Activation of neurotensin receptor type 1 attenuates locomotor activity

Abstract

Intracerebroventricular administration of neurotensin (NT) suppresses locomotor activity. However, the brain regions that mediate the locomotor depressant effect of NT and receptor subtype-specific mechanisms involved are unclear. Using a brain-penetrating, selective NT receptor type 1 (NTS1) agonist PD149163, we investigated the effect of systemic and brain region-specific NTS1 activation on locomotor activity. Systemic administration of PD149163 attenuated the locomotor activity of C57BL/6J mice both in a novel environment and in their homecage. However, mice developed tolerance to the hypolocomotor effect of PD149163 (0.1 mg/kg, i.p.). Since NTS1 is known to modulate dopaminergic signaling, we examined whether PD149163 blocks dopamine receptor-mediated hyperactivity. Pretreatment with PD149163 (0.1 or 0.05 mg/kg, i.p.) inhibited D2R agonist bromocriptine (8 mg/kg, i.p.)-mediated hyperactivity. D1R agonist SKF81297 (8 mg/kg, i.p.)-induced hyperlocomotion was only inhibited by 0.1 mg/kg of PD149163. Since the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) have been implicated in the behavioral effects of NT, we examined whether microinjection of PD149163 into these regions reduces locomotion. Microinjection of PD149163 (2 pmol) into the NAc, but not the mPFC suppressed locomotor activity. In summary, our results indicate that systemic and intra-NAc activation of NTS1 is sufficient to reduce locomotion and NTS1 activation inhibits D2R-mediated hyperactivity. Our study will be helpful to identify pharmacological factors and a possible therapeutic window for NTS1-targeted therapies for movement disorders.

Antipsychotic-like effects of a neurotensin receptor type 1 agonist

“…Our findings are also in agreement with our previous work demonstrating that PD149163 inhibits hyperactivity induced by the D1R agonist SKF-81297 and the D2R agonist bromocriptine [34]. Interestingly, PD149163 at a low dose of 0.05 mg/kg inhibited bromocriptine-, but not SKF-81297-induced hyperactivity, indicating that PD149163 more potently inhibits D2R-mediated hyperlocomotion.…”

“…Consistently, previous work has implicated the NAc in the antipsychotic-like effects of NTS1 agonists. For example, activating NT receptors in the NAc reduced basal locomotion, inhibited dopamine-mediated hyperactivity, and increased PPI [34, 46, 47]. Microinjection of NT or NT analogs in the mPFC had no effect on basal locomotion and modulated dopamine-mediated activity [34, 48].…”

“…For example, activating NT receptors in the NAc reduced basal locomotion, inhibited dopamine-mediated hyperactivity, and increased PPI [34, 46, 47]. Microinjection of NT or NT analogs in the mPFC had no effect on basal locomotion and modulated dopamine-mediated activity [34, 48]. Although it is hypothesized that the mPFC plays a role in the effects of NT on PPI, the role of mPFC NTS1 in sensory motor gating is still unclear and warrants future investigation.…”

“…Mice were placed in the PPI chambers 5 min after the injection of amphetamine. The rationale for injecting amphetamine 55 min after PD149163 stems from our previous observation that peak effect of PD149163 is reached within one hour [34]. …”

Determination of neurotensin projections to the ventral tegmental area in mice

“…Intriguingly, many of these behavioral effects are specific to the VTA because Nts administration outside of the VTA elicits different effects. For example, while Nts injection in the VTA increases locomotor activity and DA release, intra-NA or central Nts decreases locomotor activity and does not alter DA release (Elliott et al, 1986; Kalivas et al, 1983, 1984; Meisenberg and Simmons, 1985; Vadnie et al, 2014; van Wimersma Greidanus et al, 1984). Similarly, intra-VTA Nts does not alter acute locomotor response to psychostimulants (Elliott and Nemeroff, 1986), whereas ICV or intra-NA Nts reduces psychostimulant or DA-induced hyperactivity (Ervin et al, 1981; Jolicoeur et al, 1985; Nemeroff et al, 1983; Sarhan et al, 1997; Skoog et al, 1986).…”