Abstract
Rationale
Maternal separation (MS) in neonatal rats affects ethanol self-administration (SA) in adulthood; however, the conditions and mechanisms need to be clarified.
Objectives
The goal of this study was to determine the effect of MS on ethanol SA in adulthood in different groups of rats, which control for time of separation, handling, and rearing conditions and, for mechanistic assessment, to examine GABA-A receptors in the central nucleus of the amygdala (CeA) and levels of liver metabolizing enzymes.
Methods
Newborn, male Long–Evans rats were randomly assigned to different groups and treated over postnatal days 2–14. The rats were picked up by their tails and put back down with no separation (MS0), separated from their mother for 15 min/day (MS15), separated from their mother for 180 min/day (MS180), handled once for a bedding change (NH), or were animal facility reared (AFR). In adulthood, these rats were allowed 5-day continuous access to ethanol, and GABA-A receptors and liver enzymes were measured.
Results
The MS15 group consumed and preferred significantly less ethanol (about one third) than the MS180 group; however, neither group was different from the MS0 or the AFR group. The NH group consumed and preferred significantly more ethanol than all other groups, at least twice that of the MS180s. GABA-A receptors were increased in the CeA in MS15s, which could help explain the effects. Alcohol dehydrogenase may have been altered in the AFRs.
Conclusions
Various treatments in neonates affect ethanol intake and GABA-A receptors, and possibly ethanol metabolism, in adulthood. These changes were not simply related to time of separation but were also due to the degree of handling.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ader R, Grota LJ (1969) Effects of early experience on adrenocortical reactivity. Physiol Behav 4:303–305
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
Caldji C, Diorio J, Anisman H, Meaney MJ (2004) Maternal behavior regulates benzodiazepine/GABAA receptor subunit expression in brain regions associated with fear in BALB/c and C57BL/6 mice. Neuropsychopharmacology 29:1344–1352
Campbell J, Spear LP (1999) Effects of early handling on amphetamine-induced locomotor activation and conditioned place preference in the adult rat. Psychopharmacology (Berl) 143:183–189
Champagne FA, Francis DD, Mar A, Meaney MJ (2003) Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol Behav 79(3):359–371
Crow KE, Cornell NW, Veech RL (1977) The rate of ethanol metabolism in isolated rat hepatocytes. Alcohol Clin Exp Res 1:43–50
Czachowski CL, Samson HH, Denning CE (1999) Blood ethanol concentrations in rats drinking sucrose/ethanol solutions. Alcohol Clin Exp Res 23:1331–1335
Denenberg VH (1964) Critical periods, stimulus input, and emotional reactivity: a theory of infantile stimulation. Psychol Rev 71:335–351
Flagel SB, Vazquez DM, Robinson TE (2003) Manipulations during the second, but not the first, week of life increase susceptibility to cocaine self-administration in female rats. Neuropsychopharmacology 28:1741–1751
Foster KL, McKay PF, Seyoum R, Milbourne D, Yin W, Sarma PVVS, Cook JM, June HL (2004) GABAA and opioid receptors of the central nucleus of the amygdala selectively regulate ethanol-maintained behaviors. Neuropsychopharmacology 29:269–284
Francis DD, Diorio J, Plotsky PM, Meaney MJ (2002) Environmental enrichment reverses the effects of maternal separation on stress reactivity. J Neurosci 22:7840–7843
Gallegos G, Salazar L, Moises O, Marquez W, Davis A, Sanchez S, Conner D, Schreiber HL (1990) Simple disturbance of the dam in the neonatal period can alter haloperidol-induced catalepsy in the adult offspring. Behav Neural Biol 53:172–188
Hall FS, Wilkinson LS, Humby T, Robbins TW (1999) Maternal deprivation of neonatal rats produces enduring changes in dopamine function. Synapse 32:37–43
Huot RL, Thrivikraman KV, Meaney MJ, Plotsky PM (2001) Development of adult ethanol preference and anxiety as a consequence of neonatal maternal separation in Long Evans rats and reversal with antidepressant treatment. Psychopharmacology (Berl) 158:366–373
Huot RL, Plotsky PM, Lenox RH, McNamara RK (2002) Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats. Brain Res 950:52–63
Hyytia P, Koob GF (1995) GABAA receptor antagonism in the extended amygdala decreased ethanol self-administration in rats. Eur J Pharmacol 283:151–159
Kalinichev M, Easterling KW, Holtzman SG (2001) Early neonatal experience of Long–Evans rats results in long-lasting changes in morphine tolerance and dependence. Psychopharmacology (Berl) 157:305–312
Kalinichev M, Easterling KW, Holtzman SG (2002) Early neonatal experience of Long–Evans rats results in long-lasting changes in reactivity to a novel environment and morphine-induced sensitization and tolerance. Neuropsychopharmacology 27:518–533
Kalinichev M, Easterling KW, Holtzman SG (2003) Long-lasting changes in morphine-induced locomotor sensitization and tolerance in Long–Evans mother rats as a result of periodic postpartum separation from the litter: a novel model of increased vulnerability to drug abuse? Neuropsychopharmacology 28:317–328
Ladd CO, Huot RL, Thrivikraman KV, Nemeroff CB, Plotsky PM (2004) Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation. Biol Psychiatry 55:367–375
Levine S (1957) Infantile experience and resistance to physiological stress. Science 126:405
Li Y, Robinson TE, Bhatnagar S (2003) Effects of maternal separation on behavioural sensitization produced by repeated cocaine administration in adulthood. Brain Res 960:42–47
Liu D, Diorio J, Tannenbaum B, Caldji C, Francis DD, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney MJ (1997) Maternal care, hippocampal glucocorticoid receptors, and hypothalamic–pituitary–adrenal responses to stress. Science 277:1659–1662
Matthews K, Hall FS, Wilkinson LS, Robbins TW (1996) 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 (Berl) 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
McBride WJ (2002) Central nucleus of the amygdala and the effects of alcohol and alcohol-drinking behavior in rodents. Pharmacol Biochem Behav 71:509–515
Meaney MJ, Aitken DH, Bhatnagar S, Van Berkel CH, Sapolsky RM (1988) Postnatal handling attenuates neuroendocrine, anatomical, and cognitive impairments related to the aged hippocampus. Science 238:766–768
Meaney MJ, Diorio J, Francis D, Widdowson J, LaPlante P, Caldji C, Sharma S, Seckl JR, Plotsky PM (1996) Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev Neurosci 18:49–72
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
Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. II. Solubilization, purification and properties. J Biol Chem 239:7
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 4th edn. Academic, New York
Ploj K, Roman E, Nylander I (2003) Long-term effects of maternal separation on ethanol intake and brain opioid and dopamine receptors in male Wistar rats. Neuroscience 121:787–799
Plotsky PM, Meaney MJ (1993) Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res 18:195–200
Pryce CR, Feldon J (2003) Long-term neurobehavioural impact of the postnatal environment in rats: manipulations, effects and mediating mechanisms. Neurosci Biobehav Rev 27(1–2):57–71
Pryce CR, Bettschen D, Bahr NI, Feldon J (2001) Comparison of the effects of infant handling, isolation, and nonhandling on acoustic startle, prepulse inhibition, locomotion, and HPA activity in the adult rat. Behav Neurosci 115:71–83
Pryce CR, Bettschen D, Feldon J (2001) Comparison of the effects of early handling and early deprivation on maternal care in the rat. Dev Psychobiol 38(4):239–251
Samson HH (2000) The microstructure of ethanol drinking: genetic and behavioral factors in the control of drinking patterns. Addiction 95(Suppl 2):S61–S72
Thanos OK, Taintor NB, Rivera SN, Umegaki H, Ikari H, Roth G, Ingram DK, Hitzemann R, Fowler JS, Gatley SJ, Wang GJ, Volkow ND (2004) DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and non-preferring rats attenuates alcohol drinking. Alchohol Clin Exp Res 28(5):720–728
Vazquez DM, Eskandari R, Zimmer CA, Levine CA, Levine S, Lopez JF (2002) Brain 5-HT receptor system in the stressed infant rat: implications for vulnerability to substance abuse. Psychoneuroendocrinology 27(1–2):245–272
Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7(8):847–854
Acknowledgements
We thank Dr. Geraldina Dominguez for helpful discussions and Kim Zurich for excellent technical assistance. This work was supported by grants DA00418 (MJK), RR00165, DA15279 (JNJ), GM46897 (ETM) and GM000680 (CLB). All of the experiments carried out in this article complied with the current laws of the USA.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jaworski, J.N., Francis, D.D., Brommer, C.L. et al. Effects of early maternal separation on ethanol intake, GABA receptors and metabolizing enzymes in adult rats. Psychopharmacology 181, 8–15 (2005). https://doi.org/10.1007/s00213-005-2232-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-005-2232-4