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The distribution of messenger RNAs (mRNAs) encoding the 67 kDa isoform of glutamic acid decarboxylase (GAD67), a rate-limiting enzyme in the biosynthesis of gamma-aminobutyric acid, and preproenkephalin (PPE), the precursor of enkephalin, was analysed in the rat nucleus accumbens (NAS) taking in account its compartmentation in 'core' (NAS(core)) and 'shell' (NASshell). While GAD67 mRNA levels were more abundant (+48%) in NASshell than in NAS(core), hybridization signals for PPE mRNA were mainly found in NAScore. At a cellular level, hybridization signals for GAD67 mRNA were present in 75% and 80% of neurons NASshell and NAS(core), respectively. The level of GAD67 mRNA found higher in the NASshell corresponds in fact to a greater density of neurons in NASshell than in the NAS(core). The hybridization signals for PPE mRNA were observed in very few neurons of NASshell and in around half of the neurons in NAS(core). Besides this medio to lateral difference, GAD67 and PPE mRNAs were distributed in NAS(core) according to a rostro-caudal gradient, the content of both mRNAs being higher in the rostral part than the caudal part of this area.

The levels of mRNA encoding glutamic acid decarboxylase (GAD) and preproenkephalin (PPE) were measured by Northern blot analysis, in the dorsal and the ventral part of the striatum, following long-term treatments with drugs acting selectively on D1 or D2 dopaminergic receptors. Chronic injection of the selective D1 antagonist SCH 23390 elicited a significant decrease in level of both GAD and PPE mRNA (-30%) in the dorsal striatum, whereas no significant change was observed in the ventral striatum. Chronic administration of both SCH 23390 and RU 24926, a D2 agonist, decreased the GAD and PPE mRNA levels in the dorsal (-38 and -57%, respectively) as well as in the ventral (-70 and -60%, respectively) striatum. In the ventral striatum the marked reduction of GAD mRNA levels was paralleled by a significant decrease of Vmax values of GAD enzymatic activity (-41%). These results suggest that the decrease in content of both GAD and PPE mRNA, promoted by the chronic blockade of D1 receptors, is mainly due to the action of dopamine acting on unaffected D2 receptors. Indeed, this decrease is further amplified when the D2 agonist and the D1 antagonist are administered together. Our results substantiate further the molecular mechanisms by which dopamine acts on different populations of GABAergic and enkephalinergic neurons in the two striatal regions examined.

The time course changes in levels of mRNA encoding glutamic acid decarboxylase (GAD) and proenkephalin (PPE) was analyzed in the rat striatum following unilateral lesion of substantia nigra with 6-hydroxydopamine. The levels of both GAD and PPE mRNAs increased after the dopaminergic deafferentation, reaching concomitantly a maximal twofold increase on day 25. Thereafter, the mRNA levels declined; at 4 months, the amount of PPE mRNA remained slightly elevated whereas GAD mRNA had returned to the control value, suggesting the action of a compensatory mechanism. We also observed a rise of glial fibrillary acidic protein mRNA level which reflects a reactive astrocytosis. In contrast, alpha-tubulin mRNA level remained unchanged, indicating that no significant synaptogenesis occurs in this experimental situation. No obvious modification in mRNA levels was detected in the striatum contralateral to the lesion. These results highlight the role of the modulation of gene expression in adaptive processes to dopamine deficiency in striatal efferent pathways. Its relevance to the pathophysiology of Parkinson's disease is discussed.

A recombinant plasmid has been constructed containing a sequence of 186 nucleotides encoding a potent neurotoxin found in the venom of the sea-snake Laticauda semifasciata and designated as erabutoxin a. This sequence is flanked, in the upstream region, by a sequence of 60 nucleotides encoding a hydrophobic peptide fragment presumably involved in the secretion process of the neurotoxin. The sequence coding for the toxin ends with a termination codon which is followed by a 3'-untranslated sequence of approximately 240 nucleotides (excluding the poly(A) tract).