title: Combination cannabinoid and opioid receptor antagonists improves metabolic outcomes in obese mice.
abstract: The CB1 receptor antagonist, rimonabant, causes weight loss but also produces undesirable psychiatric side effects. We investigated using a combination of rimonabant with the opioid receptor antagonists naloxone and norBNI to treat the metabolic sequelae of long-term high fat diet feeding in mice. This combination has previously been shown to have positive effects on both weight loss and mood related behaviour. Diet-induced obese mice were treated chronically with either low dose rimonabant (1 mg/kg) or the combination of rimonabant, naloxone and norBNI (rim nal BNI). After 6 days of treatment, glucose and insulin tolerance tests were performed and body composition analysed using DEXA. Changes in BAT thermogenesis were assessed using implantable radio telemetry probes. Behavioural responses to acute rimonabant or rim nal BNI were examined in the forced swim test and elevated plus maze. Separately, we assessed shifts in Fos immunoreactivity in response to rimonabant or rim nal BNI. Rim nal BNI was significantly better than rimonabant treatment alone at reducing body weight and food intake. In addition, it improved fasting blood glucose and fat mass. Acute low dose rimonabant did not alter behaviour in either the forced swim test or elevated plus maze. Combination rim nal BNI reversed the behavioural effects of high dose (10 mg/kg) rimonabant in obese mice. Rim nal BNI altered Rimonabant-induced Fos in a number of nuclei, with particular shifts in expression in the central and basolateral amygdala, and insular cortex. This study demonstrates that the combination of rimonabant, naloxone and norBNI is effective at producing weight loss over a sustained period of time without altering performance in standardised mouse behaviour tests. Fos expression patterns offer insight into the neuroanatomical substrates subserving these physiological and behavioural changes. These results indicate that CB1-targeted drugs for weight loss may still be feasible.
authors.affiliation: Department of Physiology, Monash University, Wellington Rd, Clayton, Victoria, Australia. Electronic address: sarah.lockie@monash.edu.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Lockie
authors.affiliation: Department of Physiology, Monash University, Wellington Rd, Clayton, Victoria, Australia.
authors.forename: Aneta
authors.initials: A
authors.lastname: Stefanidis
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, Munich, Germany; Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.affiliation: Department of Physiology, Monash University, Wellington Rd, Clayton, Victoria, Australia.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Oldfield
mesh_terms: D000818:Animals; D001823:Body Composition / Q000187:drug effects; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009270:Naloxone / Q000008:administration & dosage / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy*; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use; D000077285:Rimonabant; D022722:Thermogenesis / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D063387:Cannabinoid Receptor Antagonists; D007328:Insulin; D009292:Narcotic Antagonists; D010880:Piperidines; D011720:Pyrazoles; D009270:Naloxone; D005947:Glucose; D000077285:Rimonabant
keywords: Cannabinoid; Diabetes; Mouse; Naloxone; Obesity; Opioid; Rimonabant; norBNI