Neurotensin inhibits glutamate-mediated synaptic inputs onto ventral tegmental area dopamine neurons through the release of the endocannabinoid 2-AG

An update on the connections of the ventral mesencephalic dopaminergic complex

“…More is known about the distributions and functions of tier 1 peptidergic inputs to the VTA, e.g., the capacity of inputs to the VTA from orexinergic (Aston-Jones et al, 2009; Cason et al 2010; Cason and Aston-Jones, 2013) and neurotensinergic (Rompre et al, 1992; St-Gelais et al, 2004; Reynolds et al, 2006; Geisler et al, 2006; Kortleven et al, 2012; Kempadoo et al, 2013) neurons in the lateral hypothalmo-preoptic-ventral pallidum continuum to facilitate DA-mediated locomotor and reward behaviors. Interestingly in this regard, Balcita-Pedicino and Sesack (2007), using electron microscopy, detected orexinergic axon terminals and synaptic contacts in the VTA that seemed to these authors inordinately few, in view of the robust functional orexigenic effects that had been reported (refs in preceding sentence).…”

Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes

“…More recently, eCB-mediated long-term regulation of glutamatergic transmission in DA neurons involving the activation of G q/11 -coupled neuropeptide receptors has been reported (Kortleven et al, 2012). In this study, neurotensin application to VTA slices caused a decrease in glutamatergic EPSCs in DA neurons, via activation of neurotensin 1 (NT1) receptors.…”

“…This inhibition persisted long after neurotensin washout from the VTA brain slices, and antagonism of CB1Rs, but not NT1Rs, reversed this long-term effect. This suggests that neurotensin triggered the long-term release of an eCB that acted at CB1Rs to inhibit glutamate release (Kortleven et al, 2012). The neurotensin-induced depression was independent of postsynaptic calcium, as it was not blocked by loading DA neurons with the calcium chelator BAPTA, but it was blocked by inhibitors of G proteins, PLC-β, or DGLα.…”

“…The neurotensin-induced depression was independent of postsynaptic calcium, as it was not blocked by loading DA neurons with the calcium chelator BAPTA, but it was blocked by inhibitors of G proteins, PLC-β, or DGLα. Therefore, the neurotensin-induced LTD was mediated by 2-AG that was released via activation of a G q/11 -linked NT1Rs and the PLC/DGLα pathway (Kortleven et al, 2012). Since NT1 receptors and neurotensin are found at relatively high concentrations in the VTA (Dana et al, 1989; Hokfelt et al, 1984), these data suggest that this neuropeptide system may be involved in regulating the activity of this nucleus, at least partly through the mobilization of 2-AG.…”

“…In addition to the Ca 2+ -dependent mobilization of 2-AG, the activation of several G q/11 protein-coupled neurotransmitter receptors (GPCRs), such as group I metabotropic glutamate receptors (mGluRI), muscarinic acetylcholine receptors (mAChR), type 1 neurotensin receptors (NT1R), and orexin receptors, can stimulate 2-AG synthesis independently of Ca 2+ (Maejima et al, 2001; Kim et al, 2002; Haj-Dahmane and Shen, 2005; Kortleven et al, 2012). These GPCRs, through coupling to G q/11 proteins, directly stimulate PLC-β, which then hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP 2 ) to DAG and inositol triphosphate (IP 3 ).…”