Abstract
The maternal separation (MS) paradigm is an animal model that has been successfully used to study the long term effects of child abuse and neglect. Experiments showed that animals subjected to trauma and stress early in life display behavioural, endocrinological and growth factor abnormalities at a later stage in life, results that mirrored clinical conditions. It is apparent that adverse events early in life may affect the development and maturation of the brain negatively. The purpose of the present study was to investigate whether the abnormal brain development occurring in separated animals would also enhance the development of a preference for psychostimulant drug usage. Rats were subjected to maternal deprivation and further exposed to methamphetamine-induced conditioned place preference (CPP) which primarily measures drug reward (ventral striatum) learning and memory. Apomorphine-induced locomotor activity was also assessed to investigate the effects of methamphetamine on the dorsal (primarily locomotor activity) striatal dopaminergic system. We found that four consecutive injections of methamphetamine resulted in CPP behaviour 24 h after the 4th injection. A further four injections yielded similar CPP results and this effect lasted for at least 7 days until the third CPP assessment. These animals also had decreased ACTH and corticosterone secretions, but the prolactin levels were increased. Prior exposure to maternal separation did not have any effect on the CPP test. The ACTH and corticosterone secretions were also similarly reduced. However maternal separation decreased the release of prolactin and this reduction was not evident in the separated group that received methamphetamine. There was no significant difference in the apomorphine-induced locomotor activity of normally reared animals whether they received methamphetamine or saline. Interestingly there was a significant difference in locomotor activity between the two groups of animals that were subjected to maternal deprivation. The separated animals that received methamphetamine displayed markedly reduced locomotor activity upon apomorphine administration when compared to those that were treated with saline. Taken together, we conclude that maternal deprivation differentially influences dorsal and ventral striatal regions implicating dopaminergic mechanisms.
Similar content being viewed by others
References
Afifi AK (2003) The basal ganglia: a neural network with more than motor function. Semin Pediatr Neurol 10:3–10
Asano Y, Moroji T (1974) Effects of methamphetamine on daily rhythms of hypothalamic norepinephrine, serotonin and plasma corticosterone levels in the rat. Life Sci 14:1463–1472
Barrot M, Marinelli M, Abrous DN, Rougé-Pont F, Le Moal M, Piazza PV (2000) The dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is hormone-dependent. Eur J Neurosci 12:973–979
Ben-Jonathan N, Hnasko R (2001) Dopamine as a prolactin (PRL) inhibitor. Endocr Rev 22:724–763
Bloise E, Carey RJ, Carrera MP (2007) Behavioral sensitization produced by a single administration of apomorphine: implications for the role of Pavlovian conditioning in the mediation of context-specific sensitization. Pharmacol Biochem Behav 86:449–457
Borlongan CV, Sanberg PR (1995) Elevated body swing test: a new behavioural parameter for rats with 6-hydroxydopamine-induced hemiparkinsonism. J Neurosci 15:5372–5378
Brake WG, Zhang TY, Diorio J, Meaney MJ, Gratton A (2004) Influence of early postnatal rearing conditions on mesocorticolimbic dopamine and behavioural responses to psychostimulants and stressors in adult rats. Eur J Neurosci 19:1863–1874
Buydens-Branchey L, Branchey M, Fergeson P, Hudson J, McKermin C (1997) The meta-chlorophenylpiperazine challenge test in cocaine addicts: hormonal and psychological responses. Biol Psychiatry 41:1071–1086
Campbell UC, Carroll ME (2001) Effects of ketoconazole on the acquisition of intravenous cocaine self-administration under different feeding conditions in rats. Psychopharmacology 154:311–318
Cherng CG, Tsai C-W, Tsai Y-P, Ho M-C, Kao S-F, Yu L (2007) Methamphetamine-disrupted sensory processing mediates conditioned place preference performance. Behav Brain Res 182:103–108
Daniels WM, Pietersen CY, Carstens ME, Stein DJ (2004) Maternal separation in rats leads to anxiety-like behaviour and a blunted ACTH response and altered neurotransmitter levels in response to a subsequent stressor. Metab Brain Dis 9:3–14
Deroche V, Piazza PV, Maccari S, Le Moal M, Simon H (1992) Repeated corticosterone administration sensitizes the locomotor responses to amphetamine. Brain Res 584:309–313
Deroche V, Marinelli M, Le Moal M, Piazza PV (1997) Glucocorticoids and behavioral effects of psychostimulants. II: cocaine intravenous self-administration and reinstatement depend on glucocorticoid levels. J Pharmacol Exp Ther 281:1401–1407
Dias FRC, Carey RJ, Carrera MP (2006) Conditioned locomotion induced by unilateral intrastriatal administration of apomorphine: D2 receptor activation is critical but not the expression of the unconditioned response. Brain Res 1083:85–95
Dobkin PL, Tremblay RE, Sacchitelle C (1997) Predicting boy’s early-onset substance abuse from father’s alcoholism, son’s disruptiveness, and mother’s parenting behaviour. J Consult Clin Psychol 65:86–92
Donovan B, Padin-Rivera E, Kowaliw S (2001) “Transcend”: initial outcomes from a posttraumatic stress disorder/substance abuse treatment program. J Trauma Stress 14:757–772
Faure J, Uys J, Marais L, Stein D, Daniels W (2006) Early maternal separation followed by later stressors leads to dysregulation of the HPA-axis and increases in hippocampal NGF and NT-3 levels in a rat model. Metab Brain Dis 21:181–188
Gawin FH (1991) Cocaine addiction: psychology and neurophysiology. Science 251:1580–1586
Goeders NE (1997) A neuroendocrine role in cocaine reinforcement. Psychoneuroendocrinology 22:237–259
Goeders NE (2003) The impact of stress on addiction. Eur Neuropsychopharmacol 13:435–441
Goto Y, Grace AA (2008) Dopamine modulation of hippocampal-prefrontal cortical interaction drives memory-guided behaviour. Cereb Cortex 18:1407–1414
Härfstrand A, Fuxe K, Cintra A, Agnati LF, Zini I, Wikstrom AC, Okret S, Yu ZY, Goldstein M, Steinbusch H et al (1986) Glucocorticoid receptor immunoreactivity in monoaminergic neurons of rat brain. Proc Natl Acad Sci USA 83:9779–9783
Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB (2001) Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry 158:575–581
Heit S, Owens MJ, Plotsky PM, Nemeroff CB (1997) Corticotropin-releasing factor, stress, and depression. Neuroscientists 3:186–194
Hooks MS, Colvin AC, Juncos JL, Justice JB Jr (1992) Individual differences in basal and cocaine-stimulated extracellular dopamine in the nucleus accumbens using quantitative microdialysis. Brain Res 587:306–312
Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 16:223–244
Kalivas PW (2004) Glutamate systems in cocaine addiction. Curr Opin Pharmacol 4:23–29
Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413
Kaneno S, Watanabe A, Takahashi R (1986) Alteration of striatal dopaminergic functions implicated in methamphetamine-induced reverse tolerance in rats. Eur J Pharmacol 123:287–294
Kashihara K, Sato M, Fukuda K, Fujiwara Y, Otsuki S (1986) Reduced apomorphine sensitivity of dopamine metabolism in rat striatum after repeated administration of methamphetamine. Neurosci Res 3:351–355
Kashihara K, Fukuda K, Sato M, Otsuki S (1987) Haloperidol prevents the methamphetamine-induced apomorphine subsensitivity of dopamine metabolism in rat striatum. Neurosci Res 4:428–432
Kehoe P, Schoemaker WJ, Arons C, Triano L, Suresh G (1998) Repeated isolation stress in the neonatal rat: relation to brain dopamine systems in the 10-day-old rat. Behav Neurosci 112:1466–1474
Khantzian EJ (1997) The self-medication hypothesis of substance use disorders: a reconsideration and recent applications. Harv Rev Psychiatry 4:231–244
Kim HS, Jang CG (1997) MK-801 inhibits methamphetamine-induced conditioned place preference and behavioral sensitization to apomorphine in mice. Brain Res Bull 44:221–227
Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13:177–184
Koob GF, Sanna PP, Bloom FE (1998) Neuroscience of addiction. Neuron 21:467–476
Ladd CO, Owens MJ, Nemeroff CB (1996) Persistent changes in corticotrophin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 137:1212–1218
Ladd CO, Huot RL, Thrivikraman KV, Nemeroff CB, Meaney MJ, Plotsky PM (2000) Long-term behavioural and neuroendocrine adaptations to adverse early experience. In: Mayer EA, Saper CB (eds) Progress in brain research: the biological basis for mind body interactions. Elsevier, Amsterdam, pp 81–103
Le Moal M, Koob GF (2007) Drug addiction: pathways to the disease and pathophysiological perspectives. Eur Neuropsychopharmacol 17:377–393
Lin SK, Pan WHT, Yeh PH (2007) Prefrontal dopamine efflux during exposure to drug-associated contextual cues in rats with prior repeated methamphetamine. Brain Res Bull 71:365–371
Lopez B, Turner RJ, Saavedra LM (2005) Anxiety and risk for substance dependence among late adolescents/young adults. J Anxiety Disord 19:275–294
Mantsch JR, Schlussman SD, Ho A, Kreek MJ (2000) Effects of cocaine self-administration on plasma corticosterone and prolactin in rats. J Pharmacol Exp Ther 294:239–247
Marais L, van Rensburg SJ, van Zyl JM, Stein DJ, Daniels WMU (2008) Maternal separation of rat pups increases the risk of developing depressive-like behaviour after subsequent chronic stress by altering corticosterone and neurotrophin levels in the hippocampus. Neurosci Res 61:106–112
Marinelli M, Piazza PV (2002) Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur J Neurosci 16:387–394
Matthews K, Wilkinson LS, Robbins TW (1996a) Repeated maternal separation of pre-weanling rats attenuates the behavioural responses to primary and conditioned incentives in adulthood. Physiol Behav 59:99–107
Matthews K, Hall FS, Wilkinson LS, Robbins TW (1996b) Retarded acquisition and reduced expression of conditioned locomotor activity in adult rats following repeated early maternal separation: effects of prefeeding, d-amphetamine, dopamine antagonists and clonidine. Psychopharmacology 126:75–84
Matthews K, Robbins TW, Everitt BJ, Caine SB (1999) Repeated neonatal maternal separation alters intravenous cocaine self-administration in adult rats. Psychopharmacology 141:123–134
McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23:3531–3537
Meaney MJ, Brake W, Gratton A (2002) Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse? Psychoneuroendocrinology 27:127–138
Mizoguchi H, Yamada K, Mizuno M, Mizuno T, Nitta A, Noda Y, Nabeshima T (2004) Regulations of methamphetamine reward by exracellular signal-regulated kinase 1/2/ets-like gene-1 signalling pathway via the activation of dopamine receptors. Mol Pharmacol 65:1293–1301
Moffett MC, Goeders NE (2005) Neither non-contingent electric footshock nor administered corticosterone facilitate the acquisition of methamphetamine self-administration. Pharmacol Biochem Behav 80:333–339
Moore KE, Lookingland KJ (2000) Dopaminergic neuronal systems in the hypothalamus. In: Meador-Woodruff JH (ed) Psychopharmacology, On-line ed, www.acnp.org. The American College of Psychoneuropharmacology, pp 1–14
Nestler EJ (2001) Molecular basis of long-term plasiticity underlying addiction. Nat Rev Neurosci 2:119–128
Ortiz J, Decaprio JL, Kosten TA, Nestler EJ (1995) Strain-selective effects of corticosterone on locomotor sensitization to cocaine and on levels of tyrosine hydroxylase and glucocorticoid receptor in the ventral tegmental area. Neuroscience 67:383–397
Oswald LM, Wong DF, McCaul M, Zhou Y, Kuwabara H, Choi L, Brasic J, Wand GS (2005) Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine. Neuropsychopharmacology 30:821–832
Penk WE, Peck RF, Robinowitz R, Bell W, Little D (1988) Coping and defending styles among Vietnam combat veterans seeking treatment for posttraumatic stress disorder and substance use disorder. Recent Dev Alcohol 6:69–88
Piazza PV, Deminiere JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511–1513
Piazza PV, Le Moal M (1998) The role of stress in drug self-administration. Trends Pharmacol Sci 19:67–74
Reid MS, Ho LB, Tolliver BK, Wolkowitz OM, Berger SP (1998) Partial reversal of stress-induced behavioral sensitization to amphetamine following metyrapone treatment. Brain Res 783:133–142
Rouge-Pont F, Marinelli M, Le Moal M, Simon H, Piazza PV (1995) Stress-induced sensitization and glucocorticoids. II. Sensitization of the increase in extracellular dopamine induced by cocaine depends on stress-induced corticosterone secretion. J Neurosci 15:7189–7195
Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42
Slotten HA, Kalinichev M, Hagan JJ, Marsden CA, Fone KCF (2006) Long-lasting changes in behavioural and neuroendocrine indices in the rat following neonatal maternal separation: gender-dependent effects. Brain Res 1097:123–132
Stanton MD (1976) Drugs, Vietnam, and the Vietnam veteran: an overview. Am J Drug Alcohol Abuse 3:557–570
Sullivan RM, Gratton A (1998) Relationships between stress-induced increases in medial prefrontal cortical dopamine and plasma corticosterone levels in rats: role of cerebral laterality. Neuroscience 83:81–91
Sullivan RM, Dufresne MM (2006) Mesocortical dopamine and HPA axis regulation: role of laterality and early environment. Brain Res 1076:49–59
Szumlinski K, Haskew R, Balogun M, Maisonneuve I, Glick S (2001) Iboga compounds reverse the behavioural disinhibiting and corticosterone effects of acute methamphetamine: implications for the antiaddictive properties. Pharmacol Biochem Behav 69:485–491
Tyssen R, Vaglum P, Aasland OG, Gronvold NT, Ekeberg O (1998) Use of alcohol to cope with tension, and its relation to gender, years in medical school and hazardous drinking: a study of two nation-wide Norwegian samples of medical students. Addiction 93:1341–1349
Uys JDK, Marais L, Faure J, Prevoo D, Swart P, Stein DJ, Daniels WMU (2006) Trauma during adolescence is associated with behavioural hyperarousal, altered HPA axis activity and decreased hippocampal neurotrophin expression in the adult rat. Ann NY Acad Sci 1071:542–546
Vazquez V, Weiss S, Giros B, Martres MP, Daugé V (2007) Maternal deprivation and handling modify the effect of the dopamine D3 receptor agonist, BP 897 on morphine-conditioned place preference in rats. Psychopharmacology 193:475–486
Volpicelli J, Balaraman G, Hahn J, Wallace H, Bux D (1999) The role of uncontrollable trauma in the development of PTSD and alcohol addiction. Alcohol Res Health 23:256–262
Wise RA (1998) Drug-activation of brain reward pathways. Drug Alcohol Depend 51:13–22
Yehuda R, Kahana B, Binder-Brunes K, Southwick SM, Mason JW, Giller EL (1995) Low urinary cortisol excretion in Holocaust survivors with post-traumatic stress disorder. Am J Psychiatry 152:982–986
Zahniser NR, Sorkin A (2004) Rapid regulation of the dopamine transporter: role in stimulant addiction? Neuropharmacology 47:80–91
Acknowledgements
This work was supported by the National Research Foundation (NRF) and the Medical Research Council (MRC) of South Africa.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Faure, J., Stein, D.J. & Daniels, W. Maternal separation fails to render animals more susceptible to methamphetamine-induced conditioned place preference. Metab Brain Dis 24, 541–559 (2009). https://doi.org/10.1007/s11011-009-9158-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-009-9158-1