title: Investigation of allyphenyline efficacy in the treatment of alcohol withdrawal symptoms.
abstract: We have recently demonstrated that allyphenyline, behaving as α2C-adrenoceptor/serotonin 5-HT1A receptor agonist and α2A-adrenoceptor antagonist, in mice enhanced morphine analgesia, attenuated morphine withdrawal symptoms, showed significant antidepressant-like activity and was devoid of sedative side effects. Opioid and alcohol withdrawal shares several common neurobiological and molecular mechanisms. Therefore, in this study we expanded our analysis of the pharmacological properties of allyphenyline by investigating its ability to prevent the expression of somatic withdrawal signs, anxiety-like behavior and hyperlocomotion associated with chronic ethanol intoxication. Rats were subjected to induction of ethanol dependence via repeated daily intragastric ethanol (20%) administration for 4 consecutive days. Twelve hours after the last alcohol administration, somatic alcohol withdrawal signs were scored. Results revealed a significant expression of physical withdrawal signs that were not affected by intraperitoneal (i.p.) administration of allyphenyline at the doses of 0.05, 0.275 and 0.5 mg/kg. In contrast, allyphenyline (0.05 and 0.275 mg/kg i.p.) significantly reduced hyperanxiety-like behavior observed 6 days after alcohol intoxication as measured using the defensive burying test. Allyphenyline also reduced open field hyperlocomotor activity associated with alcohol withdrawal. Notably, the anxiolytic effect of the compound, as well as the already reported antidepressant action, was observed at very low doses, suggesting the involvement of its α2C-adrenoceptor/serotonin 5-HT1A receptor agonism. Therefore, the present investigation suggests that allyphenyline might represent an interesting pharmacological tool to investigate the potential of compounds exhibiting α2C-adrenoceptor/serotonin 5-HT1A receptor agonism and α2A-adrenoceptor antagonism in the treatment of hyperanxiety and hyperlocomotion occurring during alcohol withdrawal in dependent subjects.
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 62032 Camerino, Italy. Electronic address: massimo.ubaldi@unicam.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ubaldi
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy. Electronic address: fabio.delbello@unicam.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 62032 Camerino, Italy.
authors.forename: Esi
authors.initials: E
authors.lastname: Domi
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 62032 Camerino, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Nasuti
mesh_terms: D000437:Alcoholism / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D000498:Allyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000473:pathology / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D048288:Imidazolines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D016896:Treatment Outcome
chemical_list: C554422:2-(1-(2-allylphenoxy)ethyl)-4,5-dihydro-1H-imidazole; D000498:Allyl Compounds; D048288:Imidazolines; D000431:Ethanol
keywords: Alcohol withdrawal; Allyphenyline; Allyphenyline (PubChem CID 24906198); Anxiety; Ethanol intoxication; Serotonin 5-HT(1A) receptor; α(2)-Adrenoceptor