, Volume 103, Issue 4, pp 513–518 | Cite as

Early life protein malnutrition changes exploration of the elevated plus-maze and reactivity to anxiolytics

  • S. S. Almeida
  • L. M. de Oliveira
  • F. G. Graeff
Original Investigations


In order to investigate whether protein malnutrition in early life causes lasting changes in reactivity to anxiolytic drugs, exploration of the elevated plus-maze was used. Rat dams during lactation (21 days) and pups after weaning until day 49 of life were fed on 8% casein diet (M rats), while their well-nourished controls received 25% casein (W rats). From day 50 on all animals ate the same balanced diet. Experiments started on day 70. Under the non-drug condition, M rats tended to explore the open arms of the maze relatively more than W rats. Diazepam (0.5–5 mg/kg, IP) dose-dependently increased the percentage of open/total arm entries without significantly affecting the total number of arm entries in W rats. This selective anxiolytic effect of diazepam was considerably smaller in M rats. Ipsapirone (0.5–5 mg/kg) caused a similar though less pronounced anxiolytic effect in W rats, whereas the drug decreased both the % open/total and total arm entries in M rats. In contrast, ritanserin (0.05–1 mg/kg) significantly increased the % open/total arm entries in M rats only, though not in a dose-dependent way. Isamoltane (2.5–20 mg/kg) was ineffective on both M and W rats. These results indicate that early protein malnutrition causes long-lasting alterations in brain systems regulating emotional behaviour.

Key words

Early protein malnutrition Elevated plusmaze Diazepam Non-benzodiazepine anxiolytics 5-HT Rat 


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  1. Almeida SS, De Oliveira LM, Bichuette MZ, Graeff FG (1988) Early malnutrition alters the effect of chlordiazepoxide on inhibitory avoidance. Braz J Med Biol Res 21:1033–1036PubMedGoogle Scholar
  2. Almeida SS, De Oliveira LM, Graeff FG (1990) Decreased reactivity to anxiolytics caused by early protein malnutrition in rats. Pharmacol Biochem Behav 36:997–1000CrossRefPubMedGoogle Scholar
  3. Barnes RH, Neely CS, Kwong E, Labadan BA, Frankova S (1968) Postnatal nutritional deprivations as determinants of adult rat behavior toward food, its consumption and utilization. J Nutr 96:467–476PubMedGoogle Scholar
  4. Brioni JD, Orsingher OA (1988) Operant behavior and reactivity to the anticonflict effect of diazepam in perinatally under-nourished rats. Physiol Behav 44:193–198CrossRefPubMedGoogle Scholar
  5. Broadhurst PL (1960) Applications of biometrical genetics to the inheritance of behaviour. In: Eysenck HJ (ed) Experiments in personality, vol. 1, Psychogenetics and psychopharmacology. Routledge and Kegan Paul, London, pp 1–102Google Scholar
  6. Commissaris RL, Harrington GM, Altman HJ (1990) Benzodiazepine anti-conflict effects in Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rats. Psychopharmacology 100:287–292PubMedGoogle Scholar
  7. Critchley MAE, Handley SL (1987) Effects in the X-maze anxiety model of agents acting at 5HT1 and 5-HT2 receptors. Psychopharmacology 93:502–506CrossRefPubMedGoogle Scholar
  8. Critchley MAE, Njung'e K, Handley SL (1988) Prevention of 8-OH-DPAT anxiogenic effect by ipsapirone and by 5-HT1 antagonist beta-adrenoceptor antagonists. Br J Pharmacol Suppl 94:389PGoogle Scholar
  9. De Oliveira LM (1985) Malnutrition and environment: interaction effects upon animal behavior. Rev Chil Nutr 13:99–108Google Scholar
  10. Durel LA, Krantz DS, Barrett JE (1986) The antianxiety effect of beta-blockers on punished responding. Pharmacol Biochem Behav 25:371–374CrossRefPubMedGoogle Scholar
  11. Falk JL, Burnidge GK (1970) Fluid intake and punishment-attenuating drugs. Physiol Behav 5:199–202PubMedGoogle Scholar
  12. File SE (1990) One-trial tolerance to the anxiolytic effects of chlordiazepoxide in the plus-maze. Psychopharmacology 100:281–282CrossRefPubMedGoogle Scholar
  13. Frankova S, Barnes RH (1968) Effect of malnutrition in early life on avoidance conditioning and behavior of adult rats. J Nutr 96:485–493PubMedGoogle Scholar
  14. Goa KL, Ward A (1986) Buspirone: a preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs 32:114–129PubMedGoogle Scholar
  15. Graeff FG (1984) The anti-aversive action of minor tranquillizers. TIPS 5:230–233Google Scholar
  16. Graeff FG (1990) Brain defense systems and anxiety. In: Roth M, Burrows GD, Noyes R (eds) The neurobiology of anxiety. Elsevier, Amsterdam, pp 307–354Google Scholar
  17. Handley SL, Mithani S (1984) Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of “fear”-motivated behavior. Naunyn-Schmiedeberg's Arch Pharmacol 327:1–5CrossRefGoogle Scholar
  18. Hernández JR, Manjarréz GG, Chagoya G (1989) Newborn humans and rats malnourished in utero: free plasmaL-tryptophan, neutral amino acids and brain serotonin syntesis. Brain Res 488:1–13CrossRefPubMedGoogle Scholar
  19. Hoyer D (1988) Molecular pharmacology and biology of 5-HT1c receptors. TIPS 9:89–94PubMedGoogle Scholar
  20. Levitsky DA, Barnes RH (1970) Effect of early malnutrition on the reaction of adult rats to aversive stimuli. Nature 225:468–469CrossRefPubMedGoogle Scholar
  21. Leysen JE, Gommeren W, Van Gompell P, Wynantes J, Janssen PFM, Laudron PM (1985) Receptor binding properties in vitro and in vivo of ritanserin: a very potent and long acting serotonin-S2 antagonist. Mol Pharmacol 27:600–611PubMedGoogle Scholar
  22. Lynch A (1976) Passive avoidance behavior and response thresholds in adult male rats after early postnatal undernutrition. Physiol Behav 16:27–32CrossRefPubMedGoogle Scholar
  23. Morgane P, Miller M, Kemper T, Stern W, Forbes W, Hall R, Bronzino J, Kissane J, Hawrylewicz E, Resnick O (1978) The effects of protein malnutrition on the developing central nervous system in the rat. Neurosci Biobehav Rev 2:137–230CrossRefGoogle Scholar
  24. Moser PC (1989) An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone. Psychopharmacology 99:48–53CrossRefPubMedGoogle Scholar
  25. Pellow S, File SE (1986) Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav 24:525–529CrossRefPubMedGoogle Scholar
  26. Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167CrossRefPubMedGoogle Scholar
  27. Rajalakshmi R, Parameswaran M, Ramakrishnan CV (1974) Effects of different levels of dietary protein on brain glutamate dehydrogenase and decarboxilase in young albino rats. J Neurochem 23:123–127PubMedGoogle Scholar
  28. Resnick O, Morgane PJ (1984) Ontogeny of the levels of serotonin in various parts of the brain in severely protein malnourished rats. Brain Res 303:163–170CrossRefPubMedGoogle Scholar
  29. Salmon P, Gray JA (1986) Effects of propranolol on conditioned suppression, discriminated punishment and discriminated non-reward in the rat. Psychopharmacology 88:252–257CrossRefPubMedGoogle Scholar
  30. Smart JL, Whatson TS, Dobbing J (1975) Thresholds of response to electric shock in previously undernourished rats. Br J Nutr 34:511–516PubMedGoogle Scholar
  31. Söderpalm B, Hjoth S, Engel JA (1989) Effects of 5-HT1a receptor agonists andL-5-HTP in Montgomery's conflict test. Pharmacol Biochem Behav 32:259–265CrossRefPubMedGoogle Scholar
  32. Traber J, Glaser T (1987) 5-HT1a receptor-related anxiolytics. TIPS 8:432–437Google Scholar
  33. Waldmeier PC, Williams M, Baumann PA, Bischoff S, Sills MA, Neale RF (1988) Interactions of isamoltane (CGP 361A), an anxiolytic phenoxypropanolamine derivate, with 5-HT1 receptor subtypes in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 337:609–620Google Scholar
  34. Wiggins R, Fuller G, Enna S (1984) Undernutrition and the development of brain neurotransmitter systems. LIfe Sci 35:2085–2094CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • S. S. Almeida
    • 1
  • L. M. de Oliveira
    • 1
  • F. G. Graeff
    • 1
  1. 1.Laboratory of PsychobiologyFFCLRP, Campus of the University of São PauloRibeirão Preto, SPBrazil

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