NMDA receptor modulation of the pedunculopontine tegmental nucleus underlies the motivational drive for feeding induced by midbrain dopaminergic neurons

Abstract

The mesolimbic system, particularly the somatodendritic ventral tegmental area (VTA), is responsible for the positive reinforcing aspects of various homeostatic stimuli. In turn, the pedunculopontine tegmental nucleus (PPN) is anatomically and functionally connected with the VTA and substantia nigra (SN). In the present study, we investigated the role of glutamate receptors in the PPN in motivated behaviors by using a model of feeding induced by electrical stimulation of the VTA in male Wistar rats (n\u202f=\u202f80). We found that injection of 2.5/5\u202fµg dizocilpine (MK-801; NMDA receptor antagonist) to the PPN significantly reduced the feeding response induced by unilateral VTA-stimulation. This reaction was significantly impaired after local injection of MK-801 into the PPN in the ipsilateral rather than the contralateral hemisphere. After NMDA injection (2/3\u202fµg) to the PPN we did not observe behavioral changes, only a trend of a lengthening/shortening of the latency to a feeding reaction at the highest dose of NMDA (3\u202fµg). Immunohistochemical TH+/c-Fos+ analysis revealed a decrease in the number of TH+ cells in the midbrain (VTA-SN) in all experimental groups and altered activity of c-Fos+ neurons in selected brain structures depending on drug type (MK-801/NMDA) and injection site (ipsi-/contralateral hemisphere). Additionally, the pattern of TH+/c-Fos+ expression showed lateralization of feeding circuit functional connectivity. We conclude that the level of NMDA receptor arousal in the PPN regulates the activity of the midbrain dopaminergic cells, and the PPN-VTA circuit may be important in the regulation of motivational aspects of food intake.