Abstract
Rationale
The neuropeptide neurotensin (NT), which has been implicated in the modulation of dopamine signaling, is expressed in a subset of dopamine neurons and antagonism of the NT receptor has been reported to reduce psychostimulant-induced behavior. Gene knockout (KO) of the neurotensin/neuromedin N precursor provides an approach to delineating possible roles of endogenous NT in psychostimulant-induced responses.
Objectives
Involvement of NT in cocaine responses was examined by comparing acute and conditioned locomotor responses, conditioned place preference, and sensitization in wild-type (WT), heterozygous, and homozygous NT KO mice.
Results
NT KO mice did not differ from their WT or heterozygous littermates in either baseline or acute cocaine-stimulated locomotor activity. The locomotor stimulant effects of cocaine were slightly prolonged in these mice under some, but not all, experimental conditions. The rewarding effects of cocaine as assessed in the conditioned place preference and conditioned locomotion paradigms were also similar between genotypes at all cocaine doses tested.
Conclusions
These results suggest that endogenous NT is not involved in cocaine-mediated behaviors in most circumstances, but under some conditions, a slight prolongation of the effects of cocaine was observed in the absence of endogenous NT.
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References
Agnati LF, Fuxe K, Benfenati F, Battistini N (1983) Neurotensin in vitro markedly reduces the affinity in subcortical limbic 3H-N-propylnorapomorphine binding sites. Acta Physiol Scand 119:459–461
Azzi M, Betancur C, Sillaber I, Spangel R, Rostene W, Berod A (1998) Repeated administration of the neurotensin receptor antagonist SR 48692 differentially regulates mesocortical and mesolimbic dopaminergic systems. J Neurochem 71:1158–1167
Bardo MT, Bevins RA (2000) Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl) 153:31–43
Bean AJ, Roth RH (1991) Extracellular dopamine and neurotensin in rat prefrontal cortex in vivo: effects of median forebrain bundle stimulation frequency, stimulation pattern, and dopamine autoreceptors. J Neurosci 11:2694–2702
Bean AJ, Dagerlind A, Hokfelt T, Dobner PR (1992) Cloning of human neurotensin/neuromedin N genomic sequences and expression in the ventral mesencephalon of schizophrenics and age/sex matched controls. Neuroscience 50:259–268
Berger B, Gaspar P, Verney C (1992) Colocalization of neurotensin in the mesocortical dopaminergic system. Restricted regional and laminar distribution in rat, lack of colocalization in human. Ann N Y Acad Sci 668:307–310
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. Brain Res Mol Brain Res 44:334–340
Betancur C, Cabrera R, de Kloet ER, Pelaprat D, Rostene W (1998) Role of endogenous neurotensin in the behavioral and neuroendocrine effects of cocaine. Neuropsychopharmacology 19:322–332
Binder EB, Kinkead B, Owens MJ, Kilts CD, Nemeroff CB (2001) Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating. J Neurosci 21:601–608
Binder EB, Kinkead B, Owens MJ, Nemeroff CB (2004) Neurotensin receptor antagonist SR 142948A alters Fos expression and extrapyramidal side effect profile of typical and atypical antipsychotic drugs. Neuropsychopharmacology 29:2200–2207
Costa FG, Frussa-Filho R, Felicio LF (2001) The neurotensin receptor antagonist, SR48692, attenuates the expression of amphetamine-induced behavioural sensitisation in mice. Eur J Pharmacol 428:97–103
Costa FG, Frussa-Filho R, Canteras NS, Valera AG, Felicio LF (2007) Blockade of neurotensin receptors during amphetamine discontinuation indicates individual variability. Neuropeptides 41:83–91
D'Este L, Casini A, Puglisi-Allegra S, Cabib S, Renda TG (2007) Comparative immunohistochemical study of the dopaminergic systems in two inbred mouse strains (C57BL/6J and DBA/2J). J Chem Neuroanat 33:67–74
Dobner PR, Fadel J, Deitemeyer N, Carraway RE, Deutch AY (2001) Neurotensin-deficient mice show altered responses to antipsychotic drugs. Proc Natl Acad Sci U S A 98:8048–8053
During MJ, Bean AJ, Roth RH (1992) Effects of CNS stimulants on the in vivo release of the colocalized transmitters, dopamine and neurotensin, from rat prefrontal cortex. Neurosci Lett 140:129–133
Ervin GN, Birkemo LS, Nemeroff CB, Prange AJ Jr (1981) Neurotensin blocks certain amphetamine-induced behaviours. Nature 291:73–76
Fadel J, Dobner PR, Deutch AY (2001) The neurotensin antagonist SR 48692 attenuates haloperidol-induced striatal Fos expression in the rat. Neurosci Lett 303:17–20
Fadel J, Dobner PR, Deutch AY (2006) Amphetamine-elicited striatal Fos expression is attenuated in neurotensin null mutant mice. Neurosci Lett 402:97–101
Felszeghy K, Espinosa JM, Scarna H, Berod A, Rostene W, Pelaprat D (2007) Neurotensin receptor antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference. Neuropsychopharmacology 32:2601–2610
Glimcher PW, Margolin DH, Giovino AA, Hoebel BG (1984) Neurotensin: a new 'reward peptide'. Brain Res 291:119–124
Glimcher PW, Giovino AA, Hoebel BG (1987) Neurotensin self-injection in the ventral tegmental area. Brain Res 403:147–150
Gruber SH, Nomikos GG, Mathe AA (2002) d-Amphetamine-induced increase in neurotensin and neuropeptide Y outflow in the ventral striatum is mediated via stimulation of dopamine D1 and D2/3 receptors. J Neurosci Res 69:133–139
Gui X, Carraway RE, Dobner PR (2004) Endogenous neurotensin facilitates visceral nociception and is required for stress-induced antinociception in mice and rats. Neuroscience 126:1023–1032
Gygi SP, Gibb JW, Hanson GR (1994) Differential effects of antipsychotic and psychotomimetic drugs on neurotensin systems of discrete extrapyramidal and limbic regions. J Pharmacol Exp Ther 270:192–197
Hall FS, Li XF, Randall-Thompson J, Sora I, Murphy DL, Lesch KP, Caron M, Uhl GR (2009) Cocaine-conditioned locomotion in dopamine transporter, norepinephrine transporter and 5-HT transporter knockout mice. Neuroscience 162:870–880
Hanson GR, Smiley P, Johnson M, Letter A, Bush L, Gibb JW (1989) Response by the neurotensin systems of the basal ganglia to cocaine treatment. Eur J Pharmacol 160:23–30
Heidbreder C, Gewiss M, De Mot B, Mertens I, De Witte P (1992) Balance of glutamate and dopamine in the nucleus accumbens modulates self-stimulation behavior after injection of cholecystokinin and neurotensin in the rat brain. Peptides 13:441–449
Hertel P, Mathe JM, Nomikos GG, Iurlo M, Mathe AA, Svensson TH (1995) Effects of D-amphetamine and phencyclidine on behavior and extracellular concentrations of neurotensin and dopamine in the ventral striatum and the medial prefrontal cortex of the rat. Behav Brain Res 72:103–114
Holst B, Holliday ND, Bach A, Elling CE, Cox HM, Schwartz TW (2004) Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem 279:53806–53817
Horger BA, Taylor JR, Elsworth JD, Roth RH (1994) Preexposure to, but not cotreatment with, the neurotensin antagonist SR 48692 delays the development of cocaine sensitization. Neuropsychopharmacology 11:215–222
Jomphe C, Lemelin PL, Okano H, Kobayashi K, Trudeau LE (2006) Bidirectional regulation of dopamine D2 and neurotensin NTS1 receptors in dopamine neurons. Eur J Neurosci 24:2789–2800
Kalivas PW, Taylor S (1985) Behavioral and neurochemical effect of daily injection with neurotensin into the ventral tegmental area. Brain Res 358:70–76
Kalivas PW, Nemeroff CB, Prange AJ Jr (1981) Increase in spontaneous motor activity following infusion of neurotensin into the ventral tegmental area. Brain Res 229:525–529
Kalivas PW, Burgess SK, Nemeroff CB, Prange AJ Jr (1983) Behavioral and neurochemical effects of neurotensin microinjection into the ventral tegmental area of the rat. Neuroscience 8:495–505
Kalivas PW, Nemeroff CB, Prange AJ Jr (1984) Neurotensin microinjection into the nucleus accumbens antagonizes dopamine-induced increase in locomotion and rearing. Neuroscience 11:919–930
Kelley AE, Cador M, Stinus L, Le Moal M (1989) Neurotensin, substance P, neurokinin-alpha, and enkephalin: injection into ventral tegmental area in the rat produces differential effects on operant responding. Psychopharmacology (Berl) 97:243–252
Kinkead B, Dobner PR, Egnatashvili V, Murray T, Deitemeyer N, Nemeroff CB (2005) Neurotensin-deficient mice have deficits in prepulse inhibition: restoration by clozapine but not haloperidol, olanzapine, or quetiapine. J Pharmacol Exp Ther 315:256–264
Leonetti M, Brun P, Sotty F, Steinberg R, Soubrie P, Bert L, Renaud B, Suaud-Chagny MF (2002) The neurotensin receptor antagonist SR 142948A blocks the efflux of dopamine evoked in nucleus accumbens by neurotensin ejection into the ventral tegmental area. Naunyn Schmiedebergs Arch Pharmacol 365:427–433
Liang Y, Boules M, Li Z, Williams K, Miura T, Oliveros A, Richelson E (2010) Hyperactivity of the dopaminergic system in NTS1 and NTS2 null mice. Neuropharmacology 58:1199–1205
Nemeroff CB, Hernandez DE, Luttinger D, Kalivas PW, Prange AJ Jr (1982) Interactions of neurotensin with brain dopamine systems. Ann N Y Acad Sci 400:330–344
Nemeroff CB, Luttinger D, Hernandez DE, Mailman RB, Mason GA, Davis SD, Widerlov E, Frye GD, Kilts CA, Beaumont K, Breese GR, Prange AJ Jr (1983) Interactions of neurotensin with brain dopamine systems: biochemical and behavioral studies. J Pharmacol Exp Ther 225:337–345
Panayi F, Dorso E, Lambas-Senas L, Renaud B, Scarna H, Berod A (2002) Chronic blockade of neurotensin receptors strongly reduces sensitized, but not acute, behavioral response to D-amphetamine. Neuropsychopharmacology 26:64–74
Panayi F, Colussi-Mas J, Lambas-Senas L, Renaud B, Scarna H, Berod A (2005) Endogenous neurotensin in the ventral tegmental area contributes to amphetamine behavioral sensitization. Neuropsychopharmacology 30:871–879
Post RM, Weiss SR, Pert A (1987) The role of context and conditioning in behavioral sensitization to cocaine. Psychopharmacol Bull 23:425–429
Reynolds SM, Geisler S, Berod A, Zahm DS (2006) Neurotensin antagonist acutely and robustly attenuates locomotion that accompanies stimulation of a neurotensin-containing pathway from rostrobasal forebrain to the ventral tegmental area. Eur J Neurosci 24:188–196
Richard F, Barroso S, Martinez J, Labbe-Jullie C, Kitabgi P (2001) Agonism, inverse agonism, and neutral antagonism at the constitutively active human neurotensin receptor 2. Mol Pharmacol 60:1392–1398
Robledo P, Maldonado R, Koob GF (1993) Neurotensin injected into the nucleus accumbens blocks the psychostimulant effects of cocaine but does not attenuate cocaine self-administration in the rat. Brain Res 622:105–112
Rompre PP (1997) Repeated activation of neurotensin receptors sensitizes to the stimulant effect of amphetamine. Eur J Pharmacol 328:131–134
Rompre PP, Bauco P (2006) Neurotensin receptor activation sensitizes to the locomotor stimulant effect of cocaine: a role for NMDA receptors. Brain Res 1085:77–86
Rompre P, Perron S (2000) Evidence for a role of endogenous neurotensin in the initiation of amphetamine sensitization. Neuropharmacology 39:1880–1892
Rompre PP, Bauco P, Gratton A (1992) Facilitation of brain stimulation reward by mesencephalic injections of neurotensin-(1–13). Eur J Pharmacol 211:295–303
Smits SM, Terwisscha van Scheltinga AF, van der Linden AJ, Burbach JP, Smidt MP (2004) Species differences in brain pre-pro-neurotensin/neuromedin N mRNA distribution: the expression pattern in mice resembles more closely that of primates than rats. Brain Res Mol Brain Res 125:22–28
Sora I, Wichems C, Takahashi N, Li XF, Zeng Z, Revay R, Lesch KP, Murphy DL, Uhl GR (1998) Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci U S A 95:7699–7704
Sotty F, Brun P, Leonetti M, Steinberg R, Soubrie P, Renaud B, Suaud-Chagny MF (2000) Comparative effects of neurotensin, neurotensin(8–13) and [D-Tyr(11)]neurotensin applied into the ventral tegmental area on extracellular dopamine in the rat prefrontal cortex and nucleus accumbens. Neuroscience 98:485–492
Tzschentke TM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56:613–672
Vita N, Oury-Donat F, Chalon P, Guillemot M, Kaghad M, Bachy A, Thurneyssen O, Garcia S, Poinot-Chazel C, Casellas P, Keane P, Le Fur G, Maffrand JP, Soubrie P, Caput D, Ferrara P (1998) Neurotensin is an antagonist of the human neurotensin NT2 receptor expressed in Chinese hamster ovary cells. Eur J Pharmacol 360:265–272
von Euler G, Fuxe K, Benfenati F, Hansson T, Agnati LF, Gustafsson JA (1989) Neurotensin modulates the binding characteristics of dopamine D2 receptors in rat striatal membranes also following treatment with toluene. Acta Physiol Scand 135:443–448
Wagstaff JD, Bush LG, Gibb JW, Hanson GR (1994) Endogenous neurotensin antagonizes methamphetamine-enhanced dopaminergic activity. Brain Res 665:237–244
Wagstaff JD, Gibb JW, Hanson GR (1996) Microdialysis assessment of methamphetamine-induced changes in extracellular neurotensin in the striatum and nucleus accumbens. J Pharmacol Exp Ther 278:547–554
Yamada M, Yamada M, Lombet A, Forgez P, Rostene W (1998) Distinct functional characteristics of levocabastine sensitive rat neurotensin NT2 receptor expressed in Chinese hamster ovary cells. Life Sci 62:PL 375–380
Zahm DS, Williams ES, Krause JE, Welch MA, Grosu DS (1998) Distinct and interactive effects of d-amphetamine and haloperidol on levels of neurotensin and its mRNA in subterritories in the dorsal and ventral striatum of the rat. J Comp Neurol 400:487–503
Zahm DS, Grosu S, Williams EA, Qin S, Berod A (2001) Neurons of origin of the neurotensinergic plexus enmeshing the ventral tegmental area in rat: retrograde labeling and in situ hybridization combined. Neuroscience 104:841–851
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This research was supported financially by the National Institute on Drug Abuse Intramural Research Program (NIH).
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Hall, F.S., Centeno, M., Perona, M.T.G. et al. Effects of neurotensin gene knockout in mice on the behavioral effects of cocaine. Psychopharmacology 219, 35–45 (2012). https://doi.org/10.1007/s00213-011-2370-9
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DOI: https://doi.org/10.1007/s00213-011-2370-9