The neurotensin receptor antagonist, SR48692, attenuates the expression of amphetamine-induced behavioural sensitisation in mice

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Abstract

The effects of acute administration of the neurotensin receptor antagonist, SR48692 (2-{[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-carbonyl]amino}adamantane-2-carboxylic acid), on amphetamine-induced behavioural sensitisation were studied with the locomotor activity of mice in an open-field as an experimental parameter. The animals were repeatedly pretreated with saline or amphetamine (2.0 mg/kg, i.p. once a day, every other day for 13 days) and 2, 9 and 16 days after the last injection they received an acute i.p. administration of saline or 0.3 mg/kg SR48692 15 min before a challenge i.p. injection of 2.0 mg/kg amphetamine. Locomotor activity of the amphetamine-challenged mice was significantly higher in amphetamine-pretreated animals than in saline-pretreated mice on days 9 and 16 after withdrawal. SR48692 prevented the expression of this behavioural sensitisation. In addition, in saline-pretreated mice, the first two challenge injections of amphetamine sufficed to induce a sensitized locomotor response to the third challenge injection of the drug. SR48692 administration before amphetamine challenge injections prevented the development of this challenge injection-induced sensitisation in saline-pretreated mice but not in amphetamine-pretreated animals. In order to determine the effects of SR48692 on the expression of amphetamine-induced behavioural sensitisation in the absence of this challenge injection-induced sensitisation, the experiment was redone with a single challenge test 9 days after pretreatment. Once again, SR48692 prevented the expression of amphetamine-induced behavioural sensitisation. These results suggest that neurotensinergic transmission has a critical role in both the initiation and expression of locomotor sensitisation to amphetamine.

Introduction

Chronic intermittent administration of amphetamine to animals produces a progressive and enduring increase in hyperactivity and stereotyped behaviour Bellot et al., 1996, Kalivas and Stewart, 1991, Nelson and Ellison, 1978. This phenomenon, called behavioural sensitisation, has been widely recognized as an animal model of lasting susceptibility to exacerbation of psychostimulant-induced psychosis (Robinson and Becker, 1986). As regards sensitisation to the locomotor stimulatory effects of amphetamine, this model has also been suggested to be useful for studying mechanisms underlying drug craving in humans (Robinson and Berridge, 1993). Indeed, whereas substantial evidence links the locomotor-stimulating effects of addictive drugs to their positive reinforcing properties (Wise and Bozarth, 1982), most drugs of abuse stimulate locomotion in rodents and induce sensitisation (Kalivas and Stewart, 1991).

It has been hypothesized that activation of mesolimbic dopaminergic pathways—from the ventral tegmental area to the nucleus accumbens—is related to both the reinforcing and locomotor-stimulating properties of drugs of abuse (Wise and Bozarth, 1987). Sensitisation to the locomotor-stimulating effects of amphetamine also appears to require alterations within the mesoaccumbens dopamine system. Indeed, a variety of data shows that the initiation of behavioural sensitisation to psychostimulants occurs in the ventral tegmental area, whereas the neuronal events associated with the expression of the phenomenon are centered in a collection of interconnected limbic nuclei, among which dopamine transmission in the nucleus accumbens seems to play a critical role (Pierce and Kalivas, 1997).

Neurotensin is an endogenous tridecapeptide which is mainly localized in regions containing either cell bodies or terminals of dopamine neurons, including the mesolimbic dopamine system (Kasckow and Nemeroff, 1991). Microinjection of neurotensin into the ventral tegmental area enhances dopamine release in the nucleus accumbens (Kalivas and Duffy, 1990) and increases locomotion of rats (Kalivas et al., 1983). Conversely, when injected into the nucleus accumbens, neurotensin inhibits the release of dopamine (Tanganelli et al., 1994) and decreases the behavioural responses induced by dopamine agonists Kalivas et al., 1984, Nemeroff et al., 1983, Ervin et al., 1981. After repeated injections with neurotensin, the locomotor-activating effect of the ventral tegmental area is increased Kalivas and Duffy, 1990, Elliot and Nemeroff, 1986, Kalivas and Taylor, 1985. In this context, a growing body of evidence suggests the involvement of neurotensin in locomotor sensitisation to psychostimulants. Thus, whereas repeated intracerebroventricular (i.c.v.) injections of neurotensin enhance the locomotor-stimulating effect of a challenge i.p. injection of amphetamine (Rompré, 1997), repeated i.p. injections of the dopamine uptake inhibitor, GBR12783 (1-[2-(diphenylmethoxy)ethyl]4-(3-pnehyl-2-(propenyl)-piperazine), increase the locomotor-stimulating effect of a challenge i.c.v. injection of [d-Trp11]neurotensin, a neurotensin derivative resistant to peptidase inactivation (Boulay et al., 1996). In addition, previous repeated administration of the neurotensin receptor antagonist, SR48692 (2-{[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-carbonyl]amino} adamantane-2-carboxylic acid), produces an attenuating effect on the development of sensitisation to the locomotor-activating effect of cocaine in rats (Horger et al., 1994). In contrast, co-treatment with SR48692 30 or 60 min before cocaine or amphetamine injection, respectively, failed to produce an antagonistic effect on the development of cocaine sensitisation (Horger et al., 1994), but inhibited the development of amphetamine sensitisation (Rompré and Perron, 2000).

To date, the involvement of neurotensin transmission blockade in the expression of behavioural sensitisation to psychostimulants in mice has not been explored. To address this question, the primary purpose of this study was to investigate the effects of acute SR48692 administration on the expression of locomotor sensitisation to amphetamine in mice.

Section snippets

Subjects

Three-month-old female Swiss mice ranging in weight from 25 to 30 g at the beginning of the experiment were used in this study. The animals were housed in groups and maintained in an environment with controlled temperature (22±1 °C) and a 12 h light/dark cycle (lights on at 06:30 h). The mice had free access to food and water. All procedures were performed in strict accordance with the guidelines of the Committee on Animals of the Colégio Brasileiro de Experimentação Animal (COBEA) and the

Experiment 1

None of the three acute SR48692 doses induced significant changes in locomotor activity (Table 1). Thus, we decided to use the highest SR48692 dose (0.3 mg/kg) to study the possible effect of neurotensin receptor blockade on the amphetamine-induced sensitisation phenomenon.

Experiment 2

Statistical analysis showed a significant main effect of pretreatment (F(1,48)=20.16; P<0.0001), challenge (F(1,48)=4.65; P<0.05) and session (F(2,96)=13.77; P<0.0001) on locomotor activity. The interactions between these

Discussion

The major findings of the present study were that: (1) the neurotensin antagonist, SR48692, prevented the expression of amphetamine-induced locomotor sensitisation but did not modify its acute locomotor-stimulating effect, (2) two challenge injections of amphetamine in saline-pretreated mice were sufficient to induce a sensitized locomotor response to a third challenge injection of the psychostimulant, (3) this (extra) sensitized response was also observed in amphetamine-pretreated animals, (4)

Acknowledgements

This research was supported by grants from Fundação de Apoio aos Docentes e Alunos da UNIFESP (FADA and AFIPE) and from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, #96/4193-0 and 95/9462-7) and Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq, # and 520656/96-2 and 922975/95-0), awarded to LFF and RFF, respectively. FGC was supported by a fellowship from FAPESP (#98/16084-7). The authors thank Ms. Clarissa Niciporciukas for helpful suggestions and

References (37)

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    Central locomotion = number of entries into any floor unit not contiguous to the apparatus walls. The evaluation of mouse behavior in the open field was conducted for 10 min because even shorter periods have proven to be optimal for reliably and accurately evaluating the effects of drugs acting on the dopaminergic systems (Castro et al., 2006; Faria et al., 2005; Frussa-Filho and Palermo-Neto, 1990, 1991; Fukushiro et al., 2007a,b, 2008; Queiroz and Frussa-Filho, 1997) and, in particular, the stimulatory effect and behavioral sensitization produced by Amp (Alvarez et al., 2006; Araujo et al., 2006; Bellot et al., 1997; Calzavara et al., 2008; Carvalho et al., 2009; Chinen et al., 2006; Costa et al., 2001; Frussa-Filho et al., 2004; Fukushiro and Frussa-Filho, 2011). Moreover, the behavioral competition between Amp-induced hyperlocomotion and stereotypy in the open-field apparatus is stronger when the mouse behavior is quantified after this optimal period (Frussa-Filho et al., 2010) and the locomotor-activating effect of Amp follows a classical habituation profile during longer sessions (Adriani and Laviola, 2000).

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