai¹, Andrea Contini², Kimberly Leite-Morris³, Giancarlo Colombo⁴

Affiliations

¹ Neuroscience Institute, Section of Cagliari, National Research Council of Italy, Monserrato, CA I-09042, Italy.
² Department of Biomedical Sciences, University of Sassari, Sassari, SS I-07100, Italy.
³ Departments of Psychiatry, Pharmacology and Experimental Therapeutics, Boston University School of Medicine, VA Boston Healthcare System, Research Service, Boston, MA 02130, USA.
⁴ Neuroscience Institute, Section of Cagliari, National Research Council of Italy, Monserrato, CA I-09042, Italy. Electronic address: colomb@unica.it.

PMID: 29050951
DOI: 10.1016/j.neuropharm.2017.10.012

Abstract

Systemic administration of the orthosteric agonist, baclofen, and several positive allosteric modulators (PAMs) of the GABA_B receptor has repeatedly been reported to decrease operant oral alcohol self-administration in rats. The aim of the present study was to evaluate the contribution of the mesolimbic dopamine system to the reducing effect of baclofen and GABA_B PAMs on the reinforcing properties of alcohol. To this end, baclofen or the GABA_B PAM CGP7930 were microinjected into the ventral tegmental area (VTA) of selectively bred, Sardinian alcohol-preferring (sP) rats trained to self-administer alcohol. Baclofen (0, 0.03, 0.1, and 0.3 μg) or CGP7930 (0, 5, 10, and 20 μg) were microinjected via indwelling unilateral guide cannula aiming at the left hemisphere of the VTA. Treatment with baclofen resulted in a dose-related suppression of the number of lever-responses for alcohol and the amount of self-administered alcohol. No dose of baclofen altered rat motor-performance, evaluated by the inverted screen test immediately before the self-administration session. Treatment with CGP7930 halved the number of lever-responses for alcohol and amount of self-administered alcohol, with no effect on rat motor-performance. Site-specificity was investigated testing the effect of microinjection of baclofen and CGP7930 into the left hemisphere of deep mesencephalic nucleus: compared to vehicle, neither 0.3 μg baclofen nor 20 μg CGP7930 altered lever-responding for alcohol and amount of self-administered alcohol. Collectively, the results of the present study suggest the involvement of GABA_B receptors located in the VTA in the mediation of alcohol reinforcing properties in sP rats. This article is part of the "Special Issue Dedicated to Norman G. Bowery".

Keywords: Alcohol self-administration; Baclofen; GABA(B) receptor; Positive allosteric modulator, CGP7930; Rat; Ventral tegmental area.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alcohol Drinking / drug therapy*
Alcohol Drinking / metabolism
Animals
Baclofen / administration & dosage*
Central Nervous System Depressants / administration & dosage
Dose-Response Relationship, Drug
Ethanol / administration & dosage
GABA-B Receptor Agonists / administration & dosage*
Genetic Predisposition to Disease
Male
Microinjections
Motor Activity / drug effects
Motor Activity / physiology
Phenols / administration & dosage*
Rats
Self Administration
Ventral Tegmental Area / drug effects*
Ventral Tegmental Area / metabolism

Substances

2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol
Central Nervous System Depressants
GABA-B Receptor Agonists
Phenols
Ethanol
Baclofen