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Maternal deprivation increases behavioural reactivity to stressful situations in adulthood: suppression by the CCK2 antagonist L365,260

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Abstract

Rationale

Maternal deprivation can result in long-term impairment of neuronal functions and in the development of long-lasting behavioural disorders.

Objectives

This study analysed the effects of a selective cholecystokinin-2 (CCK2) antagonist, 3R-(+)-N-(2,3-dihydro-1methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3yl)-N′-(3-methyl phenyl) urea (L365,260), in anxiety- and stress-related behaviours of adult rats that were deprived (D) from their mother and littermates for 3 h everyday during 14 days after birth.

Methods

The behaviour was studied in actimeter, in open field and after food and water deprivation. Corticosterone plasma levels were quantified after food and water deprivation. The effects of L365,260 were studied in the behavioural changes observed in D rats.

Results

No differences in circadian motor activity between non-deprived (ND) and D rats were observed. D rats showed a 50% decrease in their number of visits to the central (aversive) part of the open field compared to ND rats. This effect was suppressed by L365,260. After 20 h of food and water deprivation, an increase in plasma corticosterone was observed in D and ND rats. However, the raise of corticosterone secretion in D rats was dramatically increased (300%) compared to ND rats, indicating a hypersensitised state revealed by this stressful situation. Consumption of sucrose solution (1%) was higher for D rats than for ND rats after food and water deprivation. Sucrose consumption returned to control values following L365,260 treatment.

Conclusions

These results suggest that maternal deprivation led to an increase in anxiety and stress reactivity in adulthood. We propose that these long-lasting changes are partly dependent on CCKergic transmission involving the activation of CCK2 receptors.

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References

  • Adriani W, Macri S, Pacifici R, Laviola G (2002) Restricted daily access to water and voluntary nicotine oral consumption in mice: methodological issues and individual differences. Behav Brain Res 134:21–30

    Article  PubMed  CAS  Google Scholar 

  • Anisman H, Zaharia MD, Meaney MJ, Meralis Z (1998) Do early-life events permanently alter behavioral and hormonal responses to stressors. Int J Dev Neurosci 16:149–164

    Article  PubMed  CAS  Google Scholar 

  • Becker C, Thiebot MH, Touitou Y, Hamon M, Cesselin F, Benoliel JJ (2001) Enhanced cortical extracellular levels of cholecystokinin-like material in a model of anticipation of social defeat in the rat. J Neurosci 21:262–269

    PubMed  CAS  Google Scholar 

  • Bell ME, Bhatnagar S, Liang J, Soriano L, Nagy TR, Dallman MF (2000) Voluntary sucrose ingestion, like corticosterone replacement, prevents the metabolic deficits of adrenalectomy. J Neuroendocrinol 12:461–470

    Article  PubMed  CAS  Google Scholar 

  • Bertière MC, Sy TM, Baigts F, Mandenoff A, Apfelbaum M (1984) Stress and sucrose hyperphagia: role of endogenous opiates. Pharmacol Biochem Behav 20:675–679

    Article  PubMed  Google Scholar 

  • Bhatnagar S, Viau V, Chu A, Soriano L, Meijer OC, Dallman MF (2000) A cholecystokinin-mediated pathway to the paraventricular thalamus is recruited in chronically stressed rats and regulates hypothalamic–pituitary–adrenal function. J Neurosci 15:5564–5573

    Google Scholar 

  • Bock MG, Dipardo RM, Evans BE, Rittle KE, Whitter WL, Veber DF, Anderson PS, Freidinger RM (1989) Benzodiazepine gastrin and brain cholecystokinin receptor ligands: L365,260. J Med Chem 32:13–16

    Article  PubMed  CAS  Google Scholar 

  • Caldji C, Francis D, Sharma S, Plostsky PM, Meaney MJ (2000) The effects of early rearing environment on the development of GABAA and benzodiazepine receptor levels and novelty-induced fearfulness in the rat. Neuropsychopharmacology 22:219–229

    Article  PubMed  CAS  Google Scholar 

  • Calvo-Torrent A, Brain PF, Martinez M (1999) Effect of predatory stress on sucrose intake and behavior on the plus-maze in male mice. Physiol Behav 67:189–196

    Article  PubMed  CAS  Google Scholar 

  • Canetti L, Bachar E, Galili-Weisstub E, De-Nour AK, Shalev AY (1997) Parental bonding and mental health in adolescence. Adolescence 32:381–394

    PubMed  CAS  Google Scholar 

  • Crawley J, Corwin RL (1994) Biological actions of cholecystokinin. Peptides 15:731–755

    Article  PubMed  CAS  Google Scholar 

  • Daniels WM, Pietersen CY, Carstens ME, Stein DJ (2004) Maternal separation in rats leads to anxiety-like behavior and a blunted ACTH response and altered neurotransmitter levels in response to a subsequent stressor. Metab Brain Dis 19:3–14

    Article  PubMed  CAS  Google Scholar 

  • Daugé V, Léna I (1998) CCK in anxiety and cognitive processes. Neurosci Biobehav Rev 22:815–825

    Article  PubMed  Google Scholar 

  • Daugé V, Rossignol P, Roques BP (1989) Comparison of the behavioural effects induced by administration in rat nucleus accumbens or nucleus caudatus of selective mu and delta opioid peptides or kelatorphan, an inhibitor of enkephalin-metabolism. Psychopharmacology 96:343–352

    Article  Google Scholar 

  • de Kloet ER, Rots NY, Cools R (1996) Brain-corticosteroid hormone dialogue: slow and persistent. Cell Mol Neurobiol 16:345–356

    Article  PubMed  Google Scholar 

  • Dess NK (1992) Divergent responses to saccharin vs. sucrose availability after stress in rats. Physiol Behav 52:115–125

    Article  PubMed  CAS  Google Scholar 

  • Dourish CT, O'Neill MF, Coughlan J, Kitchener SJ, Hawley D, Iversen SD (1990) The selective CCK-B receptor antagonist L365,260 enhances morphine analgesia and prevents morphine tolerance in the rat. Eur J Pharmacol 176:35–44

    Article  PubMed  CAS  Google Scholar 

  • Ellenbroek BA, Cools AR (2000) The long-term effects of maternal deprivation depend on the genetic background. Neuropsychopharmacology 23:99–106

    Article  PubMed  CAS  Google Scholar 

  • Faraday MM (2002) Rat sex and strain differences in responses to stress. Physiol Behav 75:507–522

    Article  PubMed  CAS  Google Scholar 

  • Francis DD, Caldji C, Champagne FN, Plotsky PM, Meaney MJ (1999) The role of corticotropin-releasing factor-norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress. Biol Psychiatry 46:1153–1166

    Article  PubMed  CAS  Google Scholar 

  • Gosnell BA (2000) Sucrose intake predicts rate of acquisition of cocaine self-administration. Psychopharmacology 149:286–292

    Article  PubMed  CAS  Google Scholar 

  • Hall FS (1998) Social deprivation of neonatal, adolescent, and adult rats has distinct neurochemical and behavioral consequences. Crit Rev Neurobiol 12:129–162

    PubMed  CAS  Google Scholar 

  • Helga JJ, van Oers J, de Kloet R, Li C, Levine S (1998) The ontogeny of glucocorticoid negative feedback: influence of maternal deprivation. Endocrinology 439:2838–2846

    Google Scholar 

  • Holmes RD, Robbins LN (1987) The influence of childhood disciplinary experience on the development of alcoholism and depression. J Child Psychol Psychiatry 28:399–415

    Article  PubMed  CAS  Google Scholar 

  • Huot RL, Thrivikraman KV, Meaney M, 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 158:366–373

    Article  PubMed  CAS  Google Scholar 

  • Kalinichev M, Easterling KW, Plotsky PM, Holtzman SG (2001) Long-lasting changes in stress-induced corticosterone response and anxiety-like behaviors as a consequence of neonatal maternal separation in Long–Evans rats. Pharmacol Biochem Behav 73:131–140

    Article  Google Scholar 

  • Kiss A, Jezova D, Aguilera G (1994) Activity of the hypothalamic–pituitary–adrenal axis and sympathoadrenal system during food and water deprivation in the rat. Brain Res 663:84–92

    Article  PubMed  CAS  Google Scholar 

  • Ladd CO, Owens MJ, Nemeroff CB (1996) Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 137:1212–1218

    Article  PubMed  CAS  Google Scholar 

  • Ladurelle N, Keller G, Blommaert A, Roques BP, Daugé V (1997) The CCK-B agonist, BC264, increases dopamine in the nucleus accumbens and facilitates motivation and attention after intraperitoneal injection in rats. Eur J Neurosci 9:1804–1814

    Article  PubMed  CAS  Google Scholar 

  • Levine S, Coover GD (1976) Environmental control of suppression of the pituitary–adrenal system. Physiol Behav 17:35–37

    Article  PubMed  CAS  Google Scholar 

  • Levine S, Haltmeyer GC, Karas GG, Denenberg VH (1967) Physiological and behavioral effects of infantile stimulation. Physiol Behav 2:55–59

    Article  CAS  Google Scholar 

  • Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, 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

    Article  PubMed  CAS  Google Scholar 

  • Matthews K, Wilkinson LS, Robbins TW (1996) Repeated maternal separation of preweanling rats attenuates behavioural responses to primary and conditioned incentives in adulthood. Physiol Behav 59:99–107

    Article  PubMed  CAS  Google Scholar 

  • McCormick CM, Kehoe P, Kovacs S (1998) Corticosterone release in response to repeat, short episodes of neonatal isolation: evidence of sensitization. Int J Dev Neurosci 16:175–185

    Article  PubMed  CAS  Google Scholar 

  • McIntosh J, Anisman H, Merali Z (1999) Short- and long-periods of neonatal maternal separation differentially affect anxiety and feeding in adult rats: gender-dependent effects. Dev Brain Res 113:97–106

    Article  CAS  Google Scholar 

  • Meaney MJ, Aitken DH, Sharma S, Viau V, Sarrieau A (1989) Postnatal handled increases hippocampal type II, glucocorticoid receptors and enhances adrenocortical negative -feedback efficacy in the rat. Neuroendocrinology 51:597–604

    Google Scholar 

  • Ogawa T, Mikuni M, Kuroda Y, Muneoka K, Mori KJ, Takahashi K (1994) Periodic maternal deprivation alters stress response in adult offspring; potentiates the negative feedback regulation of restraint stress-induced adrenocortical response and reduces the frequencies of open field-induced behaviors. Pharmacol Biochem Behav 49:961–967

    Article  PubMed  CAS  Google Scholar 

  • Piazza PV, Le Moal M (1998) The role of stress in drug self-administration. TIPS 19:67–74

    PubMed  CAS  Google Scholar 

  • 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 18:195–200

    Article  PubMed  CAS  Google Scholar 

  • Pryce CR, Feldon J (2003) Long-term neurobehavioural impact of the postnatal environment in rats: manipulations, effects and mediating mechanisms. Neurosci Biobehav Rev 27:57–71

    Article  PubMed  Google Scholar 

  • Rosenfeld P, Wetmore JB, Levine S (1992) Effects of repeated maternal separations on the adrenocortical response in preweanling rats. Physiol Behav 52:787–791

    Article  PubMed  CAS  Google Scholar 

  • Russak LG, Schwartz GE (1997) Feelings of parental care predict health status in midlife: a 35-year follow-up of Harvard Mastery of Stress Study. J Behav Med 20:1–11

    Article  PubMed  Google Scholar 

  • Shlik J, Vasar E, Bradwejn J (1997) Cholecystokinin and psychiatric disorders. CNS Drugs 8:134–152

    Article  CAS  Google Scholar 

  • Uvnas-Moberg K (1989) Gastrointestinal hormones in mother and infant. Acta Paediatr Scand 351:88–93

    Article  CAS  Google Scholar 

  • Vazquez DM, Eskandarii R, Zimmer CA, Levine S, Lopez JF (2002) Brain 5-HT receptor system in the stressed infant rat: implications for vulnerability to substance abuse. Psychoneuroendocrinology 27:245–272

    Article  PubMed  CAS  Google Scholar 

  • Weller A, Feldman R (2003) Emotion regulation and touch in infants: the role of cholecystokinin and opioids. Peptides 24:779–788

    Article  PubMed  CAS  Google Scholar 

  • Wigger A, Neumann ID (1999) Periodic maternal deprivation induces gender-dependent alterations in behavioral and neuroendocrine responses to emotional stress in adult rats. Physiol Behav 66:293–302

    Article  PubMed  CAS  Google Scholar 

  • Willner P, Towell A, Sampson D, Muscat R, Sophokleous S (1987) Reduction of sucrose preference by chronic mild stress and its restoration by a tricyclic antidepressant. Psychopharmacology 93:358–364

    Article  PubMed  CAS  Google Scholar 

  • Workel JO, Oitzl MS, Fluttert M, Lesscher H, Karssen A, de Kloet ER (2001) Differential and age-dependent effects of maternal deprivation on the hypothalamic–pituitary–adrenal axis of brown Norway rats from youth to senescence. J Neuroendocrinol 13:569–580

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to S. Lamouraux for the technical assistance in pharmacological experiments.

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Correspondence to Valérie Daugé.

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Vazquez, V., Farley, S., Giros, B. et al. Maternal deprivation increases behavioural reactivity to stressful situations in adulthood: suppression by the CCK2 antagonist L365,260. Psychopharmacology 181, 706–713 (2005). https://doi.org/10.1007/s00213-005-0029-0

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  • DOI: https://doi.org/10.1007/s00213-005-0029-0

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