Neurotensin: dual roles in psychostimulant and antipsychotic drug responses

Life Sciences 73 (2003) 801 – 811 www.elsevier.com/locate/lifescie

Neurotensin: dual roles in psychostimulant and antipsychotic drug responses Paul R. Dobner a,*, Ariel Y. Deutch b, Jim Fadel c a

Department of Molecular Genetics and Microbiology, Program in Neuroscience, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655, USA b Departments of Psychiatry and Pharmacology, and Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN 37212, USA c Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA

Abstract Central administration of neurotensin (NT) results in a variety of neurobehavioral effects which, depending upon the administration site, resemble the effects of antipsychotic drugs (APDs) and psychostimulants. All clinically effective APDs exhibit significant affinities for dopamine D2 receptors, supporting the hypothesis that an increase in dopaminergic tone contributes to schizophrenic symptoms. Psychostimulants increase extracellular dopamine (DA) levels and chronics administration can produce psychotic symptoms over time. APDs and psychostimulants induce Fos and NT expression in distinct striatal subregions, suggesting that changes in gene expression underlie some of their effects. To gain insight into the functions of NT, we analyzed APD and psychostimulant induction of Fos in NT knockout mice and rats pretreated with the NT antagonist SR 48692. In both NT knockout mice and rats pretreated with SR 48692, haloperidol-induced Fos expression was markedly attenuated in the dorsolateral striatum; amphetamine-induced Fos expression was reduced in the medial striatum. These results indicate that NT is required for the activation of specific subpopulations of striatal neurons in distinct striatal subregions in response to both APDs and psychostimulants. This review integrates these new findings with previous evidence implicating NT in both APD and psychostimulant responses. D 2003 Elsevier Science Inc. All rights reserved. Keywords: Neurotensin; Antipsychotic drugs; Psychostimulants; Dopamine D2 receptors

* Corresponding author. Tel.: +1-508-856-2410; fax: +1-508-856-5920. E-mail address: [email protected] (P.R. Dobner). 0024-3205/03/$ - see front matter D 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0024-3205(03)00411-9

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Central NT administration produces a spectrum of effects that resemble those of both antipsychotic and psychostimulant drugs Neurotensin (NT) has been proposed to mediate certain actions of both APDs and psychostimulants. All clinically effective APDs exhibit a significant affinity for DA D2 receptors. This observation has been the cornerstone of the DA hypothesis of schizophrenia, which posits that schizophrenia is a disorder of overactivity of central DA systems. Conventional (typical) APDs, such as haloperidol, produce a spectrum of extrapyramidal motor side effects (EPS), which is thought to be due to D2 receptor blockade in the dorsal striatum. Atypical APDs, such as clozapine, have a much lower or absent incidence of EPS and have become the first line treatment for schizophrenia (Meltzer and Deutch, 1999). In contrast to APDs, the psychostimulants amphetamine and cocaine increase DA signaling in the striatum by increasing extracellular levels of the transmitter. Repeated drug exposure can result in compulsive drug taking and the development of psychotic symptoms resembling those of schizophrenia. These effects are thought to involve long-term neuroadaptive changes that result in altered drug responses (reviewed in Vanderschuren and Kalivas, 2000). Such long-term alterations in neuronal responsiveness are also thought to be involved in the therapeutic effects of APDs. There is increasing evidence that NT may mediate at least a subset of APD and psychostimulant responses and be involved in some of the long-term effects of these drugs. Whether NT produces APD- or psychostimulant-like effects depends critically on the site of administration. Intracerebroventricular (icv) NT administration was first shown to produce a variety of APD-like effects, including the potentiation of pentobarbital-and ethanol-induced sedation, muscle relaxation, and hypothermia (reviewed in Nemeroff, 1980). Subsequent site-specific microinjection studies demonstrated that NT administration in the nucleus accumbens (NAc) attenuates amphetamineinduced locomotor activity and amphetamine disruption of prepulse inhibition of the acoustic startle reflex, similar to APDs (Ervin et al., 1981; Feifel et al., 1997). In contrast, NT administration in the ventral tegmental area (VTA) increases locomotor activity in rats, an effect similar to that elicited by psychostimulant challenge (Kalivas et al., 1983). Repeated intra-VTA NT administration results in a progressive augmentation (sensitization) of this response (Kalivas and Taylor, 1985). Interestingly, repeated icv NT administration augments amphetamine-induced locomotor activity, suggesting that NT may be involved in amphetamine sensitization (Rompre, 1997). Finally, self-administration, conditioned place preference, and electrical self-stimulation experiments all indicate that NT, like psychostimulants, activates brain reward mechanisms (reviewed in Binder et al., 2001b). These APD- and psychostimulantlike effects are thought to result, at least in part, from NT modulation of DA signaling in the basal ganglia.

APD- and psychostimulant-evoked changes in Fos and NT expression The induction of immediate early gene expression has been used extensively to gain insights into the neuronal signaling mechanisms underlying both APD and psychostimulant actions (reviewed in Deutch, 1996; Hughes and Dragunow, 1995). Typical and atypical APDs produce distinct regional patterns of Fos expression. Thus, all clinically effective APDs increase Fos expression in the NAc; however, typical and atypical APDs have distinct inductive effects on Fos expression in the dorsal striatum and prefrontal cortex (PFC), respectively. These selective effects may be associated with the side effect liabilities of

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typical APDs (striatum) and the enhanced therapeutic profile of atypical APDs (PFC), while the induction of Fos expression in the NAc may be associated with the actions of both typical and atypical APDs on positive symptomatology. Psychostimulants also produce striking changes in striatal Fos expression. Amphetamine increases Fos expression in the NAc and the medial half of the dorsal striatum, while cocaine-induced Fos expression in the striatum is more widespread (Graybiel et al., 1990). Psychostimulant-evoked Fos expression in the NAc is consistent with a large body of evidence implicating the NAc in locomotor activity, while Fos induction in the dorsal striatum may be more involved in stereotyped behaviors observed in response to high dose psychostimulant challenge (Canales and Graybiel, 2000). The induction of immediate early gene products like Fos is thought to result in the subsequent induction of late response genes that may underlie longer-term changes in neuronal responsiveness. The NT gene is likely to be one such late response gene. APDs and psychostimulants induce NT gene expression in a subregionally-specific fashion that is remarkably similar to the pattern of Fos induction (reviewed in Binder et al., 2001b). Typical–but not atypical–APDs induce NT gene expression in the dorsolateral striatum, while both types of APDs increase NT expression in the NAc (Merchant et al., 1992). In contrast, psychostimulants increase NT expression predominantly in the caudal dorsomedial and ventrolateral striatum (Castel et al., 1994a; Merchant et al., 1994b; Zahm et al., 1998), although expression is also increased at more rostral levels (Castel et al., 1994b). Interestingly, many of these acute increases are sustained during chronic drug administration (Merchant et al., 1994a; Betancur et al., 1997; Betancur et al., 2001). Several lines of evidence indicate that the NT gene is a Fos target gene, perhaps explaining their overlapping expression patterns following APD treatment. First, Fos mRNA is co-expressed in the majority (f 75%) of striatal neurons expressing NT mRNA in the dorsolateral striatum following APD treatment (Merchant and Miller, 1994). Second, APD activation of NT gene expression is attenuated by antisense inhibition of Fos expression and in Fos knockout mice (Merchant, 1994; Robertson et al., 1995; Shearman and Weaver, 1997). Finally, Fos activates the NT promoter through a consensus AP-1 binding site in tissue culture cells, suggesting that increased Fos expression could result in a similar activation of NT gene expression in vivo (Harrison et al., 1995).

APD and psychostimulant effects on NT receptor expression Three NT receptors have been described, two of which are related G protein-coupled receptors designated NTR-1 and NTR-2, while the third (NTR-3) is the predominantly intracellular sortilin protein (reviewed in Vincent et al., 1999). NTR-1 appears to be the major receptor that mediates the biological effects of NT (Pettibone et al., 2002). NTR-2 may mediate the analgesic effects of NT in some but not all experimental paradigms (Dubuc et al., 1999; Remaury et al., 2002; Pettibone et al., 2002). NT also fails to stimulate intracellular signaling in transfected cells expressing NTR-2, and two non-peptide NT antagonists (SR 48692 and SR 142948A) actually display agonist activity at NTR-2 (Vita et al., 1998). Collectively, these results support the view that NTR-1 is the major receptor that mediates most of the biological effects of NT. The majority of midbrain DA neurons in the VTA and the SN express high levels of NTR-1 (Boudin et al., 1996; Alexander and Leeman, 1998), and lesions of these DA neurons result in large decreases in striatal NT binding sites, particularly in the dorsal striatum (reviewed in Binder et al., 2001b). NTR-1 is

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also expressed in cortical layer V projection neurons, at least some of which are likely to project to the striatum (Boudin et al., 1996; Alexander and Leeman, 1998). Electron microscopic immunolabeling of NTR-1 in the NAc has confirmed that these receptors are located mainly at presynaptic elements that resemble dopaminergic and glutamatergic afferents, and also on scattered neurons and glia throughout the NAc (Pickel et al., 2001). Thus, the high affinity NT receptor appears to be predominantly localized to striatal afferents, including those from the SN and cortex. Chronic treatment with typical and atypical APDs results in distinct changes in NTR-1 in the forebrain. Chronic treatment with the typical APD haloperidol increases the densities of high affinity NT binding sites in the substantia nigra (SN) and striatum. In contrast, chronic administration of atypical APDs has been reported in some studies to decrease NT receptor binding in the SN and NAc, while other studies report decreased binding in certain striatal regions (reviewed in Binder et al., 2001c). Many of the effects of APDs are maximally realized only after extended treatment, and may involve alterations in NT signaling in response to APD-induced changes in NT receptor levels. It is important to realize that the changes in NTR-1 receptors may themselves be secondary to drug-induced changes in NT expression (see below). There has been only a single report on psychostimulant-induced changes in NT receptor binding (Pilotte et al., 1991). Chronic cocaine produced a long-term decrease in NT receptor binding in the VTA, but resulted in increased binding in the SN and PFC. Although the enduring nature of these changes suggests that they could be involved in drug sensitization, further work will be required to understand the effects of chronic psychostimulant treatment on NT signaling.

Striatal signaling defects in NT knockout mice and SR 48692 pretreated rats The development of NT antagonists has provided a powerful approach toward understanding NT signaling functions; however, their usefulness is limited by the fact that they may paradoxically behave as agonists at NTR-2 and fail to block all NT-elicited effects. In order to circumvent these problems, we recently generated a line of NT knockout mice with which to investigate NT functions and have used these mice to investigate NT’s role in APD and psychostimulant responses (Dobner et al., 2001a,b). We took advantage of the fact that both typical and atypical APDs induce distinct patterns of Fos expression to compare striatal activation in NT knockout and wild type mice. Haloperidol-evoked Fos expression was markedly attenuated in the dorsolateral and central striatum, but not in other striatal sectors, of NT knockout mice. While Fos expression in the affected striatal territories was dampened along the entire anteroposterior length of the striatum, it appeared to be somewhat greater at intermediate compared to rostral levels. Similar results were obtained in rats pretreated with the NT antagonist SR 48692; thus, the decreased response to haloperidol challenge in the NT knockout mouse is not due to compensatory effects (Fadel et al., 2001). In contrast to the results obtained with haloperidol, the effects of clozapine on Fos expression in the forebrain were not altered in NT knockout mice. These results suggest that there is a regionally-specific requirement within the striatum for NT for typical APD-elicited Fos activation. Interestingly, amphetamine induction of Fos expression is also attenuated in NT knockout mice and SR 48692-pretreated rats (Dobner et al., 2001b). Amphetamine-evoked Fos expression is significantly attenuated in the medial striatum, but not in other striatal sectors or in the NAc, indicating that NT signaling is required for full Fos activation in the medial striatum.

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Thus, in NT mutant mice challenged with either haloperidol or amphetamine there is a blunted activation of striatal neurons, but in different striatal regions. Since NT is likely to act almost exclusively on striatal afferents in the dorsal striatum, it would appear that NT sets into play a common mechanism that accounts for the dampening of both APD and psychostimulant responses that involves a common effect on neurons that innervate the striatum; the corticostriatal glutamatergic neuron is the most likely candidate. The specific regional patterns of striatal activation may result from either localized NT release or combinatorial mechanisms involving NT and other neurotransmitters.

How does NT influence striatal activation? Since NTR-1 is not expressed on neurons of the dorsal striatum, NT most likely influences striatal activation through actions on dopaminergic and/or glutamatergic afferents (Fig. 1). In vivo microdialysis and voltammetry studies indicate that intra-striatal NT administration increases the extracellular levels of several neurotransmitters, including DA, GABA, and glutamate (O’Connor et al., 1992; Ferraro et al., 1995, 1997, 1998, 2001). NMDA receptor antagonists markedly attenuate both APD and psychostimulant induction of striatal Fos expression, suggesting that glutamatergic drive over striatal neurons is required for these responses (Boegman and Vincent, 1996; Torres and Rivier, 1992; Hussain et al., 2001). These responses also involve either increased DA signaling through both D1 and D2 receptors in the case of psychostimulants or decreased signaling through D2 receptors in the case of APDs (Graybiel et al., 1990; Rogue and Vincendon, 1992; Ruskin and Marshall, 1994). Amphetamine is thought to evoke DA release from the cytoplasm by reversed flow through the DA transporter (Jones et al., 1998); significant release from vesicular stores occurs at higher psychostimulant doses (Cadoni et al., 1995; Schmitz et al., 2001). In addition, D2 autoreceptor inhibition and opioid signaling have been reported to modulate amphetamine-evoked DA release (Sharp et al., 1986; Pehek, 1999; Schad et al., 2002). The ability of D2 receptor antagonists to augment amphetamine-evoked

Fig. 1. Schematic of possible NT signaling mechanisms involved in striatal activation in response to either amphetamine (left panel) or haloperidol (right panel). Psyschostimulant-evoked increases in NT release could enhance amphetamine-stimulated DA release from vesicular stores due to an antagonistic effect on D2 autoinhibition, or stimulate glutamate release from corticostriatal afferents expressing NTR-1. NT could also be required for either basal or evoked glutamate release in the dorsolateral striatum following haloperidol administration. Abbreviations: SNC, substantia nigra pars compacta; SNR, substantia nigra pars reticulata; GP, globus pallidus; Glu, glutamate.

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striatal DA release may be particularly relevant, since NT signaling through NTR-1 attenuates D2 autoinhibition (Diaz-Cabiale et al., 2002) and psychostimulant treatment stimulates striatal NT release (Wagstaff et al., 1996b). These results suggest that NT could potentiate amphetamine-stimulated DA release through antagonism of D2-mediated autoinhibition. NT may also influence amphetamine-evoked Fos expression by modulating glutamate release from corticostriatal afferents. There are, however, conflicting data regarding amphetamine effects on striatal glutamate: some reports indicate that amphetamine increases extracellular glutamate levels (Mora and Porras, 1993; Del Arco et al., 1999; Gray et al., 1999; Rawls and McGinty, 2000), while others report no effect (Nash and Yamamoto, 1993; Reid et al., 1997), or decreases (Miele et al., 2000). Intra-striatal NT administration increases extracellular glutamate levels (Ferraro et al., 1995, 1998) consistent with the possibility that psychostimulant-evoked NT release (Wagstaff et al., 1996b) may increase glutamate release. The ability of glutamate transporters to avidly clear extracellular glutamate makes it difficult to reliably detect changes in glutamate levels unless the increases are sustained or pathological, and thus it would be useful to determine if amphetamine changes extracellular glutamate levels in the presence of glutamate reuptake inhibitors. Alternatively, glutamate may play a permissive role in amphetamineevoked Fos expression that does not require phasic increases in extracellular glutamate levels. Amphetamine-induced Fos expression was selectively attenuated in the medial striatum of NT knockout mice. This suggests that amphetamine evokes the localized release of NT from medium spiny neurons in this striatal sector. The observation that methamphetamine-elicited NT release requires both D1 and NMDA receptor signaling suggests that the striatal neurons from which NT is released are the D1-expressing cells that contribute to the direct striatofugal pathway (Wagstaff et al., 1997). These results also suggest that NT, DA and glutamate may mutually enhance each other’s release –a phenomenon that could be particularly important under enhanced DA or glutamate transmission. NT immunoreactive neurons have been described along the medial border of the dorsal striatum suggesting a possible local source of striatal NT (Zahm, 1987). Similar considerations apply for APD-induced striatal Fos expression, which depends on interactions between multiple neurotransmitters (Deutch, 1996). Pretreatment with NMDA receptor antagonists attenuates haloperidol-induced Fos expression, suggesting that D2 antagonist-evoked striatal glutamate release from cortical (or thalamic) afferents determines the Fos response (De Souza and Meredith, 1999; Hussain et al., 2001). NT may influence Fos activation, at least in part, through the modulation of glutamate release by interacting with NTR-1 on the glutamatergic inputs to the striatum. The subregional specificity may arise from localized release of NT and glutamate. In fact, D2 receptor blockade inhibits NT release in the medial striatum, but results in a small (but not significant) increase in the lateral striatum (Wagstaff et al., 1996a). Chronic–but not acute–haloperidol treatment increases both basal and depolarization-evoked extracellular glutamate levels in the dorsal striatum, suggesting that basal glutamate signaling may be sufficient for acute haloperidol-evoked Fos expression (Daly and Moghaddam, 1993; Yamamoto and Cooperman, 1994; See and Chapman, 1994; See and Lynch, 1995).

NT functions in psychostimulant responses Several recent reports indicate that NT plays a key role in psychostimulant sensitization and that it may also be required, at least in part, for the acute behavioral responses to these drugs (Horger et al., 1994; Rompre and Perron, 2000; Betancur et al., 1998; Panayi et al., 2001; Costa et al., 2001). In all of

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these studies, pretreatment with SR 48692 affected psychostimulant-induced behavioral activation, although the results vary somewhat for different treatment combinations. Pretreatment with a relatively low dose of SR 48692 for five days was found to delay the development of cocaine sensitization without affecting acute behavioral responses (Horger et al., 1994). In a subsequent study, pretreatment with a higher dose of SR 48692 for five days attenuated cocaine-induced increases in both horizontal and vertical activity (Betancur et al., 1998). Various SR 48692 treatments also attenuate or block amphetamine sensitization and also attenuate certain acute responses (Rompre and Perron, 2000; Panayi et al., 2001; Costa et al., 2001). These results provide a strong indication that NT is required for certain aspects of both acute psychostimulant-induced behavioral responses and the development and expression of sensitization.

NT functions in APD responses The induction of Fos and NT expression in the dorsolateral striatum in response to typical APDs has led to the suggestion that these changes may at least partially mediate the motor side effects associated with the therapeutic use of these drugs. Chronic treatment with typical APDs can lead to tardive dyskinesia (TD). Rats treated chronically with typical APDs develop vacuous chewing movements (VCMs), similar to the orobuccofacial dyskinesias seen in patients with TD. VCMs can also be elicited in rats by administering NT into the ventrolateral striatum, and the VCMs seen in animals treated chronically with APDs are suppressed by the NTR1 antagonist SR 48692, suggesting that NT may be involved in the pathophysiology of TD (Stoessl, 1995). While these data suggest that NT may be involved in the motor side effects that accompany typical APD treatment, one finding that argues against such an interpretation is the fact that haloperidol-induced catalepsy, perhaps the most widely used screen for APD-elicited motor side effects, is not altered in NT knockout mice (Dobner et al., 2001a). NT has also been implicated in the etiology of schizophrenia and the therapeutic response to APD treatment, particularly the reduction of negative symptoms (Garver et al., 1991; Sharma et al., 1997). Thus, CSF levels of NT are reduced in schizophrenic patients with prominent negative symptoms and return to normal levels during APD treatment. Moreover, NT receptor antagonists block the ability of haloperidol to ameliorate isolation rearing-induced prepulse inhibition deficits (Binder et al., 2001a; Binder et al., 2002). Since these responses involve the integration of sensory information to influence motor responses, NT actions in the dorsolateral striatum (Dobner et al., 2001a), an area implicated in sensorimotor integration, could underlie the enhancement of sensorimotor gating responses by conventional APDs.

Summary A combination of pharmacological and genetic approaches has provided important glimpses into the functional roles of NT in APD and psychostimulant responses. The available evidence, although incomplete, suggests that NT plays key roles in APD enhancement of sensorimotor gating functions and in motor side effects that develop during chronic APD treatment. Paradoxically, NT also appears to play a critical role in psychostimulant sensitization. NT knockout mice display distinct region-specific defects in typical APD- and psychostimulant-elicited striatal Fos activation. These results suggest that NT

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signaling functions are parcelled into discrete striatal regions and most likely distinct striatal output pathways. Future studies with NT knockout mice should uncover additional neurochemical and behavioral defects that will provide new insights regarding the mechanisms through which NT modulates striatal activation and function. Acknowledgements The authors wish to acknowledge grant support from the National Institutes of Health to A.Y.D. (MH45124, MH-57795, NS-44282) and P.R.D. (HL-33307), the National Alliance for Research on Schizophrenia and Depression to J.F., the National Parkinson Foundation Center of Excellence at Vanderbilt University to A.Y.D., and the University of Massachusetts Medical School Genetics Program to P.R.D. References Alexander, M.J., Leeman, S.E., 1998. Widespread expression in adult rat forebrain of mRNA encoding high-affinity neurotensin receptor. Journal of Comparative Neurology 402, 475 – 500. Betancur, C., Cabrera, R., de Kloet, E.R., Pelaprat, D., Rostene, W., 1998. Role of endogenous neurotensin in the behavioral and neuroendocrine effects of cocaine. Neuropsychopharmacology 19, 322 – 332. Betancur, C., Lepee-Lorgeoux, I., Cazillis, M., Accili, D., Fuchs, S., Rostene, W., 2001. Neurotensin gene expression and behavioral responses following administration of psychostimulants and antipsychotic drugs in dopamine D3 receptor deficient mice. Neuropsychopharmacology 24, 170 – 182. Betancur, C., Rostene, W., Berod, A., 1997. Chronic cocaine increases neurotensin gene expression in the shell of the nucleus accumbens and in discrete regions of the striatum. Molecular Brain Research 44, 334 – 340. Binder, E., Kinkead, B., Owens, M.J., Kilts, C.D., Nemeroff, C.B., 2001a. Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating. Journal of Neuroscience 21, 601 – 608. Binder, E.B., Kinkead, B., Owens, M.J., Nemeroff, C.B., 2001b. Neurotensin and dopamine interactions. Pharmacological Reviews 53, 453 – 486. Binder, E.B., Kinkead, B., Owens, M.J., Nemeroff, C.B., 2001c. The role of neurotensin in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs. Biological Psychiatry 50, 856 – 872. Binder, E.B., Gross, R.E., Nemeroff, C.B., Kilts, C.D., 2002. Effects of neurotensin receptor antagonism on latent inhibition in Sprague-Dawley rats. Psychopharmacology 161, 288 – 295. Boegman, R.J., Vincent, S.R., 1996. Involvement of adenosine and glutamate receptors in the induction of c-fos in the striatum by haloperidol. Synapse 22, 70 – 77. Boudin, H., Pe´laprat, D., Roste`ne, W., Beaudet, A., 1996. Cellular distribution of neurotensin receptors in rat brain: immunohistochemical study using an antipeptide antibody against the cloned high affinity receptor. Journal of Comparative Neurology 373, 76 – 89. Cadoni, C., Pinna, A., Russi, G., Consolo, S., Di Chiara, G., 1995. Role of vesicular dopamine in the in vivo stimulation of striatal dopamine transmission by amphetamine: evidence from microdialysis and Fos immunohistochemistry. Neuroscience 65, 1027 – 1039. Canales, J.J., Graybiel, A.M., 2000. A measure of striatal function predicts motor stereotypy. Nature Neuroscience 3, 377 – 383. Castel, M.-N., Morino, P., Nylander, I., Terenius, L., Ho¨kfelt, T., 1994a. Differential dopaminergic regulation of the neurotensin striatonigral and striatopallidal pathways in the rat. Europrean Journal of Pharmacology 262, 1 – 10. ˚ ., Ho¨kfelt, T., 1994b. Up-regulation of neurotensin mRNA in the rat striatum after acute Castel, M.N., Morino, P., Dagerlind, A methamphetamine treatment. European Journal of Neuroscience 6, 646 – 656. Costa, F.G., Frussa-Filho, R., Felicio, L.F., 2001. The neurotensin receptor antagonist, SR48692, attenuates the expression of amphetamine-induced behavioral sensitisation in mice. European Journal of Pharmacology 428, 97 – 103.

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