The effects of cholecystokinin and leptin on glutamate synaptic transmission in the dorsomedial nucleus of the hypothalamus in rats

Abstract

Obesity is an epidemic in many developed countries caused by an imbalance in food intake and energy expenditure that presents a multitude of other health risks. In the brain, the dorsomedial nucleus of the hypothalamus (DMH) plays an important role in the regulation of appetite. Cholecystokinin (CCK), an important neuropeptide and satiety hormone acts in the DMH to suppress food intake. Although the exact mechanisms by which CCK inhibits food intake are not entirely understood, there is evidence that CCK alters neurotransmitter release onto DMH neurons. Specifically, CCK increases the release of the major inhibitory transmitter, GABA, onto putative appetite-stimulating DMH neurons. It is unknown, however, whether CCK affects the transmission of glutamate, a major excitatory transmitter, despite reports of CCK modulating glutamate release elsewhere in the brain. We hypothesized that CCK decreases neuronal activity and glutamate transmission in DMH neurons in rats. To test this hypothesis. we used young male Sprague Dawley rats and performed patch clamp electrophysiology to record action potentials and glutamate-mediated currents in living DMH neurons. Surprisingly, CCK had no effect on evoked excitatory postsynaptic currents, even following a high-frequency stimulation (HFS) into the extracellular space, causing increased neurotransmitter release. There was, however, a decrease in the frequency of spontaneous events following HFS in the presence of CCK, suggesting that CCK is involved in facilitating glutamate transmission. Another satiety hormone, leptin, has been reported to act in combination with CCK to reduce appetite when co-injected into other regions of the brain. We therefore co-administered CCK and leptin onto DMH brain slices. Interestingly, there was a significant decrease in glutamate transmission following bath application, however, following HFS, there were no significant effects. There were also no significant changes in the spontaneous activity of these DMH neurons. We then administered leptin alone to determine whether the decrease in glutamate transmission was a direct result of leptin, or if CCK and leptin act together to modulate transmission. No effect was observed following bath application of leptin alone. There was also no significant change following high-frequency stimulation, but there was a decrease in the frequency of spontaneous currents in the presence of leptin. These results suggest that CCK and leptin act synergistically in the DMH to modulate food intake via decreased glutamate transmission at DMH neurons. This research could provide important information regarding the mechanisms by which CCK and leptin suppress appetite in rats, with implications for humans living with obesity.