The Neurotensin NTS₁ Receptor Agonist PD149163 Produces Antidepressant‐Like Effects in the Forced Swim Test: Further Support for Neurotensin as a Novel Pharmacologic Strategy for Antidepressant Drugs

Abstract

Preclinical Research Neurotensin is a nonbrain penetrant neuropeptide neurotransmitter that alters dopaminergic and serotonergic neurotransmission. Previous animal behavioral studies have demonstrated that intra-ventral tegmental administration of neurotensin and system administration of the selective neurotensin NTS receptor agonist, PD149163 produce antidepressant-like effects in a forced swim test and a differential reinforcement of low rate task, respectively. The present study sought to expand upon these past findings by assessing systemic administration of PD149163 in a forced swim test, a primary antidepressant preclinical screening model, in mice. The tricyclic antidepressant drug imipramine was tested for comparison, and both compounds were also assessed in an open field test. Both PD149163 and imipramine reduced time spent immobile, an antidepressant-like effect, in the forced swim test. The highest dose of each compound significantly reduced locomotor activity. These findings provide further evidence for the putative antidepressant effects for PD149163 and suggest that NTS receptor activation may be a novel pharmacologic strategy for antidepressant drug development. Drug Dev Res 78 : 196-202, 2017. © 2017 Wiley Periodicals, Inc.

Neuropeptide Y, calcitonin gene-related peptide, and neurokinin A in brain regions of HAB rats correlate with anxiety-like behaviours

“…Elevated neurotensin levels were also observed in the Fawn-Hooded depression model (Mathé et al, 1998). On the other hand, neurotensin administration or treatment with NT1 agonists induce an antidepressant profile (Carey et al, 2017).…”

Determination of neurotensin projections to the ventral tegmental area in mice

“…In contrast, the caudal “tail” of the VTA that forms a continuum with the rostromedial tegmental nucleus (RMTg) is enriched with GABA-ergic neurons, which inhibit VTA DA neurons and serve as negative regulators of DA-mediated behaviors (Carr and Sesack, 2000; Margolis et al, 2012; Tan et al, 2012; van Zessen et al, 2012). Given that alterations in both VTA DA and Nts signaling have been implicated in the pathogenesis of drug addiction, depression, anxiety, schizophrenia, autism, pain processing and obesity, there is likely functional overlap of these systems (Boules et al, 2014; Caceda et al, 2012; Carey et al, 2017; Ellenbroek et al, 2016; Ferraro et al, 2016; Fitzpatrick et al, 2012; Howes et al, 2017; Kim and Mizuno, 2010; Li et al, 2016; Nestler and Carlezon Jr, 2006; Rothwell, 2016; Theoharides et al, 2016; Volkow et al, 2013). It is therefore critical to define the precise neural mechanisms by which Nts engages the VTA, to understand how it regulates such diverse physiology and how Nts signaling becomes maladaptive in disease.…”

Neurotensin and Neurotensin Receptors in Stress-related Disorders: Pathophysiology & Novel Drug Targets

“…A previous study reported an increase in immobility behavior in NTSR1 KO mice [ 124 ]. Thereupon, NTSR1 agonist PD149163 significantly reduced time spent immobile in the forced swim test, exhibiting an antidepressant-like effect, similar to the antidepressant imipramine [ 125 ].…”