Sensorimotor gating in neurotensin-1 receptor null mice

Abstract

BACKGROUND Converging evidence has implicated endogenous neurotensin (NT) in the pathophysiology of brain processes relevant to schizophrenia. Prepulse inhibition of the startle reflex (PPI) is a measure of sensorimotor gating and considered to be of strong relevance to neuropsychiatric disorders associated with psychosis and cognitive dysfunction. Mice genetically engineered to not express NT display deficits in PPI that model the PPI deficits seen in schizophrenia patients. NT1 receptors have been most strongly implicated in mediating the psychosis relevant effects of NT such as attenuating PPI deficits. To investigate the role of NT1 receptors in the regulation of PPI, we measured baseline PPI in wildtype (WT) and NT1 knockout (KO) mice. We also tested the effects of amphetamine and dizocilpine, a dopamine agonist and NMDA antagonist, respectively, that reduce PPI as well as the NT1 selective receptor agonist, PD149163, known to increase PPI in rats. METHODS Baseline PPI and acoustic startle response were measured in WT and NT1 knockout KO mice. After baseline testing, mice were tested again after receiving intraperatoneal (IP) saline or one of three doses of amphetamine (1.0, 3.0 and 10.0 mg/kg), dizocilpine (0.3, 1.0 and 3.0 mg/kg) and PD149163 (0.5, 2.0 and 6.0 mg/kg) on separate test days. RESULTS Baseline PPI and acoustic startle response in NT1 KO mice were not significantly different from NT1 WT mice. WT and KO mice exhibited similar responses to the PPI-disrupting effects of dizocilpine and amphetamine. PD149163 significantly facilitated PPI (P < 0.004) and decreased the acoustic startle response (P < 0.001) in WT but not NT1 KO mice. CONCLUSIONS The data does not support the regulation of baseline PPI or the PPI disruptive effects of amphetamine or dizocilpine by endogenous NT acting at the NT1 receptor, although they support the antipsychotic potential of pharmacological activation of NT1 receptors by NT1 agonists.

Sensorimotor gating in NTS1 and NTS2 null mice: effects of d-amphetamine, dizocilpine, clozapine and NT69L

“…We tested our mice at least at post-natal day 90, when the mice had reached adulthood and our results support those of Kinkead and collaborators as we found no significant differences in PPI between genotypes at this age. Our results with NTS1 -/-are consistent with reports by others (Feifel et al, 2010b), who also found no significant differences in baseline PPI between NTS1 -/-mice and their respective WT controls.…”

“…Our results are consistent with previous reports on the important role of NTS1 in the modulations of PPI, as found by pharmacological interventions (Caceda et al, 2005;Kinkead et al, 2005). Analysis of startle pulse alone ASR data showed a significant decrease in startle magnitude with amphetamine alone disruption for WT mice, a trend often reported in other studies that have used amphetamine to disrupt PPI (Dulawa and Geyer, 1996;Feifel et al, 2010b;RalphWilliams et al, 2002;Ralph et al, 2001;Ralph et al, 1999;Varty et al, 2001).…”

“…According to their studies, endogenous NT does not seem to regulate baseline PPI or the PPI-disruptive effects of amphetamine and dizocilpine at NTS1. Regulation of baseline PPI by endogenous NT may be acting via NTS2, as in comparison to WT mice, baseline PPI was significantly elevated (Feifel et al, 2010a;Feifel et al, 2010b).…”

“…PD149163 increases PPI in mice and in the Brattleboro strain of rat, which has naturally occurring PPI deficits (Feifel et al, 2004;Feifel et al, 2010b). The NT antagonist SR142948A blocks the ability of haloperidol and the atypical antipsychotic quetiapine to restore normal PPI levels in isolationreared Long Evans rats (Binder et al, 2001).…”

“…The effects of NT are hypothesized to be mediated via the G-protein-coupled neurotensin receptor subtype 1 (NTS1) and neurotensin receptor subtype 2 (NTS2) (Hwang et al, 2010;Le et al, 1996). Recently, Feifel and colleagues (Feifel et al, 2010a;Feifel et al, 2010b) tested PPI in mice lacking NTS1 and NTS2. According to their studies, endogenous NT does not seem to regulate baseline PPI or the PPI-disruptive effects of amphetamine and dizocilpine at NTS1.…”