Behavioral changes induced by long-term proline exposure are reversed by antipsychotics in zebrafish

Prog Neuropsychopharmacol Biol Psychiatry. 2012 Mar 30;36(2):258-63. doi: 10.1016/j.pnpbp.2011.10.002. Epub 2011 Oct 12.


Hyperprolinemia is an inherited disorder of proline metabolism and patients affected by this disease may present neurological manifestations, including seizures and cognitive dysfunctions. Moreover, an association between adulthood schizoaffective disorders and moderate hyperprolinemia has been reported. However, the mechanisms underlying these behavioral phenotypes still remain unclear. In the present study, we investigated the effect of proline treatments on behavioral parameters in zebrafish, such as locomotor activity, anxiety, and social interaction. Adult zebrafish (Danio rerio) were exposed to proline (1.5 and 3.0 mM) during 1h or 7 days (short- or long-term treatments, respectively). Short-term proline exposure did not promote significant changes on the behavioral parameters observed. Long-term exposure at 1.5 mM proline significantly increased the number of line crossing (47%), the total distance (29%), and the mean speed (33%) when compared to control group. A significant increase in the time spent in the upper portion of the test tank was also observed after this treatment (91%), which may be interpreted as an indicator of anxiolytic behavior. Proline at 1.5 mM also induced social interaction impairment (78%), when compared to the untreated group after long-term treatment. Moreover, these proline-induced behavioral changes in zebrafish were completely reversed by acute administration of an atypical antipsychotic drug (sulpiride), but not by a typical (haloperidol). These findings demonstrate that proline is able to induce schizophrenia-like symptoms in zebrafish, which reinforce the use of this species as a complementary vertebrate model for studying behavioral phenotypes associated with neurological dysfunctions characteristic of metabolic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Pyrroline-5-Carboxylate Dehydrogenase / deficiency
  • Amino Acid Metabolism, Inborn Errors / chemically induced
  • Amino Acid Metabolism, Inborn Errors / complications
  • Amino Acid Metabolism, Inborn Errors / drug therapy*
  • Animals
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use*
  • Anxiety / complications
  • Anxiety / drug therapy*
  • Disease Models, Animal
  • Drug Interactions
  • Female
  • Haloperidol / pharmacology
  • Haloperidol / therapeutic use
  • Locomotion / drug effects*
  • Male
  • Proline / antagonists & inhibitors*
  • Proline / pharmacology*
  • Proline Oxidase / deficiency
  • Social Behavior*
  • Sulpiride / pharmacology
  • Sulpiride / therapeutic use
  • Time Factors
  • Zebrafish


  • Antipsychotic Agents
  • Sulpiride
  • Proline
  • 1-Pyrroline-5-Carboxylate Dehydrogenase
  • Proline Oxidase
  • Haloperidol

Supplementary concepts

  • Hyperprolinemia type 2