Interactive effects of ghrelin and ketamine on forced swim performance: Implications for novel antidepressant strategies

The efficacy of ketamine to alleviate depressive symptoms has promoted a wealth of research exploring alternate therapeutic targets for depression. Given the caveats of ketamine treatment taken together with the increasingly greater emphasis on combinatorial therapeutic approaches to depression, we sought to asses whether the hypothalamic “hunger hormone”, ghrelin, would augment the effects of ketamine. Indeed, ghrelin has recently been found to possess antidepressant potential and may be especially effective against the metabolic and feeding deficits observed with depression. Two studies were performed: 1. mice were given an intraperitoneal injection of ghrelin (80 μg/kg) or saline, followed by a saline or a low or high dose of ketamine (5 or 10 mg/kg) and 2. mice received 10 mg/kg of ketamine together with saline or the ghrelin receptor antagonist JMV2959 (3 or 6 mg/kg) and Forced Swim Test (FST) performance was assessed. In both studies, ketamine alone reduced FST immobility. Similarly, ghrelin alone reduced swim immobility suggesting an antidepressant-like response. However, ghrelin did not augment the impact of ketamine when co-administered and in fact, it appeared to antagonize its actions at the lower dose. As well, JMV2959 did not significantly influence FST performance. These data confirm the antidepressant-like effects of ketamine and further suggest that ghrelin might have similar properties. Yet, our results caution against combinatorial treatment with these agents, probably owing to unexpected allosteric or other antagonist actions.