Behavioural and biochemical pharmacology of adenosine/dopamine receptor/receptor interaction

Abstract

The neurotransmitter dopamine seems to be involved in neuropsychiatric diseases such as schizophrenia and Parkinson's disease. Direct blockade of dopamine receptors of the D2 subtype has been the hallmark of pharmacotherapy for schizophrenia since early 1950s. However, the therapy is not ideal and some common adverse effects such as the extrapyramidal side effects are also a consequence of D2 receptor blockade. On the other hand, direct stimulation of dopamine receptors, with dopamine agonists, is still the main treatment in Parkinson's disease. However, important secondary effects appear as a consequence of the direct stimulation of dopamine receptors, such as dyskinesias. A new strategy for a potential pharmacotherapy for these disorders is based on the indirect modulation of dopamine receptors, which might offer the same therapeutic effect as drugs directly active on dopamine receptors but without the adverse effects.

The nucleoside adenosine exerts a modulatory action in the central nervous system through different subtypes of G protein-coupled receptors. A number of studies has shown the existence of a strong antagonistic interaction between adenosine and dopamine in the brain. This seems to depend mainly on specific antagonistic interactions between striatal adenosine A, and dopamine D1 receptors and striatal adenosine A2A and dopamine D2 receptors. Morphological and functional experiments suggest that these interactions take place in the two different GABAergic striatal efferent neurons. Thus A1/D1 and A2A/D2 interactions modulate the function of stronigro-strioentopeduncular and striopallidal GABAergic neurons, respectively.

The aim of this thesis is to better characterize these adenosine/dopamine receptor/receptor interactions by using different biochemical and behavioural experimental approaches, in order to find new pharmacotherapeutic applications for Parkinson's disease and schizophrenia, based on the indirect adenosine-mediated modulation of dopamine receptors.

In behavioural experiments, a selective adenosine A, agonist was shown to preferentially antagonize D1-induced behaviours while a selective A2A agonist antagonized D2-induced behaviours, either in naive rats or in rats with a unilateral 6-hydroxy-dopamine lesion of the nigrostriatal dopaminergic pathway. Furthermore, the adenosine A2A agonist CGS 21680 showed a clear atypical antipsychotic profile in animal models.

The expression of dopamine-mediated behaviours requires the striatal expression of the immediate early gene c-fos. The results indicated a facilitatory role of c-fos in the regulation of the strionigro-strioentopeduncolar GABA pathway but not of the striopallidal GABA pathway. Moreover, an adenosine A, agonist counteracted the dopamine D1 agonist-induced increase in c-fos, NGFI-A and junB mRNA levels in the dopamine denervated striatum and this effect was stronger in the ventral striatum corn pared to the dorsal striatum.

Activation of striatal metabotropic glutamate receptors had been shown to induce motor effects which seem to be modulated by dopamine and adenosine. The present results indicated that some of these effects can be explained by the existence of multiple receptor/receptor interactions between striatal group I metabotropic, adenosine A2A and dopamine D2 receptors.

In conclusion, these studies support the existence of antagonistic receptor/receptor interactions between striatal adenosine and dopamine receptors, which might provide a new therapeutical approach for Parkinson's disease and schizophrenia.