Abstract
Maternal care influences the development of stress reactivity in the offspring. These effects are accompanied by changes in corticotropin-releasing factor (CRF) expression in brain regions that regulate responses to stress. However, such effects appear secondary to those involving systems that normally serve to inhibit CRF expression and release. Thus, maternal care over the first week of life alters GABAA (gamma-aminobutyric acid)A receptor mRNA subunit expression. The adult offspring of mothers that exhibit increased levels of pup licking/grooming and arched back-nursing (high LG-ABN mothers) show increased α1 mRNA levels in the medial prefrontal cortex, the hippocampus as well as the basolateral and central regions, of the amygdala and increased γ2 mRNA in the amygdala. Western blot analyses confirm these effects at the level of protein. In contrast, the offspring of low LG-ABN mothers showed increased levels of α3 and α4 subunit mRNAs. The results of an adoption study showed that the biological offspring of low LG-ABN mothers fostered shortly after birth to high LG-ABN dams showed the increased levels of both α1 and γ2 mRNA expression in the amygdala in comparison to peers fostered to other low LG-ABN mothers (the reverse was true for the biological offspring of high LG-ABN mothers). These findings are consistent with earlier reports of the effects of maternal care on GABAA/benzodiazepine receptor binding and suggest that maternal care can permanently alter the subunit composition of the GABAA receptor complex in brain regions that regulate responses to stress.
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References
Amin J, Brooks-Kayal A, Weiss DS (1997). Two tyrosine residues on the alpha subunit are crucial for benzodiazepine binding and allosteric modulation of gamma-aminobutyric acidA receptors. Mol Pharmacol 51: 833–841.
Arbilla S, Allen J, Wick A, Langer SZ (1986). High affinity [3H]zolpidem binding in the rat brain: an imidazopyridine with agonist properties at central benzodiazepine receptors. Eur J Pharmacol 130: 257–263.
Bakshi VP, Shelton SE, Kalin NH (2000). Neurobiological correlates of defensive behaviors. Prog Brain Res 122: 105–115.
Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G et al (1988). International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev 50: 291–313.
Bechara A, Tranel D, Damasio H, Adolphs R, Rockland C, Damasio AR (1995). Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 269: 1115–1118.
Bradford MM (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein using the principle of protein–dye binding. Anal Biochem 72: 248–254.
Braestrup C, Honore T, Nielsen M, Petersen EN (1984). Ligands for benzodiazepine receptors with positive and negative efficacy. Biochem Pharmacol 33: 859–862.
Brioni JD, Nagahara AH, McGaugh JL (1989). Involvement of the amygdala GABAergic system in the modulation of memory storage. Brain Res 487: 105–112.
Buhr A, Schaerer MT, Baur R, Sigel E (1997). Residues at positions 206 and 209 of the alpha1 subunit of gamma-aminobutyric acidA receptors influence affinities for benzodiazepine binding site ligands. Mol Pharmacol 5: 676–682.
Buhr A, Sigel E (1997). A point mutation in the gamma2 subunit of gamma-aminobutyric acid type A receptors results in altered benzodiazepine binding site specificity. Proc Natl Acad Sci USA 94: 8824–8829.
Butler PD, Weiss JM, Stout JC, Nemeroff CB (1990). Corticotropin-releasing factor produces fear-enhancing and behavioural activating effects following infusion into the locus coeruleus. J Neurosci 10: 176–183.
Cahill L, McGaugh JL (1998). Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci 21: 294–299.
Caldji C, Francis D, Sharma S, Plotsky PM, Meaney MJ (2000). The effects of early rearing environment on the development of GABAA and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat. Neuropsychopharmacology 22: 219–229.
Caldji C, Tannenbaum B, Sharma S, Francis DD, Plotsky PM, Meaney MJ (1998). Maternal care during infancy regulates the development of neural systems mediating the expression of behavioral fearfulness in adulthood in the rat. Proc Nat Acad Sci USA 95: 5335–5340.
Champagne F, Francis DD, Mar A, Meaney MJ (in press). Naturally-occurring variations in maternal care in the rat as a mediating influence for the effects of environment on the development of individual differences in stress reactivity. Physiol Behav.
Da Cunha C, Roozendaal B, Vazdarjanova A, McGaugh JL (1999). Microinfusions of flumazenil into the basolateral but not the central nucleus of the amygdala enhance memory consolidation in rats. Neurobiol Learn Mem 72: 1–7.
Dickinson-Anson H, McGaugh JL (1997). Bicuculline administered into the amygdala after training blocks benzodiazepine-induced amnesia. Brain Res 752: 197–202.
Francis DD, Diorio J, Liu D, Meaney MJ (1999). Nongenomic transmission across generations in maternal behavior and stress responses in the rat. Science 286: 1155–1158.
Furmark T, Fischer H, Wik G, Larsson M, Fredrikson M (1997). The amygdala and individual differences in human fear conditioning. Neuroreport 22: 3957–3960.
Glue P, Wilson S, Coupland N, Ball D, Nutt D (1995). The relationship between benzodiazepine receptor sensitivity and neuroticism. J Anxiety Dis 9: 33–45.
Gonzalez LE, Andrews N, File SE (1996). 5-HT1A and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the social interaction test, but not in the elevated plus-maze. Brain Res 732: 145–153.
Gorman JM, Kent JM, Sullivan GM, Coplan JD (2000). Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 157: 493–505.
Griebel G, Perrault G, Letang V, Granger P, Avenet P, Schoemaker H et al (2000). New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ (omega) receptor subtypes. Psychopharmacology (Berl) 146: 205–213.
Gunther U, Benson J, Benke D, Fritschy JM, Reyes G, Knoflach F et al (1995). Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci USA 92: 7749–7753.
Hadingham KL, Wingrove P, Le Bourdelles B, Palmer KJ, Ragan CI, Whitiing PJ (1993). Cloning of cDNA sequences encoding human α2 and α3 gama-aminobutyric acidA receptor sub-units and characterization of the benzodiazepine pharmacology of recombinant α1-, α2-, α3- and α5-containing human g-aminobutyric acidA receptors. Mol Pharmacol 3: 970–975.
Haefely W (1994). In: Mohler H, DaPrada M (eds) The Challenge of Neuropharmacology. Roche, Basel: Switzerland. pp 15–40.
Helmstetter FJ, Bellgowan PS (1994). Effects of muscimol applied to the basolateral amygdala on acquisition and expression of contextual fear conditioning in rats. Behav Neurosci 108: 1005–1009.
Hodges H, Green S, Glenn B (1987). Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on punished responding, but not discrimination. Psychopharmacology 92: 491–504.
Im WB, Blakeman DP (1991). Correlation between gamma-aminobutyric acidA receptor ligand-induced changes in t-butylbicyclophosphoro[35S]thionate binding and 36Cl− uptake in rat cerebrocortical membranes. Mol Pharmacol 39: 394–398.
Khan ZU, Gutierrez A, De Blas AL (1996). The α1 and α6 sub-units can co-exist in the same cerebellar GABAA receptor maintaining their individual benzodiazepine-binding specificities. J Neurochem 66: 685–691.
LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA (1998). Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron 20: 937–945.
LaBar KS, LeDoux JE, Spencer DD, Phelps EA (1995). Impaired fear conditioning following unilateral temporal lobectomy in humans. J Neurosci 15: 6846–6855.
Liu D, Tannenbaum B, Caldji C, Francis DD, Freedman A, Sharma S et al (1997). Maternal care, hippocampal glucocorticoid receptor gene expression and hypothalamic–pituitary–adrenal responses to stress. Science 277: 1659–1662.
Ma W, Barker JL (1995). Complementary expressions of transcripts encoding GAD67 and GABAA receptor a4, β1 and g1 subunits in the proliferative zone of the embryonic rat central nervous system. J Neurosci 15: 2547–2560.
Maccari S, Piazza PV, Kabbaj M, Barbazanges A, Simon H, LeMoal M . (1995). Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress. J Neurosci 15: 110–116.
Maksay G (1993). Partial and full agonists/inverse agonists affect [35S]TBPS binding at different occupancies of central benzodiazepine receptors. Eur J Pharmacol 246: 255–260.
Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ (1998). Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry 55: 715–720.
McCarty R, Lee JH (1996). Maternal influences on adult blood pressure of SHRs: a single pup cross-fostering study. Physiol Behav 59: 71–75.
McKernan RM, Quirk K, Prince R, Cox PA, Gillard NP, Ragan CI et al (1991). GABAA receptor subtypes immunopurified from rat brain with alpha subunit-specific antibodies have unique pharmacological properties. Neuron 4: 667–676.
McKernan RM, Whiting PJ (1997). Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci 19: 139–143.
Mehta AK, Ticku MK (1999). An update on GABAA receptors. Brain Res Rev 29: 196–217.
Melo de Paula AJ (1977). A comparative study of lormetazepam and flurazepam in the treatment of insomnia. Clin Ther 64: 500–508.
Muller J, Corodimas KP, Fridel Z, LeDoux JE (1997). Functional inactivation of the lateral and basal nuclei of the amygdala by muscimol infusion prevents fear conditioning to an explicit conditioned stimulus and to contextual stimuli. Behav Neurosci 111: 683–691.
Myers MM, Brunelli SA, Squire JM, Shindeldecker RD, Hoffer MA (1989). Maternal behavior of SHR rats and its relationship to offspring blood pressures. Dev Psychobiol 22: 29–53.
Oblowitz H, Robins AH (1983). The effect of clobazam and lorazepam on the psychomotor performance of anxious patients. Br J Clin Pharmacol 16: 95–99.
Owens MJ, Vargas MA, Knight DL, Nemeroff CB (1991). The effects of alprazoplam on corticotropin-releasing factor neurons in the rat brain: acute time course, chronic treatment and abrupt withdrawal. J Pharmacol Exp Therap 258: 349–356.
Paxinos G, Watson D (1982). The Rat Brain in Stereotaxic Coordinates. Academic Press: New York, NY.
Pesold C, Treit D (1995). The central and basolateral amygdala differentially mediate the anxiolytic effects of benzodiazepines. Brain Res 671: 213–221.
Pitkanen A, Savander V, LeDoux JE (1997). Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci 20: 517–523.
Poulter MO, Barke JL, O'Carroll A-M, Lolait SJ, Mahan LC (1992). Differential and transient expression of GABAA receptor a-sub-unit mRNAs in the developing rat CNS. J Neurosci 12: 2888–2900.
Pritchett DB, Seeburg PH (1991). Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science 245: 1389–1391.
Pruessner J, Champagne FA, Dagher A, Meaney MJ (2000). Parental care and stress-induced dopamine release assessed in a PET study of raclopride in young, health human subjects. Soc Neurosci Abst.
Ressnick HS, Kilpatrick DG, Dansky BS, Saunders BE, Best CL (1993). Prevalence of civilian trauma and post-traumatic stress disorders in a representative national sample. J Clin Consul Psychol 61: 984–991.
Roy-Byrne P, Cowley DS, Greenblatt DJ, Shader RI, Hommer D (1990). Reduced benzodiazepine sensitivity in panic disorder. Arch Gen Psychiatry 47: 534–538.
Roy-Byrne P, Wingerson DK, Radant A, Greenblatt DJ, Cowley DS (1996). Reduced benzodiazepine sensitivity in patients with panic disorder: comparison with patients with obsessive–compulsive disorder and normal subjects. Am J Psychiatry 153: 1444–1449.
Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM et al (1999). Benzodiazepine actions mediated by specific gammaaminobutyric acid(A) receptor subtypes. Nature 401: 796–800.
Schafe GE, Nader K, Blair HT, LeDoux JE (2001). Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosciences 24: 540–546.
Sieghart W (1995). Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol Rev 47: 181–234.
Skelton KH, Nemeroff CB, Knight DL, Owens MJ (2000). Chronic administration of the triazolobenzodiazepine alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems. J Neurosci 20: 1240–1248.
Stein MB, Walker JR, Anderson G, Hazen AL, Ross CA, Eldridge G et al (1996). Childhood physical and sexual abuse in patients with anxiety disorders and in a community sample. Am J Psychiatry 153: 257–275.
Tomaz C, Dickinson-Anson H, McGaugh JL, Souza-Silva MA, Viana MB, Graeff FG (1993). Localization in the amygdala of the amnestic action of diazepam on emotional memory. Behav Brain Res 58: 99–105.
Tweed JL, Schoenbach VJ, George LK, Blazer DG (1989). The effects of childhood parental death and divorce on six-month history of anxiety disorders. Br J Psychiatry 154: 823–828.
Udwin O, Boyle S, Yule W, Bolton D, O'Ryan O (2000). Risk factors for long-term psychological effects of a disaster experienced in adolescence: predictors of post-traumatic stress disorder. J Child Psychol Psychiatry 41: 969–979.
Valentino RJ, Curtis AL, Page ME, Pavcovich LA, Florin-Lechner SM (1998). Activation of the locus cereuleus brain noradrenergic system during stress: circuitry, consequences, and regulation. Adv Pharmacol 42: 781–784.
Wilcox AS, Warrington JA, Gardiner K, Berger R, Whiting P, Altherr MR et al (1992). Human chromosomal localization of genes encoding the gamma 1 and gamma 2 subunits of the gamma-aminobutyric acid receptor indicates that members of this gene family are often clustered in the genome. Proc Natl Acad Sci USA 89: 5857–5861.
Wingrove PB, Thompson SA, Wafford KA, Whiting PJ (1997). Key amino acids in the gamma subunit of the gamma-aminobutyric acidA receptor that determine ligand binding and modulation at the benzodiazepine site. Mol Pharmacol 52: 874–881.
Wisden W, Laurie DJ, Monyer H, Seeburg PH (1992). The distribution of 13 GABAA receptor submit mRNAs in the rat brain. 1: Telencephalon diencephalon, mesencephalon. J Neurosic 12: 1040–1062.
Yang W, Drewe JA, Lan NC (1995). Cloning and characterization of the human GABAA receptor alpha 4 subunit: identification of a unique diazepam-insensitive binding site. Eur J Pharmacol 291: 319–325.
Ymer S, Schofield PR, Draguhn A, Werner P, Kohler M, Seeburg PH (1989). GABAA receptor β submit heterogeneity: functional expression of cloned cDNAs. EMBO J 3: 1665–1671.
Acknowledgements
This research was supported by a grant from the Canadian Institutes of Health Research to MJM. CC is a graduate fellow and a recipient of a Canadian Institutes of Health Research Doctoral Research Award. MJM was supported by a Senior Scientist award from the Canadian Institutes of Health Research and an NARSAD Distinguished Investigator award.
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Caldji, C., Diorio, J. & Meaney, M. Variations in Maternal Care Alter GABAA Receptor Subunit Expression in Brain Regions Associated with Fear. Neuropsychopharmacol 28, 1950–1959 (2003). https://doi.org/10.1038/sj.npp.1300237
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