Neurotensin inhibits both dopamine- and GABA-mediated inhibition of ventral tegmental area dopamine neurons.

Dopamine is an essential neurotransmitter that plays an important role in a number of different physiological processes and disorders. There is substantial evidence that the neuropeptide neurotensin interacts with the mesolimbic dopamine system and can regulate dopamine neuron activity. In these studies we have used whole cell patch-clamp electrophysiology in brain slices from mice to examine how neurotensin regulates dopamine neuron activity by examining the effect of neurotensin on the inhibitory postsynaptic current generated by somatodendritic dopamine release (D2R IPSC) in ventral tegmental area (VTA) dopamine neurons. Neurotensin inhibited the D2R IPSC and activated an inward current in VTA dopamine neurons that appeared to be at least partially mediated by activation of a transient receptor potential C-type channel. Neither the inward current nor the inhibition of the D2R IPSC was affected by blocking PKC or calcium release from intracellular stores, and the inhibition of the D2R IPSC was greater with neurotensin compared with activation of other Gq-coupled receptors. Interestingly, the effects of neurotensin were not specific to D2R signaling as neurotensin also inhibited GABAB inhibitory postsynaptic currents in VTA dopamine neurons. Finally, the effects of neurotensin were significantly larger when intracellular Ca(2+) was strongly buffered, suggesting that reduced intracellular calcium facilitates these effects. Overall these results suggest that neurotensin may inhibit the D2R and GABAB IPSCs downstream of receptor activation, potentially through regulation of G protein-coupled inwardly rectifying potassium channels. These studies provide an important advance in our understanding of dopamine neuron activity and how it is controlled by neurotensin.

Regulation of the mesocorticolimbic and mesostriatal dopamine systems by α-melanocyte stimulating hormone and agouti-related protein.

The melanocortin system of the hypothalamus, including the neuropeptides α-melanocyte stimulating hormone (αMSH) and agouti-related protein (AgRP), and their receptors, the melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R), have been well-studied for their roles in the central control of feeding and body weight. In this review, we discuss the evidence demonstrating that αMSH and AgRP also act on the mesocorticolimbic and mesostriatal dopamine systems to regulate a wide variety of behaviors. In addition to the well described ability of αMSH to increase dopamine transmission and to increase grooming and rearing when injected directly into the ventral tegmental area, a growing body of evidence indicates that αMSH and AgRP can also act on dopamine pathways to regulate feeding and drug abuse, including reward-related behaviors toward food and drugs. Increasing our understanding of how αMSH and AgRP act on dopamine pathways to affect behavior may allow for identification of new strategies to combat disorders involving dysfunction of dopamine pathways, such as obesity and drug abuse.