Chronic neuroleptic treatment combined with a high fat diet elevated [3H] flunitrazepam binding in the cerebellum

Abstract

Clinical and preclinical studies have shown dysfunctions in genetic expression and neurotransmission of γ-Aminobutyric acid (GABA), GABAA receptor subunits, and GABA-synthesizing enzymes GAD67 and GAD65 in schizophrenia. It is well documented that there is significant weight gain after chronic neuroleptic treatment in humans. While there are limited studies on the effects of diet on GABA signaling directly, a change in diet has been used clinically as an adjunct to treatment for schizophrenic relief. In this study, rats chronically consumed either a chow diet (CD) or a 60% high-fat diet (HFD) and drank from bottles that contained one of the following solutions: water, haloperidol (1.5 mg/kg), or olanzapine (10 mg/kg) for four weeks. Rats were then euthanized and their brains were processed for GABAA in-vitro receptor autoradiography using [3H] flunitrazepam. A chronic HFD treatment yielded significantly increased [3H] flunitrazepam binding in the rat cerebellum independent of neuroleptic treatment. The desynchronization between the prefrontal cortex and the cerebellum is associated with major cognitive and motor dysfunctions commonly found in schizophrenic symptomatology, such as slowed reaction time, motor dyscoordination, and prefrontal activations related to speech fluency and cognitive alertness. These data support the notion that there is a dietary effect on GABA signaling within the cerebellum, as well as the importance of considering nutritional intervention methods as an adjunct treatment for patients chronically treated with neuroleptics. Finally, we indicate that future studies involving the analysis of individual patient's genetic profiles will further assist towards a precision medicine approach to the treatment of schizophrenia.