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Review
. 2019 Mar;49(6):784-793.
doi: 10.1111/ejn.13858. Epub 2018 Feb 28.

Diverse actions of the modulatory peptide neurotensin on central synaptic transmission

Christopher W Tschumi  1 , Michael J Beckstead  1
Affiliations
Review

Diverse actions of the modulatory peptide neurotensin on central synaptic transmission

Christopher W Tschumi et al. Eur J Neurosci. 2019 Mar.

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.

Keywords: VTA; endocannabinoids; methamphetamine; neuropeptide; substantia nigra.

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Figures

Figure 1
Figure 1
Diverse NT action in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). This schematic indicates the architecture and behavioral roles of specific NT circuits, as well as NT-induced modulation of neurotransmitter signaling in the SNc/VTA. Purple lines and ovals represent sources of NT, including inputs from the LH that either co-express NT and glutamate (NT/glutamate) or express leptin receptors (LepRB). Purple arrows indicate an increase or decrease in signaling at a given synapse, including the responsible receptor subtype (if it is known). The location of the arrow indicates if the effect of NT occurs presynaptically (near the input), postsynaptically (adjacent to the receptor), or was not determined (between the input and receptor). NT release from dopamine neurons is putative and indicates possible retrograde transmission of NT at dendro-dendritic synapses between dopamine neurons.
Figure 2
Figure 2
NT induces endocannabinoid release in multiple brain regions. This schematic indicates actions of NT mediated by endocannabinoid release in the striatum, VTA/SNc, and periaqueductal gray (PAG). In striatal medium spiny projection neurons, NT induces endocannabinoid release in a process that depends on D2 and/or metabotropic glutamate receptor activation. Released endocannabinoids then reduce glutamatergic EPSCs. In the VTA, released endocannabinoids also reduce glutamatergic EPSCs. In SNc dopamine neurons, production of 2-AG decreases conductance through A-type K+ channels. In the PAG, NT induces endocannabinoid release in a process that depends on metabotropic glutamate signaling. Released endocannabinoids then reduce GABAA IPSCs. Light blue lines represent paths of endocannabinoid signal. Colored lines represent glutamate (red), dopamine (dark blue), or GABA (orange) input. Arrows represent resultant endocannabinoid-induced reduction of neurotransmission or ion conductance (i.e., the indirect effect of NT receptor activation). Note that while the circles in each brain region represent postsynaptic cells in the context of endocannabinoid release, it is not clear if the D2 or metabotropic glutamate receptors necessary for NT-induced release of endocannabinoids are present on that same postsynaptic cell or if some other intermediary cell is involved.
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