Skip to main content
SpringerLink
Log in

Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

It has been suggested that behavioral aberrations observed in autism could be the result of dysfunction of the neuroregulatory role performed by the endogenous opioid peptides. Many of those aberrations have been recently modeled in rats exposed to valproic acid (VPA) on the 12th day of gestation (VPA rats).

Objectives

The aim of the present study was to elucidate functioning of the enkephalinergic system, one of the endogenous opioid peptide systems strongly involved in emotional responses, in VPA rats using both biochemical and behavioral methods.

Materials and methods

In situ hybridization was used to measure proenkephalin mRNA expression in adult VPA rats’ central nucleus of the amygdala, the dorsal striatum, and the nucleus accumbens. Additional groups of animals were examined in a conditioned place aversion to naloxone, the elevated plus maze, and object recognition tests to assess their basal hedonic tone, anxiety, learning and memory, respectively.

Results

Prenatal exposure to VPA decreased proenkephalin mRNA expression in the dorsal striatum and the nucleus accumbens but not in the central nucleus of the amygdala. It also increased anxiety and attenuated conditioned place aversion to naloxone but had no impact on learning and memory.

Conclusions

The present results suggest that prenatal exposure to VPA may lead to the decreased activity of the striatal enkephalinergic system and in consequence to increased anxiety and disregulated basal hedonic tone observed in VPA rats. Presented results are discussed in light of interactions between enkephalinergic, GABAergic, and dopaminergic systems in the striatum and mesolimbic areas of the brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM (1984) Endogenous opioids: biology and function. Annu Rev Neurosci 7:223–255

    Article  PubMed  CAS  Google Scholar 

  • Akil H, Owens C, Gutstein H, Taylor L, Curran E, Watson S (1998) Endogenous opioids: overview and current issues. Drug Alcohol Depend 51:127–140

    Article  PubMed  CAS  Google Scholar 

  • American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders (4th edn.). Washington, DC, pp 66–71

  • Angulo JA (1992) Involvement of dopamine D1 and D2 receptors in the regulation of proenkephalin mRNA abundance in the striatum and accumbens of the rat brain. J Neurochem 58:1104–1109

    Article  PubMed  CAS  Google Scholar 

  • Bauman ML, Kemper TL (1994) Neuroanatomic observation of the brain in autism. In: Bauman ML, Kemper TL (eds) The neurobiology of autism. John Hopkins Univ. Press, Baltimore, pp 119–145

    Google Scholar 

  • Belzung C (1992) Hippocampal mossy fibres: implication in novelty reactions or in anxiety behaviours? Behav Brain Res 51:149–155

    Article  PubMed  CAS  Google Scholar 

  • Bilkei-Gorzo A, Racz I, Michel K, Zimmer A, Klingmuller D, Zimmer A (2004) Behavioral phenotype of pre-proenkephalin-deficient mice on diverse congenic backgrounds. Psychopharmacology (Berl) 176:343–352

    Article  CAS  Google Scholar 

  • Chen JF, Aloyo VJ, Weiss B (1993) Continuous treatment with the D2 dopamine receptor agonist quinpirole decreases D2 dopamine receptors, D2 dopamine receptor messenger RNA and proenkephalin messenger RNA, and increases mu opioid receptors in mouse striatum. Neuroscience 54:669–680

    Article  PubMed  CAS  Google Scholar 

  • Courchesne E (1997) Brain stem, cerebellar and limbic neuroanatomical abnormalities in autism. Curr Opin Neurobiol 7:269–278

    Article  PubMed  CAS  Google Scholar 

  • da Silva Torres IL, Cucco SN, Bassani M, Duarte MS, Silveira PP, Vasconcellos AP, Tabajara AS, Dantas G, Fontella FU, Dalmaz C, Ferreira MB (2003) Long-lasting delayed hyperalgesia after chronic restraint stress in rats—effect of morphine administration. Neurosci Res 45:277–283

    Article  PubMed  CAS  Google Scholar 

  • Di Chiara G, Tanda G, Bassareo V, Pontieri F, Acquas E, Fenu S, Cadoni C, Carboni E (1999) Drug addiction as a disorder of associative learning Role of nucleus accumbens shell/extended amygdala dopamine. Ann NY Acad Sci 877:461–485

    Article  PubMed  Google Scholar 

  • Drolet G, Dumont EC, Gosselin I, Kinkead R, Laforest S, Trottier JF (2001) Role of endogenous opioid system in the regulation of the stress response. Prog Neuropsychopharmacol Biol Psychiatry 25:729–741

    Article  PubMed  CAS  Google Scholar 

  • Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats 1: behavioral data. Behav Brain Res 31:47–59

    Article  PubMed  CAS  Google Scholar 

  • Ennaceur A, Meliani K (1992) A new one-trial test for neurobiological studies of memory in rats 3: spatial vs non-spatial working memory. Behav Brain Res 51:83–92

    Article  PubMed  CAS  Google Scholar 

  • File SE (1993) The interplay of learning and anxiety in the elevated plus-maze. Behav Brain Res 58:199–202

    Article  PubMed  CAS  Google Scholar 

  • File SE, Hyde JR (1978) Can social interaction be used to measure anxiety? Br J Pharmacol 62:19–24

    PubMed  CAS  Google Scholar 

  • File SE, Zangrossi H Jr, Viana M, Graeff FG (1993) Trial 2 in the elevated plus-maze: a different form of fear? Psychopharmacology (Berl) 111:491–494

    Article  CAS  Google Scholar 

  • Frith U, Happe F (2005) Autism spectrum disorder. Curr Biol 15:786–790

    Article  CAS  Google Scholar 

  • Gaffney GR, Kuperman S, Tsai LY, Minchin S (1988) Morphological evidence for brainstem involvement in infantile autism. Biol Psychiatry 24:578–586

    Article  PubMed  CAS  Google Scholar 

  • Ghaziuddin M, Ghaziuddin N, Greden J (2002) Depression in persons with autism: implications for research and clinical care. J Autism Dev Disord 32:299–306

    Article  PubMed  Google Scholar 

  • Good AJ, Westbrook RF (1995) Effects of a microinjection of morphine into the amygdala on the acquisition and expression of conditioned fear and hypoalgesia in rats. Behav Neurosci 109:631–641

    Article  PubMed  CAS  Google Scholar 

  • Grevert P, Goldstein A (1977) Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects. Proc Natl Acad Sci USA 74:1291–1294

    Article  PubMed  CAS  Google Scholar 

  • Hablitz JJ, Tehrani MH, Barnes EM Jr (1989) Chronic exposure of developing cortical neurons to GABA down-regulates GABA/benzodiazepine receptors and GABA-gated chloride currents. Brain Res 501:332–338

    Article  PubMed  CAS  Google Scholar 

  • Haller J, Bakos N (2002) Stress-induced social avoidance: a new model of stress-induced anxiety? Physiol Behav 77:327–332

    Article  PubMed  CAS  Google Scholar 

  • Haller J, Leveleki C, Baranyi J, Mikics E, Bakos N (2003) Stress, social avoidance and anxiolytics: a potential model of stress-induced anxiety. Behav Pharmacol 14:439–446

    PubMed  CAS  Google Scholar 

  • Hashimoto T, Tayama M, Murakawa K, Yoshimoto T, Miyazaki M, Harada M, Kuroda Y (1995) Development of the brainstem and cerebellum in autistic patients. J Autism Dev Disord 25:1–18

    Article  PubMed  CAS  Google Scholar 

  • Hollister LE, Johnson K, Boukhabza D, Gillespie HK (1981) Aversive effects of naltrexone in subjects not dependent on opiates. Drug Alcohol Depend 8:37–41

    Article  PubMed  CAS  Google Scholar 

  • Ikemoto S, Kohl RR, McBride WJ (1997) GABA(A) receptor blockade in the anterior ventral tegmental area increases extracellular levels of dopamine in the nucleus accumbens of rats. J Neurochem 69:137–143

    Article  PubMed  CAS  Google Scholar 

  • Ingram JL, Peckham M, Tisdale B, Rodier PM (2000) Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 22:319–324

    Article  PubMed  CAS  Google Scholar 

  • Ishizaki T, Yokochi K, Chiba K, Tabuchi T, Wagatsuma T (1981) Placental transfer of anticonvulsants (phenobarbital, phenytoin, valproic acid) and the elimination from neonates. Pediatr Pharmacol (New York) 1:291–303

    CAS  Google Scholar 

  • Kalat JW (1978) Speculations of similarities between autism and opiate addiction. J Autism Child Schizophrenia 8:477–479

    Article  CAS  Google Scholar 

  • King CD, Devine DP, Vierck CJ, Rodgers J, Yezierski RP (2003) Differential effects of stress on escape and reflex responses to nociceptive thermal stimuli in the rat. Brain Res 987:214–222

    Article  PubMed  CAS  Google Scholar 

  • Knott PJ, Hutson PH (1982) Stress-induced stereotypy in the rat: neuropharmacological similarities to Tourette syndrome. Adv Neurol 35:233–238

    PubMed  CAS  Google Scholar 

  • Konig M, Zimmer AM, Steiner H, Holmes PV, Crawley JN, Brownstein MJ, Zimmer A (1996) Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 383:535–538

    Article  PubMed  CAS  Google Scholar 

  • Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129

    Article  PubMed  CAS  Google Scholar 

  • Kowalski C, Giraud P (1993) Dopamine decreases striatal enkephalin turnover and proenkephalin messenger RNA abundance via D2 receptor activation in primary striatal cell cultures. Neuroscience 53:665–672

    Article  PubMed  CAS  Google Scholar 

  • LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184

    Article  PubMed  CAS  Google Scholar 

  • Levine S (1962) Plasma-free corticosteroid response to electric shock in rats stimulated in infancy. Science 9:795–796

    Article  Google Scholar 

  • Levine S (1967) Maternal and environmental influences on the adrenocortical response to stress in weanling rats. Science 156:258–260

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Morrow AL, Devaud L, Grayson DR, Lauder JM (1997) GABAA receptors mediate trophic effects of GABA on embryonic brainstem monoamine neurons in vitro. J Neurosci 17:2420–2428

    PubMed  CAS  Google Scholar 

  • Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW (1977) Endogenous opioid peptides: multiple agonists and receptors. Nature 267:495–499

    Article  PubMed  CAS  Google Scholar 

  • Martin del Campo AF, McMurray RG, Besser GM, Grossman A (1992) Effect of 12-hour infusion of naloxone on mood and cognition in normal male volunteers. Biol Psychiatry 32:344–353

    Article  PubMed  CAS  Google Scholar 

  • McGaugh JL, Cahill L, Roozendaal B (1996) Involvement of the amygdala in memory storage: interaction with other brain systems. Proc Natl Acad Sci USA 93:13508–13514

    Article  PubMed  CAS  Google Scholar 

  • Mesdjian E, Ciesielski L, Valli M, Bruguerolle B, Jadot G, Bouyard P, Mandel P (1982) Sodium valproate: kinetic profile and effects on GABA levels in various brain areas of the rat. Prog Neuro-psychopharmacol Biol Psychiatry 6:223–233

    Article  CAS  Google Scholar 

  • Miyazaki C, Matsuyama K, Ichikawa M, Goto S (1988) Effect of sodium valproate (VPA) on cerebral amino acids: mechanism of gamma-aminobutyric acid (GABA) elevation and possible causal relation of VPA-induced encephalopathy and glutamine level. Chem Pharm Bull (Tokyo) 36:3589–3594

    CAS  Google Scholar 

  • Morris BJ, Hollt V, Herz A (1988) Dopaminergic regulation of striatal proenkephalin mRNA and prodynorphin mRNA: contrasting effects of D1 and D2 antagonists. Neuroscience 25:525–532

    Article  PubMed  CAS  Google Scholar 

  • Mucha RF, Millan MJ, Herz A (1985) Aversive properties of naloxone in non-dependent (naive) rats may involve blockade of central beta-endorphin. Psychopharmacology (Berl) 86:281–285

    Article  CAS  Google Scholar 

  • Muris P, Steerneman P, Merckelbach H, Holdrinet I, Meesters C (1998) Comorbid anxiety symptoms in children with pervasive developmental disorders. J Anxiety Disord 12:387–393

    Article  PubMed  CAS  Google Scholar 

  • Napier TC, Pirch JH, Strahlendorf HK (1983) Naloxone antagonizes striatally-induced suppression of globus pallidus unit activity. Neuroscience 9:53–59

    Article  PubMed  CAS  Google Scholar 

  • Narayanan S, Lam H, Christian L, Levine MS, Grandy D, Rubinstein M, Maidment NT (2004) Endogenous opioids mediate basal hedonic tone independent of dopamine D-1 or D-2 receptor activation. Neuroscience 124:241–246

    Article  PubMed  CAS  Google Scholar 

  • Nau H, Hauck RS, Ehlers K (1991) Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms. Pharmacol Toxicol 69:310–321

    Article  PubMed  CAS  Google Scholar 

  • Nieto MM, Guen SL, Kieffer BL, Roques BP, Noble F (2005) Physiological control of emotion-related behaviors by endogenous enkephalins involves essentially the delta opioid receptors. Neuroscience 135:305–313

    Article  PubMed  CAS  Google Scholar 

  • Olson GA, Olson RD, Kastin AJ (1996) Endogenous opiates. Peptides 17:1421–1466

    Article  PubMed  CAS  Google Scholar 

  • Ozonoff S, Goodlin-Jones BL, Solomon M (2005) Evidence-based assessment of autism spectrum disorders in children and adolescents. J Clin Child Adolesc Psychol 34:523–540

    Article  PubMed  Google Scholar 

  • Palermo-Neto J, de Oliveira Massoco C, Robespierre de Souza W (2003) Effects of physical and psychological stressors on behavior, macrophage activity, and Ehrlich tumor growth. Brain Behav Immun 17:43–54

    Article  PubMed  CAS  Google Scholar 

  • Panksepp J (1979) A neurochemical theory of autism. Trends Neurosci 2:174–177

    Article  Google Scholar 

  • Panksepp J, Herman B, Villberg T (1978) An opiate excess model of childhood autism. Neuroscience 4:500 (Abstract)

    Google Scholar 

  • Parker LA, Rennie M (1992) Naltrexone-induced aversions: assessment by place conditioning, taste reactivity, and taste avoidance paradigms. Pharmacol Biochem Behav 41:559–565

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, Sydney, Australia

    Google Scholar 

  • 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 14:149–167

    Article  PubMed  CAS  Google Scholar 

  • Przewlocki R, Lason W, Hollt V, Silberring J, Herz A (1987) The influence of chronic stress on multiple opioid peptide systems in the rat: pronounced effects upon dynorphin in spinal cord. Brain Res 413:213–219

    Article  PubMed  CAS  Google Scholar 

  • Ragnauth A, Schuller A, Morgan M, Chan J, Ogawa S, Pintar J, Bodnar RJ, Pfaff DW (2001) Female preproenkephalin-knockout mice display altered emotional responses. Proc Natl Acad Sci USA 9:1958–1963

    Article  Google Scholar 

  • Robbins TW, Everitt BJ (1996) Neurobehavioural mechanisms of reward and motivation. Curr Opin Neurobiol 6:228–236

    Article  PubMed  CAS  Google Scholar 

  • Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J (1996) Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol 370:247–261

    Article  PubMed  CAS  Google Scholar 

  • Rodier PM, Ingram JL, Tisdale B, Croog VJ (1997) Linking etiologies in humans and animal models: studies of autism. Reprod Toxicol 11:417–422

    Article  PubMed  CAS  Google Scholar 

  • Sahley TL, Panksepp J (1987) Brain opioids and autism: an updated analysis of possible linkages. J Autism Dev Disord 17:201–216

    Article  PubMed  CAS  Google Scholar 

  • Saitoh A, Yoshikawa Y, Onodera K, Kamei J (2005) Role of delta-opioid receptor subtypes in anxiety-related behaviors in the elevated plus-maze in rats. Psychopharmacology (Berl) 182:327–334

    Article  CAS  Google Scholar 

  • Schneider T, Przewlocki R (2005) Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30:80–89

    Article  PubMed  CAS  Google Scholar 

  • Schneider T, Turczak J, Przewlocki R (2006) Environmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism. Neuropsychopharmacology 31:36–46

    PubMed  CAS  Google Scholar 

  • Schousboe A, Redburn DA (1995) Modulatory actions of gamma aminobutyric acid (GABA) on GABA type A receptor subunits expression. J Neurosci Res 41:1–7

    Article  PubMed  CAS  Google Scholar 

  • Shattock P, Whiteley P (2002) Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets 6:175–183

    Article  PubMed  CAS  Google Scholar 

  • Shippenberg TS, Bals-Kubik R (1995) Involvement of the mesolimbic dopamine system in mediating the aversive effects of opioid antagonists in the rat. Behav Pharmacol 6:99–106

    Article  PubMed  CAS  Google Scholar 

  • Skoubis PD, Maidment NT (2003) Blockade of ventral pallidal opioid receptors induces a conditioned place aversion and attenuates acquisition of cocaine place preference in the rat. Neuroscience 119:241–249

    Article  PubMed  CAS  Google Scholar 

  • Skoubis PD, Matthes HW, Walwyn WM, Kieffer BL, Maidment NT (2001) Naloxone fails to produce conditioned place aversion in mu-opioid receptor knock-out mice. Neuroscience 106:757–763

    Article  PubMed  CAS  Google Scholar 

  • Skoubis PD, Lam HA, Shoblock J, Narayanan S, Maidment NT (2005) Endogenous enkephalins, not endorphins, modulate basal hedonic state in mice. Eur J Neurosci 21:1379–1384

    Article  PubMed  CAS  Google Scholar 

  • Stinus L, Le Moal M, Koob GF (1990) Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal. Neuroscience 37:767–773

    Article  PubMed  CAS  Google Scholar 

  • Tehrani MH, Barnes EM Jr (1988) GABA down-regulates the GABA/benzodiazepine receptor complex in developing cerebral neurons. Neurosci Lett 87:288–292

    Article  PubMed  CAS  Google Scholar 

  • Towbin KE, Pradella A, Gorrindo T, Pine DS, Leibenluft E (2005) Autism spectrum traits in children with mood and anxiety disorders. J Child Adolesc Psychopharmacol 15:452–464

    Article  PubMed  Google Scholar 

  • Valverde O, Fournie-Zaluski MC, Roques BP, Maldonado R (1996) Similar involvement of several brain areas in the antinociception of endogenous and exogenous opioids. Eur J Pharmacol 312:15–25

    Article  PubMed  CAS  Google Scholar 

  • Vanderschuren LJ, Niesink RJ, Spruijt BM, Van Ree JM (1995) Influence of environmental factors on social play behavior of juvenile rats. Physiol Behav 58:119–123

    Article  PubMed  CAS  Google Scholar 

  • Yoshikawa K, Williams C, Sabol S (1984) Rat brain preproenkephalin mRNA–cDNA cloning, primary structure, and distribution in the central nervous system. J Biol Chem 259:14301–14308

    PubMed  CAS  Google Scholar 

  • Young WS, Bonner TI, Brann MR (1986) Mesencephalic dopamine neurons regulate the expression of neuropeptide mRNAs in the rat forebrain. Proc Natl Acad Sci USA 83:9827–9831

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Tomasz Schneider

    Present address: Behavioural Pharmacology, Institute of Psychiatry P049, King’s College London, De Crespigny Park, London, SE5 8AF, UK

Authors and Affiliations

  1. Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Science s, 12 Smętna Street, 31-343, Kraków, Poland

    Tomasz Schneider, Barbara Ziòłkowska, Agnieszka Gieryk, Anna Tyminska & Ryszard Przewłocki

Authors
  1. Tomasz Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Ziòłkowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Agnieszka Gieryk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Tyminska
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryszard Przewłocki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ryszard Przewłocki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schneider, T., Ziòłkowska, B., Gieryk, A. et al. Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism. Psychopharmacology 193, 547–555 (2007). https://doi.org/10.1007/s00213-007-0795-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0795-y

Keywords

Search

Navigation