Implications for the treatment of schizophrenia and Parkinson’s disease

Dopamine is fundamental in human behavior for movement, cognition and reward. A dysfunctional dopamine system is implicated in several neurological and psychiatric disorders such as Parkinson’s disease and schizophrenia. Dopamine mediates its effects through five receptors. Dopamine D2 receptors are well studied and successful drug targets in the treatment of Parkinson’s disease and schizophrenia. The functional role of dopamine D1 receptors is not fully understood and the clinical potential remains elusive. In the present thesis, full dopamine D1 receptor agonists were used to characterize the functional roles of these dopamine receptor subtypes. A number of aspects of psychomotor activation relevant for Parkinson’s disease and schizophrenia were examined with the full dopamine D1 receptor agonists dihydrexidine and A 68930. Stimulation of dopamine D1 receptors by dihydrexidine and A 68930 resulted in inhibition of locomotor activity in rats exploring an open-field. In habituated animals, with a low baseline activity, as well as in dopamine depleted rats, no locomotor activation was evident following dopamine D1 receptor stimulation. The results suggest inhibitory actions of dopamine D1 receptors in psychomotor activation. In fact, dihydrexidine and A 68930 blocked amphetamine-induced hyperactivity, a traditional sign of antipsychotic action. A possible site of action for the effects of dihydrexidine and A 68930 is stimulation of prefrontal dopamine D1 receptors, as indexed by neuronal activation (c-fos). A different approach to examine dopamine D1 receptor agonism was used with clozapine that previously has been shown to possess dopamine D1 receptor agonist properties in vivo. Clozapine does not cause extrapyramidal side effects and can be used in drug-induced psychosis in Parkinson’s disease. Two new atypical antipsychotics, olanzapine and quetiapine, that both have a similar pharamacological profile to clozapine, were compared with clozapine on drug-induced catalepsy. In contrast to olanzapine and quetiapine, clozapine blocked catalepsy. It is concluded that the pharmacological profile of clozapine differs from olanzapine and quetiapine, a finding that possibly can be explained by dopamine D1 receptor agonism as a feature of clozapine. Whether the inhibition of psychomotor activity by dihydrexidine and A 68930 reside in specific D1 or D5 receptor stimulation is not known. In an attempt to functionally separate dopamine D1 and D5 receptor function, siRNA for induction of RNA interference (RNAi) was used to specifically knock-down D1 receptors. Despite high efficacy in an in vitro system, no receptor knockdown was obtained in rodent brain with siRNA. The results suggest that a refinement of the RNAi technology is needed before functional studies in vivo is possible. The present thesis suggests important functional roles of brain dopamine D1 receptors that may have relevance for schizophrenia and Parkinson’s disease. A particularly interesting finding is an inhibitory role of prefrontal dopamine D1 receptors on psychomotor activation, a finding that may have clinical implications in the treatment of schizophrenia. LIST OF PUBLICATIONS I. Ahlqvist J, Isacson R, Wahlestedt C, Salmi P. Anti-cataleptic effects of clozapine, but not olanzapine and quetiapine, on SCH 23390or raclopride-induced catalepsy in rats. Eur Neuropsychopharmacol 2003; 13: 177-182. II. Isacson R, Kull B, Wahlestedt C, Salmi P. A 68930 and dihydrexidine inhibit locomotor activity and d-amphetamineinduced hyperactivity in rats: a role of inhibitory dopamine D1/5 receptors in the prefrontal cortex? Neuroscience 2004; 124: 33-42. III. Isacson R, Hillegaart V, Wahlestedt C, Salmi P. Full dopamine D1 receptor agonists fail to activate locomotion in reserpinized rats unless combined with a dopamine D2 receptor agonist. Manuscript. IV. Isacson R, Kull B, Salmi P, Wahlestedt C. Lack of efficacy of 'naked' small interfering RNA applied directly to rat brain. Acta Physiol Scand 2003; 179: 173-177.