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

Endogenous 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). These data support the regulation of baseline PPI, ASR and locomotor activity by endogenous NT acting at the NT2 receptor. Further studies investigating the role of NT2 receptors in the modulation of APD-like effects are warranted.

The effects of chronic administration of established and putative antipsychotics on natural prepulse inhibition deficits in Brattleboro rats.

We previously reported that vasopressin deficient Brattleboro (BRAT) rats exhibit deficits in prepulse inhibition (PPI) of the startle reflex that are consistent with PPI deficits exhibited by patients with schizophrenia and other neuropsychiatric disorders. Preliminary evidence indicates that this may be the basis of a predictive model for antipsychotic drug efficacy. Here we report the effects of acute and chronic administration of established and putative antipsychotics on these PPI deficits. BRAT rats, compared to their derivative strain, Long Evans rats, exhibited significantly decreased PPI and startle habituation consistent with patients with schizophrenia and other neuropsychiatric disorders. The second generation antipsychotics, risperidone and clozapine as well as a neurotensin agonist (PD149163) increased BRAT rat PPI, whereas saline, the typical antipsychotic, haloperidol, and a vasopressin analog (1-desamino-D-arginine vasopressin) did not. Similar to their effects in humans, chronic administration of antipsychotic drugs produced stronger effects than acute administration. These results further support the BRAT rat as a model of sensorimotor gating deficits with predictive validity for antipsychotics. The model appears to be able to differentiate first generation from second generation antipsychotics, identify putative antipsychotics with novel mechanisms (i.e., peptides) and reasonably model the therapeutic time course of antipsychotic drugs in humans.

Upregulation of striatal dopamine-2 receptors in Brattleboro rats with prepulse inhibition deficits.

BACKGROUND: Brattleboro rats (BRATs) have natural deficits in prepulse inhibition (PPI) of the startle response similar to those exhibited by schizophrenia patients, which are reversed by antipsychotics. We sought to determine whether they also have increases in striatal dopamine-2 (D2) receptors found in some studies examining the brains of schizophrenia patients. METHODS: Several days after startle testing, the brains of BRAT and Long Evans (LE) rats were removed, and D1 and D2 receptor levels were measured by autoradiography. RESULTS: PPI was lower in BRATs consistent with previous reports. D2, but not D1, receptor binding was significantly higher in the nucleus accumbens shell and the dorsomedial caudate of BRAT compared with LE rats, consistent with some findings in schizophrenia patients. Furthermore, individual rat PPI was inversely correlated with D2 binding density. CONCLUSIONS: These findings suggest that the dopamine system in BRATs is dysregulated and these abnormalities may contribute to the PPI deficits observed in these rats.