Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice |
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Authors: | Umathe Sudhir N Manna Shyamshree S S Jain Nishant S |
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Institution: | a Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Mahatma Jyotiba Fuley Shaikshanik Parisar, Amravati Road, Nagpur 440033, Maharastra, India b J.L.C. College of Pharmacy, M.I.D.C., Hingna Road, Nagpur 440016, Maharastra, India |
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Abstract: | Endocannabinoid analogues exhibit antidepressant and anti-compulsive like effects similar to that of serotonin selective reuptake inhibitors (SSRIs) indicating a parallelism between the effects of serotonin and endocannabinoids. Therefore, the present study was designed to investigate the role of endocannabinoids in the antidepressant and anti-compulsive like effect of fluoxetine using mice model of forced swim test (FST) and marble-burying behavior (MBB). The results revealed that intracerebroventricular injections of endocannabinoid analogues, anandamide, a CB1 agonist (AEA: 1-20 μg/mouse); AM404, an anandamide transport inhibitor (0.1-10 μg/mouse); and URB597, a fatty acid amide hydrolase inhibitor (0.05-10 μg/mouse) produced antidepressant-like effect dose-dependently, whereas influenced the MBB in a biphasic manner (produced a U-shaped dose-response curve). Fluoxetine (2.5-20 mg/kg, i.p.) dose dependently decreased the immobility time as well as burying behavior. Co-administration of sub-effective dose of fluoxetine (2.5 mg/kg, i.p.) potentiated the effect of sub-effective dose of AEA (0.5 μg/mouse, i.c.v.), AM404 (0.05 μg/mouse, i.c.v) or URB597 (0.01 μg/mouse, i.c.v) in both the paradigms. Interestingly, pretreatment with AM251, a CB1 antagonist, blocked the effect of fluoxetine in FST and MBB at a dose (1 μg/mouse, i.c.v) that per se had no effect on either parameter. Similar effects were obtained with endocannabinoid analogues in AM251 pretreated mice. However, AM251 increased the burying behavior in MBB at a highest dose tested (5 μg/mouse). None of the treatments had any influence on locomotor activity. Thus, the study indicates an interaction between endocannabinoid and serotonergic system in regulation of depressive and compulsive-like behavior. |
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Keywords: | 2-AG 2-arachidonoylglycerol 5-HT serotonin 5-HT2A serotonin receptor type 2A 5-HT2C serotonin receptor type 2C 8-OH-DPAT 8-hydroxy-2-(dipropylamino)tetralin AEA N-arachidonoylethanolamide AM251 N-(piperidin-1yl)-5-(4-iodophenyl)-1-(2 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) AM404 N-(4-hydroxyphenyl)-arachidonylethanolamide ANOVA analyses of variance CB1 cannabinoid receptor type 1 CB2 cannabinoid receptor type 2 CNS central nervous system DMSO dimethylsulfoxide DOI 1-(2 5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride FAAH fatty acid amide hydrolase FST forced swim test GABA gamma-aminobutyric Acid GTPγS guanosine 5&prime -O-(3-thiotriphosphate) i c v intracerebroventricular MBB marble-burying behavior OCD obsessive-compulsive disorder SSRIs selective serotonin reuptake inhibitors TRPV1 transient receptor potential vanilloid 1 cation channels URB597 cyclohexylcarbamic acid-3&prime -carbamoyl-biphenyl-3-yl ester |
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