Baclofen but Not Diazepam Alleviates Alcohol-Seeking Behavior and Hypothalamic–Pituitary–Adrenal Axis Dysfunction in Stressed Withdrawn Mice
Front. Psychiatry. 2019-04-16; 10:
DOI: 10.3389/fpsyt.2019.00238
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Rabat Y(1), Henkous N(1), Corio M(1), Nogues X(2), Beracochea D(1).
Author information:
(1)Université de Bordeaux, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine (INCIA), CNRS UMR 5287, Pessac, France.
(2)Université de Bordeaux, Bordeaux, France.
This study compares the impact of repeated injections of baclofen (an agonist of
GABAB receptors) or diazepam (a benzodiazepine having an agonist action on GABAA
receptors) given during the alcohol-withdrawal period on the stress-induced
restoration of alcohol-seeking behavior and hypothalamic-pituitary-adrenal (HPA)
axis dysfunction after a long (4 weeks) abstinence. Thus, C57BL/6 mice were
submitted to a 6-month alcohol consumption [12% volume/volume (v/v)] and were
progressively withdrawn to water before testing. Diazepam (Valium®, Roche) and
baclofen (Baclofen®, Mylan) were administered intraperitoneally for 15
consecutive days (1 injection/day) during the withdrawal period at decreasing
doses ranging from 1.0 mg/kg (Day 15) to 0.25 mg/kg (Day 1) for diazepam and from
1.5 mg/kg (Day 15) to 0.37 mg/kg (Day 1) for baclofen. Alcohol-seeking behavior
was evaluated by alcohol-place preference in an odor recognition task. In the
stress condition, mice received three electric footshocks 45 min before
behavioral testing. Blood was sampled immediately after behavioral testing, and
plasma corticosterone concentrations were measured by commercial enzyme
immunoassay kits. Results showed that non-stressed withdrawn mice did not exhibit
alcohol-place preference or alteration of plasma corticosterone concentrations
relative to water controls. After stress, however, withdrawn mice exhibited a
significant alcohol-place preference and higher circulating corticosterone
concentrations as compared to stressed water controls. Interestingly, repeated
administration during the withdrawal phase of baclofen but not diazepam
suppressed both the alcohol-place preference and normalized corticosterone levels
in stressed withdrawn animals. In conclusion, this study evidences that a
pre-treatment with baclofen but not with diazepam during the withdrawal phase
normalized, even after a long period of abstinence, the HPA axis response to
stress, which contributes to the long-term preventing effects of this compound on
alcohol-seeking behavior.
DOI: 10.3389/fpsyt.2019.00238
PMCID: PMC6492502
PMID: 31105600