The Reversal of Amphetamine-Induced Locomotor Activation by a Selective Neurotensin-1 Receptor Agonist Does Not Exhibit Tolerance

摘要

Neurotensin-1 (NT1) receptor agonists have been proposed as putative antipsychotic drugs. Recently brain penetrating NT analogues produced by stability enhancing modification of the smallest NT fragment, NT(8–13), have demonstrated antipsychotic-like efficacy after acute systemic injection in several preclinical animal tests predictive for antipsychotic efficacy. However, the evidence regarding the persistence versus tolerance of these effects after repeated administration is ambiguous. Previous studies have used compounds that non-selectively activated both NT1 and NT2 receptors, a factor which may have contributed to the ambiguity in findings regarding the emergence of tolerance. In this study, we investigated the effects of subchronic systemic administration of PD149163, a brain penetrating NT analogue with selectivity for the NT1 receptor, on amphetamine-induced locomotor activation, a classic preclinical test of antipsychotic-efficacy. Sprague Dawley rats were pretreated with eight consecutive daily subcutaneous (SC) injections of PD149163 or saline. On the ninth day rats received a pair of SC injections consisting of PD149163 or saline, followed by amphetamine (0.5mg/kg) or saline. Locomotor activity was then measured in photobeam equipped cages. The results indicated that repeated daily administration of PD149163 was able to antagonize amphetamine’s locomotor activating effect comparable to that of the first dose, despite that repeated administration of PD149163 produced an increase in baseline locomotor activity not seen after the first dose. The results do not support development of tolerance for the acute antipsychotic-like effect of NT1 agonists and thus lend support to the contention that NT1 agonists are viable candidates as putative novel antipsychotic drugs.