Neurotensin Induces Presynaptic Depression of D2 Dopamine Autoreceptor-Mediated Neurotransmission in Midbrain Dopaminergic Neurons

Abstract

Increased dopaminergic signaling is a hallmark of severe mesencephalic pathologies such as schizophrenia and psychostimulant abuse. Activity of midbrain dopaminergic neurons is under strict control of inhibitory D 2 autoreceptors. Application of the modulatory peptide neurotensin (NT) to midbrain dopaminergic neurons transiently increases activity by decreasing D 2 dopamine autoreceptor function, yet little is known about the mechanisms that underlie long-lasting effects. Here, we performed patch-clamp electrophysiology and fast-scan cyclic voltammetry in mouse brain slices to determine the effects of NT on dopamine autoreceptor-mediated neurotransmission. Application of the active peptide fragment NT 8 -13 produced synaptic depression that exhibited short-and long-term components. Sustained depression of D 2 autoreceptor signaling required activation of the type 2 NT receptor and the protein phosphatase calcineurin. NT application increased paired-pulse ratios and decreased extracellular levels of somatodendritic dopamine, consistent with a decrease in presynaptic dopamine release. Surprisingly, we observed that electrically induced long-term depression of dopaminergic neurotransmission that we reported previously was also dependent on type 2 NT receptors and calcineurin. Because electrically induced depression, but not NT-induced depression, was blocked by postsynaptic calcium chelation, our findings suggest that endogenous NT may act through a local circuit to decrease presynaptic dopamine release. The current research provides a mechanism through which augmented NT release can produce a long-lasting increase in membrane excitability of midbrain dopamine neurons.

Depression of substantia nigra dopamine transmission is driven by retrograde neurotensin release and is enhanced by methamphetamine self-administration

“…Pre-incubation with the non-selective NT type 1/2 receptor antagonist SR 142948 prevented LTDDA (Figure 2 A 1-2, F; one-way ANOVA, F4,26 = 18.92, p < 0.0001, Tukey's, p = 0.0001). Conversely and consistent with our previous findings (Piccart et al, 2015), a selective NT type-1 receptor antagonist failed to prevent LTDDA (Figure 2 B 1-2, F; p = 0.99). As presumably only dopamine neurons are being depolarized by the blue light, this suggests that dopamine neurons are themselves releasing NT that induces LTDDA though activation of NT type-2 receptors.…”

“…We previously found that stimulation-induced long-term depression of D2-IPSCs (LTDDA, Beckstead and Williams, 2007) is driven by endogenous NT signaling (Piccart et al, 2015) and suggested that dopamine neurons might also release NT. Thus, to determine the source of NT which drives LTDDA we used a combination of transgenic and optogenetic tools to delineate the role of dopamine neurons and NT afferents to the midbrain.…”

“…Dendritic dopamine neurotransmission can be measured in mouse brain slices by electrically evoking dopamine release and electrophysiologically recording the subsequent D2R-, potassium channel-mediated inhibitory postsynaptic currents (D2-IPSCs, Beckstead et al, 2004). Previous work from our lab shows that D2-IPSCs undergo long-term depression (LTDDA) subsequent to low-frequency electrical stimulation (Beckstead and Williams, 2007;Piccart et al, 2015) through a mechanism likely involving signaling by the neuropeptide neurotensin (NT, Piccart et al, 2015).…”

“…Conversely, exposure to abused drugs including morphine, cocaine, and methamphetamine can induce NT peptide upregulation or release across different brain regions (Betancur et al, 2001;Frankel et al, 2011;Geisler and Zahm, 2006;Hanson et al, 2013;Stiller et al, 1997;Tschumi and Beckstead, 2019). Incredibly, exogenous NT application induces synaptic plasticity of GABAergic, dopaminergic, and glutamatergic input to dopamine neurons, as well as activating cell-autonomous endocannabinoid signaling in those cells (Kortleven et al, 2012;Kempadoo et al, 2013;Bose et al, 2015;Stuhrman and Roseberry, 2015;Piccart et al, 2015;Gantz and Bean, 2017;Tschumi and Beckstead, 2018;Tschumi and Beckstead, 2019). NT release from lateral hypothalamic inputs to the VTA drives plasticity at glutamatergic synapses (Kempadoo et al, 2013), but the endogenous source of NT which drives plasticity at dendrodendritic dopamine synapses is not known.…”

Neurotensin Receptor-1 Identifies a Subset of Ventral Tegmental Dopamine Neurons that Coordinates Energy Balance

“…Since NtsR1 is a Gα q -coupled GPCR (Tanaka et al, 1990), our findings indicate a mechanism for Nts to directly enhance the activation of NtsR1-expressing DA neurons, consistent with the established roles for NtsR1 in promoting DA release to the striatum and DA-mediated locomotor activity (Remaury et al, 2002; Steinberg et al, 1994), anorexia (Remaury et al, 2002), and reward (Kempadoo et al, 2013; Rouibi et al, 2015) Our data do not, however, rule out roles for the non-DAergic populations of NtsR2 cells to indirectly promote DA signaling. The TH-negative NtsR2 neurons found primarily within the ventromedial, GABA-rich portion of the VTA may disinhibit local DA neurons and promote their activation (Kempadoo et al, 2013; Piccart et al, 2015). Nts may also act via the numerous NtsR2-expressing astrocytes within the VTA to indirectly modify DA-mediated behavior, consistent with reports of glial cells mediating NtsR2-dependent fear behavior (Yamauchi et al, 2007).…”