Abstract
Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration ofd-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2:d-amphetamine, 0.25 µg/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not “primed” with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration ofd-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a fulld-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses ofd-amphetamine. In experiment 2c, the infusate (1 µgd-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbicstriatal systems, with particular reference to the mesoaccumbens dopamine projection.
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Alexander BK, Coambs RB, Hadaway PF (1978) The effect of housing and gender on morphine self-administration in rats. Psychopharmacology 58: 175–179
Alexander BK, Beyerstein BL, Hadaway PF, Coambs RB (1981) Effect of early and later colony housing on oral ingestion of morphine in rats. Pharmacol Biochem Behav 15: 571–576
Boyle AE, Gill K, Smith BR, Amit Z (1991) Differential effects of an early housing manipulation on cocaine-induced activity and self-administration in laboratory rats. Pharmacol Biochem Behav 39: 269–274
Bozarth MA, Wise RA (1981) Intracranial self-administration of morphine into the ventral tegmental area in rats. Life Sci 28: 551–555
Bozarth MA, Murray A, Wise RA (1989) Influence of housing conditions on the acquisition of intravenous heroin and cocaine self-administration in rats. Pharmacol Biochem Behav 33: 903–907
Britton DR, Curzon P, MacKenzie RG, Kebabian JW, Williams JE, Kerkman D (1991) Evidence for involvement of both D1 and D2 receptors in maintaining cocaine self-administration. Pharmacol Biochem Behav 39: 911–915
Caine SB, Koob GF (1993) Modulation of cocaine self-administration in the rat through D-3 dopamine receptors. Science 260: 1814–1816
Caine SB, Lintz R, Koob GF (1982) Intravenous drug self-administration techniques in animals. In: Sahgal A. (ed) Behavioural neuroscience: a practical approach. Oxford University Press
Corrigall WA, Coen KM (1991) Cocaine self-administration is increased by both D1 and D2 dopamine antagonists. Pharmacol Biochem Behav 39: 799–802
Creese I, Sibley DR, Hamblin MW, Leff SE (1983) The classification of dopamine receptors. Annu Rev Neurosci 6: 43–71
Deminière JM, Piazza PV, Guegan G, Abrous N, Maccari S, Le Moal M, Simon H (1992) Increased locomotor response to novelty and propensity to I–V amphetamine self-administration in adult offspring of stressed anothers. Brain Res 586: 135–139
de Wit H, Wise RA (1977) Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine or phenoxybenzamine. Can J Psychol 31: 195–202
Einon DF, Morgan MJ (1978) Early isolation produces enduring hyperactivity in the rat, but no effects on spontaneous alternation. Q J Exp Psychol 30: 151–156
Einon DF, Sahakian BJ (1979) Environmentally induced differences in the susceptibility of rats to CNS stimulants and CNS depressants: evidence against a unitary explanation. Psychopharmacology 61: 299–307
Ettenberg A, Pettit HO, Bloom FE, Koob GF (1982) Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems. Psychopharmacology 78: 204–209
Fiala BFM, Snow FM, Greenough WT (1977) “Impoverished” rats weigh more than “enriched” rats because they eat more. Dev Psychobiol 10: 537–541
Fowler SC, Johnson JS, Kallman MJ, Liou J-R, Wilson MC, Hikal AH (1993) In a drug discrimination procedure isolation-reared rats generalize to lower doses of cocaine and amphetamine than rats reared in an enriched environment. Psychopharmacology 110: 115–118
Garzon J, Del Rio J (1981) Hyperactivity induced in rats by long-term isolation: further studies on a new animal model for the detection of antidepressants. Eur J Pharmacol 74: 287–294
Garzon J, Fuentes JA, Del Rio J (1979) Antidepressants selectively antagonize the hyperactivity induced in rats by long-term isolation. Eur J Pharmacol 59: 293–296
Gentsch C, Lichtsteiner M, Feer H (1981a) Locomotor activity, defecation score and corticosterone levels during an openfield exposure: a comparison among individually and group-housed rats, and genetically selected rat lines. Physiol Behav 27: 183–186
Gentsch C, Lichtsteiner M, Feer H (1981b) Individual housing of rats causes divergent changes in spontaneous and reactive activity. Experientia 37: 61–62
Goeders NE, Smith JE (1983) Cortical dopaminergic involvement in cocaine reinforcement. Science 221: 773–775
Guisado E, Fernandez-Tome P, Garzon J, Del Rio J (1980) Increased receptor binding in the striatum of rats after long term isolation. Eur J Pharmacol 65: 463–464
Hadaway PF, Alexander BK, Coambs RB, Beyerstein B (1979) The effect of housing and gender on preference for morphine-sucrose solutions in rats. Psychopharmacology 66: 87–91
Hoebel BG, Monaco AP, Hernandez L, Aulisi EF, Stanley BG, Lenard L (1983) Self-injection of amphetamine directly into the brain. Psychopharmacology 81: 158–163
Hubner CB, Moreton JE (1991) Effects of selective D1 and D2 dopamine antagonists on cocaine self-administration in the rat. Psychopharmacology 105: 151–156
Iorio LC, Barnett A, Leitz FH, Houser VP, Korduba CA (1983) SCH-23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems. J Pharmacol Exp Ther 226: 462–468
Izenwasser S, Cox BM (1990) Daily cocaine treatment produces a persistent reduction of [3H]dopamine uptake in vitro in rat nucleus accumbens but not in striatum. Brain Res 531: 338–341
Izenwasser S, Werling LL, Cox BM (1990) Comparison of the effects of cocine and other inhibitors of dopamine uptake in rat striatum, nucleus accumbens, olfactory tubercle, and medial prefrontal cortex. Brain Res 520: 303–309
Jenner P, Marsden CD (1981) Substituted benzamide drugs as selective neuroleptic agents. Neuropharmacology 20: 1258–1293
Jones GH, Marsden CA, Robbins TW (1990) Increased sensitivity to amphetamine and reward-related stimuli following social isolation in rats: possible disruption of dopamine-dependent mechanisms of the nucleus accumbens. Psychopharmacology 102: 364–372
Jones GH, Hernandez TD, Kendall DA, Marsden CA, Robbins TW (1992) Dopaminergic and serotonergic function following isolation rearing in rats: study of behavioural responses and postmortem and in vivo neurochemistry. Pharmacol Biochem Behav 43: 17–35
Kalivas PW, Duffy P (1987) Sensitization to repeated morphine injection in the rat: possible involvement of A10 dopamine neurons. J Pharmacol Exp Ther 241: 201–212
Kalivas PW, Duffy P (1990) Effect of acute and daily neurotensin and enkephalin treatments on extracellular dopamine in the nucleus accumbens. J Neurosci 10: 2940–2949
Kalivas PW, Duffy P (1993a) Time course of extracellular dopamine and behavioural sensitization to cocaine. I. Dopamine axon terminals. J Neurosci 13: 266–275
Kalivas PW, Duffy P (1993b) Time course of extracellular dopamine and behavioural sensitization to cocaine. II. Dopamine Perikarya. J Neurosci 13: 276–284
Katz RJ (1982) Animal model of depression: pharmacological sensitivity of a hedonic deficit. Pharmacol Biochem Behav 16: 965–968
Katz DM, Steinberg H (1972) Factors which might modify morphine-dependence in rats. In: Van Praag HM, De Ewen F, Bohn NV (eds) Biochemical and pharmacological aspects of dependence and reports on marijuana research. De Erven, Bonn, pp 46–61
Koob GF, Le HT, Creese I (1987) The D1 dopamine receptor antagonist SCH 23390 increases cocaine self-administration in the rat. Neurosci Lett 79: 315–320
Kostowski W, Czlondowski A (1973) The activity of some neuroleptic drugs and amphetamine in normal and isolated rats. Psychopharmacology 10: 82–87
Kostowski W, Czlonkowski A, Rewerski W, Peichoki T (1977) Morphine action in grouped and isolated rats and mice. Psychopharmacology 53: 191–193
Kuczenski R (1983) Biochemical actions of amphetamine and other stimulants. In: Creese I (ed) Central nervous system pharmacology: stimulants: neurochemical, behavioral, and clinical perspectives. Raven Press, New York, pp 31–61
Marks-Kaufman R, Lewis MJ (1984) Early housing experience modifies morphine self-administration and physical dependence in adult rats. Addict Behav 9: 235–243
Morgan MJ, Einon D (1975) Incentive motivation and behavioural inhibition in socially-isolated rats. Physiol Behav 15: 405–409
Morgan MJ (1973) Effects of post-weaning environment on learning in the rat. Anim Behav 21: 429–442
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edition. Academic Press, Sydney
Pellegrino LJ, Pellegrino AS, Cushman AJ (1979) A stereotaxic atlas of the rat brain, 2nd edition. Plenum Press, New York
Peltier R, Schenk S (1991) GR38032F, a serotonin 5-HT3 antagonist, fails to alter cocaine self-administration in rats. Pharmacol Biochem Behav 39: 133–136
Pettit HO, Ettenberg A, Bloom FE, Koob GF (1984) Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats. Psychopharmacology 84: 167–173
Phillips GD, Howes SR, Whitelaw RB, Wilkinson LS, Robbins TW, Everitt BJ (1994a) Isolation-rearing enhances the locomotor response to cocaine and a novel environment, but impairs the intravenous self-administration of cocaine. Psychopharmacology (in press)
Phillips GD, Robbins TW, Everitt BJ (1994b) Bilateral intra-accumbens self-administration ofd-amphetamine: antagonism with intra-accumbens SCH-23390 and sulpiride. Psychopharmacology 114: 477–485
Phillips GD, Robbins TW, Everitt BJ (1994c) Mesoaccumbens dopamine-opiate interactions in the control over behaviour by conditioned reinforcement. Psychopharmacology 114: 345–359
Piazza PV, Deminière JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine selfadministration. Science 245: 1511–1513
Reith ME (1988) Cocaine receptors on monoamine transporters and sodium channels. NIDA Res Monogr 88: 23–43
Richfield EK (1991) Quantitative autoradiography of the dopamine uptake complex in rat brain using [3H]GBR 12935: binding characteristics. Brain Res 540: 1–13
Risner ME, Jones BE (1980) Intravenous self-administration of cocaine and norcocaine by dogs. Psychopharmacology 71: 83–89
Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237: 1219–1223
Roberts DC, Corcoran ME, Fibiger HC (1977) On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol Biochem Behav 6: 615–620
Roberts DC, Koob GF, Klonoff P, Fibiger HC (1980) Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav 12: 781–787
Robinson TE (1988) Stimulant drugs and stress: factors influencing individual differences in the susceptibility to sensitization. In: Kalivas PW, Barnes C (eds) Sensitization of the nervous system. Telford Press, New Jersey, pp 145–173
Robledo P, Maldonado-Lopez R, Koob GF (1992) Role of dopamine receptors in the nucleus accumbens in the rewarding properties of cocaine. Ann NY Acad Sci 654: 509–512
Rosellini RA, De Cola JP, Shapiro NR (1982) Cross-motivational effects of inescapable shock are associative in nature. J Exp Psychol [Anim Behav Proc] 8: 376–388
Sahakian BJ, Robbins TW (1977) Isolation rearing enhances tail pinch-induced oral behaviour in rats. Physiol Behav 18: 53–58
Sahakian BJ, Robbins TW, Morgan MJ, Iversen SD (1975) The effects of psychomotor stimulants on stereotypy and locomotor activity in socially-deprived and control rats. Brain Res 84: 195–205
Schenk S, Lacelle G, Gorman K, Amit Z (1987) Cocaine self-administration in rats influenced by environmental conditions: implications for the etiology of drug abuse. Neurosci Lett 81: 227–231
Schenk S, Gorman K, Amit Z (1990) Age-dependent effects of isolation housing on the self-administration of ethanol in laboratory rats. Alcohol 7: 321–326
Sokoloff P, Giros J-C, Martres M-P, Bouthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347: 146–151
Stamford JA, Muscat R, O'Connor JJ, Patel J, Trout SJ, Wieczorek WJ, Kruk ZL, Willner P (1991) Voltammetric evidence that subsensitivity to reward following chronic mild stress is associated with increased release of mesolimbic dopamine. Psychopharmacology 105: 275–282
Vezina P, Kalivas PW, Stewart J (1987) Sensitization occurs to the locomotor effects of morphine and the specific mu opioid receptor agonist, DAGO, administered repeatedly to the ventral tegmental area but not to the nucleus accumbens. Brain Res 417: 51–58
Weinstock M, Speiser Z (1973) The effect ofd-propranolol and practolol on the hyperactivity induced in rats by prolonged isolation. Psychopharmacologia 30: 241–250
Wilkinson LS, Marsden CA, Kendall D, Hall S, Humby T, Robbins TW (1993) The effects of social isolation on pre- and post-synaptic indices of dopaminergic function. Pharmacol Biochem Behav, submitted
Willner P, Muscat R, Papp M, Sampson D (1991) Dopamine, depression and anti-depressant drugs. In: Willner P, Scheel-Kruger J (eds) The mesolimbic dopamine system: from motivation to action. Wiley, Chichester, pp 387–410
Winer BJ (1971) Statistical principles in experimental design. McGraw-Hill, New York
Wolf ME, White FJ, Nassar R, Brooderson RJ, Khansa MR (1993) Differential development of autoreceptor subsensitivity and enhanced dopamine release during amphetamine sensitization. J Pharmacol Exp Ther 264: 249–255
Woolverton WL (1986) Effects of a D1 and a D2 dopamine antagonist on the self-administration of cocaine and piribedil by rhesus monkeys. Pharmacol Biochem Behav 24: 531–535
Zacharko RM, Bowers WJ, Kokkinidis L, Anisman H (1983) Region specific reductions of intracranial self-stimulation after uncontrollable stress: possible effects on reward processes. Behav Brain Res 9: 129–141
Zacharko RM, Kasain M, MacNeil G, Anisman H (1990) Stressor induced behavioural alterations in intracranial self-stimulation from the ventral tegmental area: evidence for regional variations. Brain Res Bull 25: 241–246
Zetterström T, Sharp T, Ungerstedt U (1986) Further evaluation of the mechanism by which amphetamine reduces striatal dopamine metabolism: a brain dialysis study. Eur J Pharmacol 132: 1–9
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Phillips, G.D., Howes, S.R., Whitelaw, R.B. et al. Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbensd-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists. Psychopharmacology 115, 419–429 (1994). https://doi.org/10.1007/BF02245085
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DOI: https://doi.org/10.1007/BF02245085