Effects of neurotensin-2 receptor deletion on sensorimotor gating and locomotor activity

Abstract

SUMMARYEndogenous neurotensin (NT) has been implicated in brain processes relevant to schizophrenia as well as the therapeutic effects of antipsychotic drugs (APDs) used to treat this disorder. Converging evidence suggests that NT1 receptors mediate the antipsychotic-like effects of NT, such as prepulse inhibition (PPI) elevation. However, the role of NT2 receptors in these effects is not known. To investigate the contribution of NT2 receptors to the regulation of PPI, we measured baseline PPI and acoustic startle response (ASR), in male and female wild type (WT) and NT2 knockout (KO) mice. For comparison, we also measured locomotor activity.Baseline PPI was significantly elevated in both male (P < 0.01) and female (P < 0.01) NT2 KO compared to WT mice, while ASR was significantly decreased in KO mice of both genders (P < 0.01). In contrast, female but not male KO mice exhibited significantly less baseline ambulations (P < 0.05).

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

“…Based on these data, it appears that NTS1 and NTS2 do not play a role in the modulation of baseline PPI. A recent report by Feifel and collaborators examined baseline PPI in NTS2 -/-mice (Feifel et al, 2010a). The authors found that NTS2 -/-mice show higher baseline PPI as well as a lower ASR in comparison to WT mice and conclude that endogenous NT plays a role in regulating PPI via activation of NTS2.…”

“…Some changes in knockout mice can be compensatory in nature. Recent reports by Feifel and collaborators do not implicate NTS1 in the disruption of PPI by d-amphetamine and dizocilpine, and attribute the regulation of baseline PPI to NTS2 (Feifel et al, 2010a;Feifel et al, 2010b). There are limitations that occur as a result of differences in environmental conditions between animal facilities and different experimental parameters.…”

“…These factors are likely to account for the differences observed in results between studies. For example, in one study, Feifel and colleagues challenged a combined group of male and female mice (WT or NTS1 -/-) with amphetamine and dizocilpine (Feifel et al, 2010b), while in a study of NTS2 -/-they examined locomotor activity immediately prior to PPI experimentation (Feifel et al, 2010a). In our study, we used only males and allowed 1h of undisturbed acclimation to the experimental room prior to PPI experimentation.…”

“…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).…”

“…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.…”