Attenuation of ethanol abstinence-induced anxiety- and depressive-like behavior by the phosphodiesterase-4 inhibitor rolipram in rodents

• Published in: Psychopharmacology Vol. 234; no. 20; pp. 3143 - 3151
• Main Authors: Gong, Mei-Fang, Wen, Rui-Ting, Xu, Ying, Pan, Jian-Chun, Fei, Ning, Zhou, Yan-Meng, Xu, Jiang-Ping, Liang, Jian-Hui, Zhang, Han-Ting
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2017; Springer; Springer Nature B.V
• Subjects: Abstinence; Alcohol; Alcohol Abstinence - psychology; Alcohol Drinking - drug therapy; Alcohol Drinking - psychology; Alcoholism; Alcohols; Animal models; Animals; Anti-Anxiety Agents - pharmacology; Anti-Anxiety Agents - therapeutic use; Antidepressants; Antidepressive Agents - pharmacology; Anxiety; Anxiety - chemically induced; Anxiety - drug therapy; Anxiety - psychology; Anxiolytics; Biomedical and Life Sciences; Biomedicine; Depression - chemically induced; Depression - drug therapy; Depression - psychology; Dosage and administration; Dose-Response Relationship, Drug; Drinking behavior; Drug abuse; Drug dependence; Drug interactions; Ethanol; Ethanol - administration & dosage; Ethanol - toxicity; Male; Mental depression; Mice; Mice, Inbred C57BL; Neurosciences; Observations; Open-field behavior; Original Investigation; Pharmacology/Toxicology; Phosphodiesterase; Phosphodiesterase 4 Inhibitors - pharmacology; Phosphodiesterase 4 Inhibitors - therapeutic use; Psychiatry; Psychopharmacology; Random Allocation; Rats; Rodentia; Rodents; Rolipram; Rolipram - pharmacology; Rolipram - therapeutic use; Substance Withdrawal Syndrome - drug therapy; Substance Withdrawal Syndrome - psychology; Ethanol abstinence; Rolipram; Rodents; Phosphodiesterase-4 (PDE4); Depression; Anxiety; Behavior; Mei-Fang Gong, Rui-Ting Wen, and Ying Xu contributed equally to this work
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-017-4697-3

Rationale Withdrawal symptoms stand as a core feature of alcohol dependence. Our previous results have shown that inhibition of phosphodiesterase-4 (PDE4) decreased ethanol seeking and drinking in alcohol-preferring rodents. However, little is known about whether PDE4 is involved in ethanol abstinence-related behavior. Objective The objective of this study was to characterize the role of PDE4 in the development of anxiety- and depressive-like behavior induced by abstinence from ethanol exposure in different animal models. Methods Using three rodent models of ethanol abstinence, we examined the effects of rolipram, a prototypical, selective PDE4 inhibitor, on (1) anxiety-like behavior induced by repeated ethanol abstinence in the elevated plus maze test in fawn-hooded (FH/Wjd) rats, (2) anxiety-like behavior in the open-field test and light-dark transition test following acute ethanol abstinence in C57BL/6J mice, and (3) anxiety- and depressive-like behavior induced by protracted ethanol abstinence in the elevated plus maze, forced-swim, and tail-suspension tests in C57BL/6J mice. Results Pretreatment with rolipram (0.1 or 0.2 mg/kg) significantly increased entries and time spent in the open arms of the elevated plus maze test in rats with repeated ethanol abstinence. Similarly, in mice with acute ethanol abstinence, administration of rolipram (0.25 or 0.5 mg/kg) dose-dependently increased the crossings in the central zone of the open-field test and duration and transitions on the light side of the light-dark transition test, suggesting anxiolytic-like effects of rolipram. Consistent with these, chronic treatment with rolipram (0.1, 0.3, or 1.0 mg/kg) increased entries in the open arms of the elevated plus maze test; it also reduced the increased duration of immobility in both the forced-swim and tail-suspension tests in mice after protracted ethanol abstinence, suggesting antidepressant-like effects of rolipram. Conclusions These results provide the first demonstration for that PDE4 plays a role in modulating the development of negative emotional reactions associated with ethanol abstinence, including anxiety and depression. PDE4 inhibitors may be a novel class of drugs for treatment of alcoholism.