CHARACTERIZATION OF METHIONINE-ENKEPHALIN RELEASE IN THE RAT STRIATUMBY IN-VIVO DIALYSIS - EFFECTS OF GAMMA-HYDROXYBUTYRATE ON CELLULAR AND EXTRACELLULAR METHIONINE-ENKEPHALIN LEVELS

The opioid system is implicated in mediating the effects produced upon administration of gamma-hydroxybutyrate. Gamma-hydroxybutyrate occurs endogenously in the mammalian brain, and is most probably involved in the regulation of some basic brain functions, particularly those conc erning the dopaminergic nigrostriatal pathway, which is closely linked to the expression of enkephalins in the striatum. In the present stud y, in vivo microdialysis was used to examine the basic characteristics of methionine-enkephalin (met-enkephalin) release in the striatum of Wistar rats, using a high performance radioimmunoassay. Administration of gamma-hydroxybutyrate to the rats induced a dose-dependent decreas e in the extracellular release of met-enkephalin. In parallel, a dose- and time-dependent gammahydroxybutyrate-induced accumulation of met-e nkephalin in striatum was observed. These two phenomena (tissue accumu lation and inhibition of release) were blocked by NCS-382, a gamma-hyd roxybutyrate receptor antagonist. The striatal met-enkephalin accumula tion does not seem to be exclusively due to the inhibition of its rele ase. Thus, a gamma hydroxybutyrate mediating effect on met-enkephalin synthesis is suggested, most probably occurring via functional modulat ion of striatal dopamine synthesis and release. To understand the role of this dopaminergic mechanism, unilateral lesions of the nigrostriat al dopaminergic pathway were carried out. In gamma-hydroxybutyrate-tre ated rats, striata exhibited a similar increase in met-enkephalin cont ent. In untreated rats, only the lesioned striatum showed an identical increase in met-enkephalin levels. Thus, striatal met-enkephalin accu mulation could be attributed to the suppression of the dopaminergic im pulse flow, due to gamma-hydroxybutyrate or to the action of 6-hydroxy dopamine. In the extracellular spaces (microdialysis experiments), gam ma-hydroxybutyrate administration induced identical modifications of m et-enkephalin release in lesioned or non-lesioned striata. These modif ications could be reproduced by peripheral or striatal administration of sulpiride, a D-2/D-3 antagonist. From a functional point of view, t he dopaminergic D-2 receptor blockade or the gamma-hydroxybutyrate-ind uced inhibition of dopamine release could be considered to induce simi lar results, with identical consequences on striatal met-enkephalin ac cumulation and release. These results suggest that gamma-hydroxybutyra te-induced modifications in met-enkephalin release, presumably potenti ated by 6-hydroxydopamine treatment, act via a functional modification of the nigrostriatal dopaminergic pathway.