Psychopharmacology

, Volume 216, Issue 3, pp 333–343

The effect of age on the discriminative stimulus effects of ethanol and its GABAA receptor mediation in cynomolgus monkeys

Original Investigation

Abstract

Rationale

Excessive alcohol consumption is less common among aged compared to young adults, with aged adults showing greater sensitivity to many behavioral effects of ethanol.

Objectives

This study compared the discriminative stimulus effects of ethanol in young and middle-aged adult cynomolgus monkeys (Macaca fascicularis) and its γ-aminobutyric acid (GABA)A receptor mediation.

Methods

Two male and two female monkeys trained to discriminate ethanol (1.0 g/kg, i.g.; 60-min pre-treatment interval) from water at 5–6 years of age (Grant et al. in Psychopharmacology 152:181–188, 2000) were re-trained in the current study more than a decade later (19.3 ± 1.0 years of age) for a within-subjects comparison. Also, four experimentally naïve middle-aged (mean ± SEM, 17.0 ± 1.5 years of age) female monkeys were trained to discriminate ethanol for between-subjects comparison with published data from young adult naïve monkeys.

Results

Two of the naïve middle-aged monkeys attained criterion performance, with weak stimulus control and few discrimination tests, despite greater blood–ethanol concentration 60 min after 1.0 g/kg ethanol in middle-aged compared to young adult female monkeys (Green et al. in Alcohol Clin Exp Res 23:611–616, 1999). The efficacy of the GABAA receptor positive modulators pentobarbital, midazolam, allopregnanolone, pregnanolone, and androsterone to substitute for the discriminative stimulus effects of 1.0 g/kg ethanol was maintained from young adulthood to middle age.

Conclusions

The data suggest that 1.0 g/kg ethanol is a weak discriminative stimulus in naive middle-aged monkeys. Nevertheless, the GABAA receptor mechanisms mediating the discriminative stimulus effects of ethanol, when learned as a young adult, appear stable across one third of the primate lifespan.

Keywords

Ethanol Discrimination Monkey Aging GABA receptor 

References

  1. Akinci MK, Johnston GAR (1997) Sex differences in the effects of gonadectomy and acute swim stress on GABAA receptor binding in mouse forebrain membranes. Neurochem Int 31:1–10PubMedCrossRefGoogle Scholar
  2. Akk G, Covey DF, Evers AS, Steinbach JH (2007) Mechanisms of neurosteroid interactions with GABAA receptors. Pharmacol Ther 116:35–57PubMedCrossRefGoogle Scholar
  3. Albrecht S, Ihmsen H, Hering W, Geisslinger G, Dingemanse J, Schwilden H, Schüttler J (1999) The effect of age on the pharmacokinetics and pharmacodynamics of midazolam. Clin Pharmacol Ther 65:630–639PubMedCrossRefGoogle Scholar
  4. Belelli D, Casula A, Ling A, Lambert JJ (2002) The influence of subunit composition on the interaction of neurosteroids with GABAA receptors. Neuropharmacology 43:651–661PubMedCrossRefGoogle Scholar
  5. Blow FC, Barry KL (2002) Use and misuse of alcohol among older women. Alcohol Res Health 26:308–315PubMedGoogle Scholar
  6. Center for Disease Control and Prevention (2010) Vital and health statistics. Health behaviors of adults: United States 2005–2007. US Department of Health and Services, Washington, DC, Series 10, No. 245; DHHS Publication No. (PHS) 2010-1573Google Scholar
  7. Grant KA (1999) Strategies for understanding the pharmacological effects of ethanol with drug discrimination procedures. Pharmacol Biochem Behav 64:261–267PubMedCrossRefGoogle Scholar
  8. Grant KA, Azarov A, Shively CA, Purdy RH (1997) Discriminative stimulus effects of ethanol and 3α-hydroxy-5α-pregnan-20-one in relation to menstrual cycle phase in cynomolgus monkeys (Macaca fascicularis). Psychopharmacology 130:59–68PubMedCrossRefGoogle Scholar
  9. Grant KA, Waters CA, Green-Jordan K, Azarov A, Szeliga KT (2000) Characterization of the discriminative stimulus effects of GABAA receptor ligands in Macaca fascicularis monkeys under different ethanol training conditions. Psychopharmacology 152:181–188PubMedCrossRefGoogle Scholar
  10. Grant BF, Stinson FS, Harford TC (2001) Age at onset of alcohol use and DSM-IV alcohol abuse and dependence: a 12-year follow-up. J Subst Abuse 13:493–504PubMedCrossRefGoogle Scholar
  11. Grant BF, Dawson DA, Stinson FS, Chou SP, Dufour MC, Pickering RP (2004) The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991–1992 and 2001–2002. Drug Alcohol Dep 74:223–234CrossRefGoogle Scholar
  12. Grant BF, Dawson DA, Stinson FS, Chou P, Dufour MC, Pickering RP (2006) The 12-month prevalence and trends in DSM-IV alchol abuse and dependence: United States, 1991–1992 and 2001–2002. Alcohol Res Health 29:79–993Google Scholar
  13. Grant KA, Helms CM, Rogers LSM, Purdy RH (2008) Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys. J Pharmacol Exp Ther 326:354–361PubMedCrossRefGoogle Scholar
  14. Green KL, Szeliga KT, Bowen CA, Kautz MA, Azarov AV, Grant KA (1999) Comparison of ethanol metabolism in male and female cynomolgus macaques (Macaca fascicularis). Alcohol Clin Exp Res 23:611–616PubMedCrossRefGoogle Scholar
  15. Groerer JC, Penne MA, Pemberton MR, Folsom RE (2003) Substance abuse treatment need among older adults in 2020: the impact of the aging baby-boom cohort. Drug Alcohol Abuse 69:127–135Google Scholar
  16. Groseclose CH, Middaugh LD (1997) The discrimination and durability of an ethanol cue in young and mid-aged female mice. Alcohol 14:191–197PubMedCrossRefGoogle Scholar
  17. Helms CM, Rogers LSM, Waters CA, Grant KA (2008) Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol. Alcohol Clin Exp Res 32:1197–1206PubMedCrossRefGoogle Scholar
  18. Jensen JT, Zelinski MB, Stanley JE, Fanton JW, Stouffer RL (2008) The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation in the naturally selected dominant follicle in rhesus macaques. Contraception 77:303–307PubMedCrossRefGoogle Scholar
  19. Jones MK, Jones BM (1980) The relationship of age and drinking habits to the effects of alcohol on memory in women. J Stud Alcohol 41:179–186PubMedGoogle Scholar
  20. Jung S, Harris RA (2006) Sites in TM2 and 3 are critical for alcohol-induced conformational changes in GABAA receptors. J Neurochem 96:885–892PubMedCrossRefGoogle Scholar
  21. Kanaumi T, Takashima S, Iwasaki H, Mitsudome A, Hirose S (2006) Developmental changes in the expression of GABAA receptor alpha 1 and gamma 2 subunits in human temporal lobe, hippocampus and basal ganglia: an implication for consideration on age related epilepsy. Epilepsy Res 71:47–53Google Scholar
  22. Kanazu T, Yamaguchi Y, Okamura N, Baba T, Koike M (2004) Model for the drug-drug interaction responsible for CYP3A enzyme inhibition. I: evaluation of cynomolgus monkeys as surrogates for humans. Xenobiotica 34:391–402PubMedCrossRefGoogle Scholar
  23. Kelly TH, Stoops WW, Perry AS, Prendergast MA, Rush CR (2003) Clinical neuropharmacology of drugs of abuse: a comparison of drug-discrimination and subject-report measures. Behav Cog Neurosci Rev 2:227–260CrossRefGoogle Scholar
  24. Kemnitz JW, Roecker EB, Haffa ALM, Pinheiro J, Kurzman I, Ramsey JJ, MacEwen EG (2000) Serum dehydroepiandrosterone sulfate concentrations across the life span of laboratory-housed rhesus monkeys. J Med Primatol 29:330–337PubMedCrossRefGoogle Scholar
  25. Khalsa SS, Rudrauf D, Tranel D (2009) Interoceptive awareness declines with age. Psychophysiol 46:1130–1136CrossRefGoogle Scholar
  26. Klotz U (2009) Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 41:67–76PubMedCrossRefGoogle Scholar
  27. Kumar S, Porcu P, Werner DF, Matthews DB, Diaz-Granados JL, Helfand RS, Morrow AL (2009) The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress. Psychopharmacology 205:529–564PubMedCrossRefGoogle Scholar
  28. Leibenluft E, Fiero PL, Rubinow DR (1994) Effects of menstrual cycle on dependent variables in mood disorder research. Arch Gen Psychiatry 51:761–781PubMedGoogle Scholar
  29. Lucey MR, Hill EM, Young JP, Demo-Dananberg L, Beresford TP (1999) The influences of age and gender on blood ethanol concentrations in health humans. J Stud Alcohol 60:103–110PubMedGoogle Scholar
  30. Mennerick S, He Y, Jiang X, Manion BD, Wang M, Shute A, Benz A, Evers AS, Covey DF, Zorumski CF (2004) Selective antagonism of 5α-reduced neurosteroid effects at GABAA receptors. Mol Pharmacol 65:1191–1197PubMedCrossRefGoogle Scholar
  31. Mhatre MC, Ticku MK (1992) Aging related alterations in GABAA receptor subunit mRNA levels in fischer rats. Mol Brain Res 14:71–78PubMedCrossRefGoogle Scholar
  32. Möhler H, Fritschy JM, Rudolph U (2002) A new benzodiazepine pharmacology. J Pharmacol Exp Ther 300:2–8PubMedCrossRefGoogle Scholar
  33. National Research Council (1996) Guide for the care and use of laboratory animals. National Academy Press, Washington, p 125Google Scholar
  34. Noriega NC, Eghlidi DH, Garyfallou VT, Kohama SG, Kryger SG, Urbanski HF (2010) Influence of 17β-estradiol and progesterone on GABAergic gene expression in the arcuate nucleus, amygdala and hippocampus of the rhesus macaque. Brain Res 1307:28–42PubMedCrossRefGoogle Scholar
  35. O’Brien CP, McLellan AT (1996) Myths about the treatment of addiction. Lancet 347:237–240PubMedCrossRefGoogle Scholar
  36. Park-Chung M, Malayev A, Purdy RH, Gibbs TT, Farb DH (1999) Sulfated and unsulfated steroids modulate γ-aminobutyric acidA receptor function through distinct sites. Brain Res 830:72–87PubMedCrossRefGoogle Scholar
  37. Rissman RA, Nocera R, Fuller LM, Kordower JH, Armstrong DM (2006) Age-related alterations in GABAA receptor subunits in the nonhuman primate hippocampus. Brain Res 1073–1074:120–130PubMedCrossRefGoogle Scholar
  38. Schechter MD, Signs SA, Boja JW (1989) Stability of the stimulus properties of drugs over time. Pharmacol Biochem Behav 32:361–364PubMedCrossRefGoogle Scholar
  39. Schumacher M, Weill-Engerer S, Liere P, Robert F, Franklin RJM, Garcia-Segura LM, Lambert JJ, Mayo W, Melcangi RC, Parducz A, Suter U, Carelli C, Baulieu EE, Akwa Y (2003) Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog Neurobiol 71:3–29PubMedCrossRefGoogle Scholar
  40. Takahashi M, Washio T, Suzuki N, Igeta K, Yamashita S (2010) Investigation of the intestinal permeability and first-pass metabolism of drugs in cynomolgus monkeys using single-pass intestinal perfusion. Biol Pharm Bull 33:111–116PubMedCrossRefGoogle Scholar
  41. Central Intelligence Agency (2009) The World Factbook. https://www.cia.gov/library/publications/the-world-factbook/index.html Accessed 19 July 2010
  42. Thompson SA, Whiting PJ, Wafford KA (1996) Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination. Br J Pharmacol 117:521–527PubMedGoogle Scholar
  43. Thummel KE, Wilkinson GR (1998) In vitro and in vivo drug interaction involving human CYP3A. Ann Rev Pharmacol Toxicol 38:389–430CrossRefGoogle Scholar
  44. Voytko ML (1999) Impairments in acquisition and reversals of two-choice discriminations by aged rhesus monkeys. Neurobiol Aging 20:617–627PubMedCrossRefGoogle Scholar
  45. Yu Z-Y, Wang W, Fritschy J-M, Witte OW, Redecker C (2006) Changes in neocortical and hippocampal GABAA receptor subunit distribution during brain maturation and aging. Brain Res 1099:73–81PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Behavioral NeuroscienceOregon Health & Science UniversityPortlandUSA
  2. 2.Division of Neuroscience, Oregon National Primate Research CenterOregon Health & Science UniversityBeavertonUSA

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