The reversal of amphetamine-induced locomotor activation by a selective neurotensin-1 receptor agonist does not exhibit tolerance

Abstract

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, , 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 amphetamineinduced 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.

Effect of Methamphetamine Self-Administration on Neurotensin Systems of the Basal Ganglia

“…Although lever-pressing behavior was still diminished the next day, it returned to normal levels by day 7. This confirmed conclusions by other investigators and us that activation of this NT system has a general inhibitory influence on METH-mediated behaviors that have a DA basis, and we now know that this probably includes some factors that are associated with drug self-administration (Wagstaff et al, 1994;Nicola 2007;Feifel et al, 2008). Pretreatment with the NT antagonist (SR48692) before days 5 to 7 enabled us to assess the state of endogenous NT release during METH selfadministration.…”

“…Although little is known about its precise role, studies have suggested that NT has an inhibitory influence on the stimulatory behavioral effects of psychostimulants (Wagstaff et al, 1994;Chartoff et al, 2004;Feifel et al, 2008), possibly through an indirect mechanism involving increased striatal GABA activity and subsequent reduced DA release (Ferraro et al, 1998). This inhibitory action has been speculated to be of potential clinical value, suggesting that activation of NT receptors may have a neuroleptic action and be useful in the management of conditions of excessive DA activity (Chartoff et al, 2004;Feifel et al, 2008).…”

“…In a separate study, the effect of stimulating and blocking the NT receptors on METH SA was examined by administering a NT agonist [Lys(CH2NH)Lys-Pro,Trp-tert-Leu-Leu-Oet (PD149163); obtained from the National Institutes of Health National Institute of Mental Health], a stable NT fragment ) that stimulates central nervous system NT1 receptors when delivered systemically (0.5 mg/kg s.c.; Feifel et al, 2008), and an antagonist [0.3 mg/kg 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazol-3-yl)carbonylamino]tricy clo(3.3.1.1. (3.7))decan-2-carboxylic acid (SR48692); purchased from Tocris Bioscience, Ellisville, MO] (Antonelli et al, 2007;Wagstaff et al, 1994) before day 5 (PD149163) or days 5 to 7 (SR48692) of METH SA.…”

“…This dual anatomical arrangement makes NT uniquely positioned to differentially regulate the basal ganglia DA pathway through either D1 (direct feedback pathway) or D2 (indirect feedback pathway) receptor mechanisms. Overall, activation of NT systems or receptors antagonizes DA activity (Chartoff et al, 2004;Feifel et al, 2008), with an apparent physiological role to counteract overactive DA pathways (Wagstaff et al, 1994), leading to the conclusion that NT is a natural neuroleptic and that NT agonists would be an effective treatment for hyperDA psychoses such as schizophrenia (Hadden et al, 2005;Feifel et al, 2008).…”

Response of Neurotensin Basal Ganglia Systems during Extinction of Methamphetamine Self-Administration in Rat

“…D1 (SCH23390, R(1)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrohydro-1H-3-benzazepine hydrochloride; Research Biochemicals Inc., Natick, MA) or D2 (eticlopride, S-(2)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride) antagonists were obtained commercially. A NTR1 agonist [PD149163 [a gift from the National Institute of Mental Health, NIH]; a stable NT fragment ) that stimulates CNS NTR1 receptors when delivered systemically; 0.25 or 0.5 mg/kg s.c.; Feifel et al, 2008] or antagonist [SR48692 [2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-imethoxyphenyl)pyrazol-3-yl)carbonylamino]tricyclo(3.3.1.1. (3.7))decan-2-carboxylic acid; purchased from Tocris Bioscience]; 0.3 mg/kg; Wagstaff et al, 1994;Antonelli et al, 2007] was used to study the role of NT receptors in METH SA.…”