VALPROIC ACID-INDUCED RAPID CHANGES OF MET-ENKEPHALIN LEVELS IN RAT-BRAIN - PROBABLE ASSOCIATION WITH ABSTINENCE BEHAVIOR AND ANTICONVULSANT ACTIVITY

Valproic acid (VPA) induces abstinence behavior and analgesia and displays an anticonvulsant effect, but its exact mechanism of action is not yet clear. In order to view whether proenkephalin derived-peptides are involved in the mechanism of VPA-induced behavior, we analyzed immunoreactive-met-enkephalin (IR-ME) in rat striatum, midbrain, and amygdala 10, 20, and 45 min after i.p. injection of 200 mg/kg of VPA. VPA induced body shakes that peaked within 5 to 10 min. IR-ME increased in the striatum and decreased in the midbrain at 10, 20, and 45 min, reaching the highest and lowest levels at 10 and 20 min, respectively. No changes occurred in the amygdala. Gel filtration chromatography followed by HPLC of striatum extracts showed that the increased IR-ME levels corresponded to low molecular weight peptides, including ME. These results indicate that VPA produced rapid changes of IR-ME levels in rat brain and suggest peptide participation in the mechanisms of VPA-induced behavior. The anticonvulsant effect of VPA was tested in rats treated with pentylenetetrazol (70 mg/kg) 30 min after VPA (400 mg/kg) administration, and IR-ME was analyzed in striatum 15 min later. No changes in striatal IR-ME levels occurred in protected rats (no behavioral convulsions), compared with those treated only with VPA, but a significant decrease appeared in unprotected animals (clonic convulsions). These results suggest that striatal ME may participate in the mechanism of VPA-induced abstinence behavior and in the anticonvulsant effect. Otherwise, midbrain ME might be involved in other VPA behaviors such as analgesia.