Diverse actions of the modulatory peptide neurotensin on central synaptic transmission

Abstract

Neurotensin (NT) is a 13 amino acid neuropeptide that is expressed throughout the central nervous system and is implicated in the etiology of multiple diseases and disorders. Many primary investigations of NT-induced modulation of neuronal excitability at the level of the synapse have been conducted, but they have not been summarized in review form in nearly 30 years. Therefore, the goal of this review is to discuss the many actions of NT on neuronal excitability across brain regions as well as NT circuit architecture. In the basal ganglia as well as other brain nuclei, NT can act through diverse intracellular signaling cascades to enhance or depress neuronal activity by modulating activity of ion channels, ionotropic and metabotropic neurotransmitter receptors, and presynaptic release of neurotransmitters. Further, NT can produce indirect effects by evoking endocannabinoid release, and recently has itself been identified as a putative retrograde messenger. In the basal ganglia, the diverse actions and circuit architecture of NT signaling allow for input-specific control of reward-related behaviors.

Neurotensin and Dynorphin Bi-Directionally Modulates CeA Inhibition of oval BNST Neurons in Male Mice

“…Interestingly, the NTR2 specific agonist JMV431 resulted in LTD GABA in 38% of recorded neurons, indicating that both NT receptors may have opposing modulatory roles on inhibitory transmission in the ovBNST. NT has a higher affinity to NTR1 than NTR2, suggesting that post-synaptic activation may release low to moderate amounts of endogenous NT that may only activate NTR1s (Tschumi and Beckstead, 2018). Additionally, NTR2 are preferentially expressed intra-cellularly whereas NTR1s are expressed at the cell membrane, potentially increasing NT's ability to bind and activate NTR1s (Perron et al, 2007).…”

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

“…We next investigated two prominent NT-expressing inputs to the VTA: 1) the LH afferents to the VTA, which have only weak projection to the SNc (Patterson et al, 2015), and 2) the NAc inputs to the VTA, which express increased levels of NT following methamphetamine exposure (Geisler and Zahm, 2006). NT, like many neuropeptides, is coexpressed in neurons that form synaptic connections and generate either GABA-or glutamate-mediated postsynaptic currents in VTA dopamine neurons (Leinninger et al, 2013;Kempadoo et al, 2013;Tschumi and Beckstead, 2019). In order to specifically stimulate these inputs, NTS-Cre mice that express Cre-recombinase specifically in cells that express NT were administered bilateral intra-LH or intra-NAc injections of AAV to drive cre-inducible expression of ChR2 ; t7 = 0.223, p = 0.87).…”

“…NT is expressed throughout the central nervous system, and in both the midbrain and striatum (a major dopamine projection region) it can affect dopamine-mediated behaviors including food-and psychostimulant-reinforced responding (Dominguez-Lopez et al, 2018;Kempadoo et al, 2013;Leinninger et al, 2011;Patterson et al, 2015;Tschumi and Beckstead, 2018;Tschumi and Beckstead, 2019). 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).…”

“…NT is expressed throughout the central nervous system, and in both the midbrain and striatum (a major dopamine projection region) it can affect dopamine-mediated behaviors including food-and psychostimulant-reinforced responding (Dominguez-Lopez et al, 2018;Kempadoo et al, 2013;Leinninger et al, 2011;Patterson et al, 2015;Tschumi and Beckstead, 2018;Tschumi and Beckstead, 2019). 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).…”

“…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.…”