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

Abstract

Stuhrman K, Roseberry AG. Neurotensin inhibits both dopamine-and GABA-mediated inhibition of ventral tegmental area dopamine neurons. J Neurophysiol 114: 1734 -1745, 2015. First published July 15, 2015 doi:10.1152/jn.00279.2015-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 G q -coupled receptors. Interestingly, the effects of neurotensin were not specific to D2R signaling as neurotensin also inhibited GABA B inhibitory postsynaptic currents in VTA dopamine neurons. Finally, the effects of neurotensin were significantly larger when intracellular Ca 2ϩ was strongly buffered, suggesting that reduced intracellular calcium facilitates these effects. Overall these results suggest that neurotensin may inhibit the D2R and GABA B 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.

Neurotensin receptor 1 deletion suppresses methamphetamine self-administration and the associated reduction in dopamine cell firing

“…Consistent with this, acute systemic injections of METH dose-dependently decrease the firing frequency of dopamine neurons recorded in the VTA and the SN [28]. Our previous work suggests that D2 autoreceptor signaling is impaired after METH self-administration [29], and there is strong evidence that neurotensin decreases the functionality of D2 autoreceptors in dopamine cells [16,19,30,31]. While this might be expected to increase dopamine neuron firing in vivo, no study to date has explored how dopamine cell firing is affected by chronic METH self-administration.…”

Alpha‐melanocyte stimulating hormone increases the activity of melanocortin‐3 receptor‐expressing neurons in the ventral tegmental area

“…Acute brain slices were prepared in a manner similar to that described previously (Roseberry et al . ; Stuhrman & Roseberry, ; West & Roseberry, ). Briefly, adult mice were anaesthetized with isofluorane and decapitated.…”

Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders

“…However, there are many NtsR2-expressing astrocytes within the VTA, so it is entirely possible that Nts might indirectly alter DA signaling through signaling in astrocytes [28]. Nts acting directly via VTA NtsR1 increases the activity of DA neurons via several mechanisms, including attenuating D2R auto-inhibition via NtsR1/D2R hetero-complexes, inhibiting IPSCs induced via D2R and GABA B receptors and activating a nonselective inward cation current [99]. However, the source of Nts input to the VTA that activates DA neurons and mediates anorectic actions via this circuit has yet to be defined.…”