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Sodium valproate: Effects on social behaviour and physical development in the mouse

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Abstract

Sodium valproate given in drinking fluid at 600 mg/l (160–180 mg/kg daily) to breeding mice did not affect fertility, birth weights or physical development of pups. Postnatal and postweaning administration of this dose also had no effects upon development or weight gain. The offspring ingested 103–158 mg/kg valproate daily after weaning. Behaviour was examined in a neutral enclosure by ethological methods. Offspring exposed to valproate in utero and throughout postnatal life showed no behavioural changes at 5 weeks, although at 15 weeks Immobility was reduced in females and Social Investigation increased. At 25 weeks when encountering mice of the opposite sex, treated males showed increase in Social Investigation and treated females increases in Other Non-social Activity. Postnatal and postweaning treatment with valproate caused behavioural changes both in juveniles and adults. After postnatal exposure, reduced Immobility with increased Social Investigation and Explore and Scan occurred at 5 and 15 weeks, at 25 weeks valproate increased Social Investigation in males encountering females and at 30 weeks enhanced Aggression in pair-housed males. Stimulation of Social Investigation was the only significant behavioural effect after postweaning exposure. Overall valproate appears to enhance behaviour stimulated by the test situation; urinary pheromones do not appear to play a part in this behavioural action.

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References

  • Anlezark G, Horton RW, Meldrum BS, Sawaya MCB (1976) Anticonvulsant action of ethanolamine-o-sulphate and di-n-propylacetate and the metabolism of γ-aminobutyric acid (GABA) in mice with audiogenic seizures. Biochem Pharmacol 25:413–417

    Google Scholar 

  • Bailey CJ Pool RW, Poskitt EME, Harris F (1983) Valproic acid and fetal abnormality. Br Med J 286:190

    Google Scholar 

  • Betts TA, Crowe A, Alford C (1982) Psychotropic effects of sodium valproate. Br J Clin Pract Suppl 18:145–146

    Google Scholar 

  • Brown NA, Kao J, Fabro S (1980) Teratogenic potential of valproic acid. Lancet 1:660–661

    Google Scholar 

  • Bruckner A, Lee YJ, O'Shea KS, Henneberry RC (1983) Teratogenic effects of valproic acid and diphenylhydantoin on mouse embryos in culture. Teratology 27:29–43

    Google Scholar 

  • Chapman A, Keane PE, Meldrum BS, Simiand J, Vernieres JC (1982) Mechanism of action of valproate. Prog Neurobiol 19:315–359

    Google Scholar 

  • Chapman JB, Cutler MG (1983) Behavioural effects of phenobarbitone. 1. Effects in the offspring of laboratory mine. Psychopharmacology 79:155–160

    Google Scholar 

  • Cutler MG, Mackintosh JH, Chance MRA (1975) Effects of the environment on the behavioural response of mice to non-ataxic doses of ethyl alcohol. Neuropharmacology 14:841–846

    Google Scholar 

  • Diaz J, Shields WD (1978) Chronic administration of dipropylacetate early in life: effects on brain development and behaviour. Ann Neurol 4:198

    Google Scholar 

  • Dixon AK (1982) A possible olfactory component in the effects of diazepam on social behaviour of mice. Psychopharmacology 77:246–252

    Google Scholar 

  • Eymard P, Werbenec JP (1972) Etude pharmacologique complémentaire du di-n-propylacétamide ou depamide. Thérapie 27:11–24

    Google Scholar 

  • Fox WM (1965) Reflex ontogeny and behavioural development of the mouse. Anim Behav 13:234–241

    Google Scholar 

  • Gomez M (1981) Possible teratogenicity of valproic acid. J Pediatr 98:508

    Google Scholar 

  • Janz D (1982) Antiepileptic drugs and pregnancy: altered utilization patterns and teratogenesis. Epilepsia 23:suppl 1:553–563

    Google Scholar 

  • Jeavons PM, Clark JE, Maheshwari MC (1977) Treatment of generalised epilepsies of childhood and adolescence with sodium valproate (Epilim) Dev Med Child Neurol 19:9–25

    Google Scholar 

  • Kao J, Brown NA, Schnid B, Goulding EH, Fabro S (1981) Teratogenicity of valproic acid: in vivo and in vitro investigations. Teratogenesis Carcinogen Mutagen 1:367–382

    Google Scholar 

  • Katz RJ, Schmaltz K (1981) Behavioural interactions between opiate and antiepileptic drugs in the mouse. Neuropharmacology 20:375–379

    Google Scholar 

  • Kellogg C, Tervo D, Ison J, Parisi T, Miller RK (1980) Prenatal exposure to diazepam alters behavioural development in rats. Science 207:205–207

    Google Scholar 

  • Kempf E, Mack G, Schleef C, Mandel P (1982) Effect of valproic acid on brain serotonin metabolism in isolated and grouped rats. Pharmacol Biochem Behav 17:49–52

    Google Scholar 

  • Krsiak M, (1974) Behavioural changes and aggressivity evoked by drugs in mice. Res Commun Chem Pathol Pharmacol 7:238–255

    Google Scholar 

  • Lal H, Shearman GT, Fielding S, Dunn R, Kruse H, Theurer K (1980) Effect of valproic acid on anxiety related behaviours in the rat. Brain Res Bull 5:suppl 2, 575–577

    Google Scholar 

  • Loescher W, Nau H (1982) Valproic acid: metabolite concentrations in plasma and brain, anticonvulsant activity and effects on γ-aminobutyric acid metabolism during subacute treatment in mice. Arch Int Pharmacodyn Ther 257:20–31

    Google Scholar 

  • Mackintosh JH, Chance MRA, Silverman AP (1977) The contribution of ethological techniques to the study of drug effects. In: Iversen LI, Iversen SD, Snyder SN (eds) Handbook of psychopharmacology, vol 7, Plenum, London, pp 3–35

    Google Scholar 

  • Mandel P, Cielsielski L, Maitre M, Simler S, Mack G, Kempf E (1979) Involvement of central gabaergic systems in convulsions and aggressive behaviour. Adv Exp Med Biol 123:475–492

    Google Scholar 

  • Misslin R, Ropartz Ph, Mandel P (1972) Effects du di-n-propylacétate sur l'activité spontanée et conditionée de la souris. CR Acad Sci (Paris) 275:1279–1281

    Google Scholar 

  • Misslin R, Ropartz Ph, Mandel P (1975) The effects of n-dipropylacetate on the acquisition of conditioned behaviour with negative reinforcement in mice. Psychopharmacologia 44:263–265

    Google Scholar 

  • Moorcroft WH (1971) Ontogeny of forebrain inhibition of behavioural arousal in the rat. Brain Res 35:513–522

    Google Scholar 

  • Patsalos PM, Wiggins RC (1982) Brain maturation following administration of phenobarbital, phenytoin and sodium valproate to developing rats or to their dams: effects on synthesis of brain myelin and other subcellular membrane proteins. J Neurochem 39:915–923

    Google Scholar 

  • Paulson GW, Paulson RB (1981) Teratogenic effect of anticonvulsants. Arch Neurol 38:140–143

    Google Scholar 

  • Puglisi-Allegra S, Mack G, Oliverio A, Mandel P (1979) Effect of apomorphine and sodium di-n-propylacetate on the aggressive behaviour in three strains of mice. Prog Neuropsychopharmacol 3:491–502

    Google Scholar 

  • Puglisi-Allegra S, Mandel P (1980) Effect of sodium n0dipropylacetate, muscimol hydrobromide and nipecotid acid amide on isolation-induced aggressive behaviour in mice. Psychopharmacology 70:287–290

    Google Scholar 

  • Robert E, Guibaud P (1982) Maternal valproic acid and congenital neutral tube defects. Lancet II:937

    Google Scholar 

  • Simiand J, Keane PE, Eymard P, Santucci V, Morre M, Roncucci R (1983) Antiaggressive, anxiolytic and antimanic effects of valproate in animals. Br J Clin Pract Suppl 27:155–160

    Google Scholar 

  • Silverman AP (1966) Barbiturates, LSD and the social behaviour of the laboratory rat. Psychopharmacologia 10:155–171

    Google Scholar 

  • Taylor DG, Taylor KA, Antonaccio MJ (1982) Pharmacological studies on sympathoinhibition produced by the medial medullary depressor region: proposed γ-aminobutyric acid involvement in inhibition of somatosympathetic reflexes. J Pharmacol Exp Ther 222:517–525

    Google Scholar 

  • Van der Laan JW, Bruinvels J (1982) Dipropylacetate induced quasimorphine abstinence behaviour in the rat: Involvement of amygdaloid and thalamic structures. Brain Res 229:113–146

    Google Scholar 

  • Vorhees CV, Butcher RE (1982) Behavioural teratogenicity. In: Snell K (ed) Developmental toxicology. Croom Helm Ltd., London, pp 247–298

    Google Scholar 

  • Whittle BA (1976) Pre-clinical teratological studies on sodium valproate (Epilim) and other anticonvulsants. In: Legg NJ (ed) Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy. MCS Consultants, Tunbridge Wells pp 105–110

    Google Scholar 

  • Will B, Misslin R, Ropartz Ph, Mandel P (1972) Effets du di-n-propylacétate sur diverses réactions conditionnées chez le rat. CR Acad Sci (Paris) 275:2921–2923

    Google Scholar 

  • Wood PL (1982) Actions of GABAergic agents on dopamine metabolism in the nigrostriatal pathway of the rat. J Pharmacol Exp Ther 222:674–679

    Google Scholar 

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Chapman, J.B., Cutler, M.G. Sodium valproate: Effects on social behaviour and physical development in the mouse. Psychopharmacology 83, 390–396 (1984). https://doi.org/10.1007/BF00428553

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