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