Abstract
Background: Obesity is a complex disorder with both metabolic and neurocognitive consequences, including impairments in prefrontal cortex (PFC)-dependent learning and memory. Combination pharmacotherapy may offer a more effective approach for addressing obesity-induced cognitive deficits. Objective: This study evaluated the effects of 30-day co-administration of lorcaserin (5-HT(2)C agonist) and betahistine (H(1) agonist/H(3) antagonist) in reversing cognitive deficits in a diet-induced obesity (DIO) rat model. Methods: Male Lewis rats were subjected to DIO and administered lorcaserin (2 mg/kg) and betahistine (5 mg/kg), either alone or in combination, via intraperitoneally implanted osmotic minipumps for 30 days. Y-maze, novel object recognition, and object-in-place (OIP) tests were used to assess cognitive functions. In vivo electrophysiological recordings were employed to examine effects of the combination treatment on ventral tegmental area (VTA) dopaminergic neuron activity. Results: Obese Western-diet-fed rats showed lower discrimination scores in the OIP task, a behavioral test that engages PFC functions, while their performance in the Y-maze and novel object recognition tasks was similar to that of non-obese Control-diet-fed rats. Combination treatment with lorcaserin and betahistine significantly improved the OIP scores of obese rats. However, the combination treatment did not reduce body weight or obesity-associated morphometrical parameters. Electrophysiological recordings revealed a reduction in the number of spontaneously active dopaminergic neurons in the VTA of obese rats. Lorcaserin and betahistine co-treatment significantly increased the number of spontaneously active dopaminergic neurons of obese animals. Conclusions: These results demonstrate the potential of combination lorcaserin-betahistine treatment to reverse obesity-related cognitive deficits, possibly through enhancement of mesocortical dopaminergic neuron activity.