Diverse actions of the modulatory peptide neurotensin on central synaptic transmission

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‐induced modulation of neuronal excitability is reviewed here, revealing diverse actions across many brain regions. In midbrain dopamine neurons, neurotensin induces plasticity at glutamatergic, GABAergic, and dopaminergic synapses, leading to complex effects on motivated behavior. The diverse signaling mechanisms and actions of this neuromodulatory peptide will require further investigation but could provide promising treatments for mood and motivation‐related disorders.