Behavioral changes induced by long-term proline exposure are reversed by antipsychotics in zebrafish.
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.
Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600-Anexo, 90035-003 Porto Alegre, RS, Brazil.
Luiz Eduardo Baggio
LE
Savio
Fernanda Cenci
FC
Vuaden
Angelo L
AL
Piato
Carla Denise
CD
Bonan
Angela T S
AT
Wyse
D050842:1-Pyrroline-5-Carboxylate Dehydrogenase / Q000172:deficiency; D000592:Amino Acid Metabolism, Inborn Errors / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D011392:Proline / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011394:Proline Oxidase / Q000172:deficiency; D012919:Social Behavior; D013469:Sulpiride / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D015027:Zebrafish
D014150:Antipsychotic Agents; D013469:Sulpiride; D011392:Proline; D050842:1-Pyrroline-5-Carboxylate Dehydrogenase; D011394:Proline Oxidase; D006220:Haloperidol