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.