D2 Autoreceptor Signaling is Depressed by Neurotensin Released from Discrete Inputs to Midbrain Dopamine Neurons.

Abstract

Midbrain dopamine neurons play physiological roles in many processes including reward learning and motivated behavior. Neurotensin (NT) is a neuropeptide which acutely modulates midbrain dopamine neuron excitability through multiple mechanisms, including a decrease in dopamine D2 autoreceptor‐mediated inhibition. While there are dense neurotensinergic inputs to the midbrain that arise from many different brain regions, most studies to date have relied on exogenous application of NT and NT ligands to determine physiological consequences of NT signaling. As such, the mechanisms involved in release and signaling of endogenous NT from different sources are poorly understood. Here we used transgenic mice that express channelrhodopsin in neurons that also either express NT or the dopamine transporter. We then combined patch clamp electrophysiology of dopamine neurons in midbrain slices with blue light stimulation to specifically activate either neurotensinergic or dopamine neurons (respectively). We found that low frequency stimulation of dopamine neurons alone was sufficient to induce long‐term depression (LTD) of D2 autoreceptor inhibitory postsynaptic currents (IPSCs) and that this LTD could be blocked by either chelation of calcium in the patched cell or by preincubating the slice with a non‐selective NT type 1 and 2 receptor antagonist. It is believed that dopamine neurons do not synthesize NT, but rather take up NT via internalization of NT receptors. Consistent with this, in mice that expressed channelrhodopsin in neurotensinergic neurons, blue light did not cause a channelrhodopsin‐mediated excitation of dopamine neurons. However, low frequency stimulation of neurotensinergic neurons did result in a depression of D2‐IPSCs (though to a lesser extent than stimulation of dopamine neurons) and this depression was blocked by preincubating the slice with a non‐selective NT type 1 and 2 receptor antagonist. Together, these results suggest that neurotensin could be released either by dopamine neurons themselves to act as a retrograde messenger or released by non‐dopaminergic neurons to act as an anterograde messenger, and in both cases can cause LTD of D2 autoreceptor signaling. These findings are the first steps in defining the circuit‐specific NT‐induced plasticity which regulates dopamine neuron activity.Support or Funding InformationThis work was supported by National Institute on Drug Abuse Grant R01 DA32701 (M.J.B.), as well as funds from the Presbyterian Health Foundation and the Oklahoma Center for Adult Stem Cell Research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.