title: Paracetamol potentiates the antidepressant-like and anticompulsive-like effects of fluoxetine.
abstract: Recent studies suggest the possible involvement of serotonergic and endocannabinoid systems in analgesic, anxiolytic, and anticonvulsant-like actions of paracetamol. Considering the fact that these systems play intricate roles in affective disorders, we investigated the effects of paracetamol in depression-like and compulsion-like behavior. Swiss mice (20-22 g) were subjected to forced swim, tail suspension, or marble-burying tests after an injection of paracetamol either alone or in the presence of AM251 (a CB1 antagonist), fenclonine (pCPA: a 5-HT synthesis inhibitor), AM404 (anandamide uptake inhibitor) or fluoxetine. Paracetamol dose dependently (50-400 mg/kg) decreased depressive and compulsive behaviors. These effects were comparable to those of fluoxetine (5, 10, or 20 mg/kg) and AM404 (10 or 20 mg/kg). Interestingly, fenclonine pretreatment completely abolished the effects of a 50 mg/kg dose of paracetamol. However, similar effects were not observed in AM251-pretreated mice at the same dose. In contrast, AM251 completely antagonized the effects of the 400 mg/kg dose, which was otherwise partially blocked in fenclonine-treated mice. Similar sets of results were observed with fluoxetine and AM404. Thus, it appears that paracetamol-induced antidepressant-like and anticompulsive effects may, at least partially, involve both the serotonergic and the endocannabinoid system. In addition, coadministration of paracetamol and fluoxetine/AM404 at subeffective doses produced synergistic effects, indicating that subthreshold doses of fluoxetine and paracetamol may enable better management in depression and obsessive-compulsive disorder comorbid patients.
authors.affiliation: aHimalayan Pharmacy Institute, Department of Pharmacology, Majhitar, Rangpo, Sikkim bDepartment of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra, India.
authors.forename: Shyamshree S S
authors.initials: SS
authors.lastname: Manna
authors.forename: Sudhir N
authors.initials: SN
authors.lastname: Umathe
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology; D003192:Compulsive Behavior / Q000188:drug therapy*; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D063388:Endocannabinoids / Q000378:metabolism; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D001095:Arachidonic Acids; D063388:Endocannabinoids; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors; C107594:N-(4-hydroxyphenyl)arachidonylamide