Antipsychotic-like effects of a neurotensin receptor type 1 agonist

作者：Vadnie Chelsea A; Ayers Ringler Jennifer; Oliveros Alfredo; Abulseoud Osama A; Choi Sun; Hitschfeld Mario J; Choi Doo Sup^*

来源：Behavioural Brain Research, 2016, 305: 8-17.

DOI：10.1016/j.bbr.2016.02.019

• Amphetamine
• Prepulse inhibition
• Locomotion
• Neurotensin type 1 receptor
• Glycogen synthase kinase 3

Although neurotensin (NT) analogs are known to produce antipsychotic-like effects, the therapeutic possibility of a brain penetrant NTS1 agonist in treating psychiatric disorders has not been well studied. Here, we examined whether PD149163, a brain-penetrant NTS1-specific agonist, displays antipsychotic-like effects in C57BL/6J mice by investigating the effect of PD149163 on amphetamine-mediated hyperactivity and amphetamine-induced disruption of prepulse inhibition. In addition, we assessed the effect of PD149163 on glycogen synthase kinase-3 (GSK-3) activity, a downstream molecular target of antipsychotics and mood stabilizers, using phospho-specific antibodies. PD149163 (0.1 and 0.5 mg/kg) inhibited amphetamine-induced hyperactivity in mice, indicating that NTS1 activation inhibits psychomotor agitation. PD149163 (0.5 mg/kg) also increased prepulse inhibition, suggesting that NTS1 activation reduces prepulse inhibition deficits which often co-occur with psychosis in humans. Interestingly, PD149163 increased the inhibitory serine phosphorylation on both GSK-3 alpha and GSK-3 beta in a dose- and time dependent manner in the nucleus accumbens and medial prefrontal cortex of the mice. Moreover, PD149163 inhibited GSK-3 activity in the nucleus accumbens and medial prefrontal cortex in the presence of amphetamine. Thus, like most current antipsychotics and mood stabilizers, PD149163 inhibited GSK-3 activity in cortico-striatal circuitry. Together, our findings indicate that PD149163 may be a novel antipsychotic.

• 出版日期2016-5-15