Novel pharmacological approaches to the treatment of schizophrenia.

Schizophrenia is a devastating mental disease that affects the human population worldwide with an incidence of about 1%. Over the last decades basic and clinical research has considerably increased our understanding of the pathophysiology of schizophrenia, as well as the mechanism of action of antipsychotic compounds (neuroleptics), and new atypical neuroleptics with equipotent or improved antipsychotic effects and fewer motoric side effects have been developed. However, the pharmacological intervention does not effectively treat all the symptoms of the disease, and there is still a need for new, more effective antipsychotic compounds. Studies of brain function have demonstrated a reduced activation of prefrontal cortical areas during cognitive tasks in schizophrenics. It is hypothesized, that this hypofrontality is associated with a reduced dopaminergic tonus in the prefrontal cortex, which subsequently causes the negative symptoms of schizophrenia, such as apathy and social withdraw. It has also been suggested, that increased dopaminergic activity in striatal areas is related to the wellknown positive schizophrenic symptoms, such as delusions and hallucinations. The present thesis addresses the regional effects of prototypical and atypical neuroleptics on nerve cell activity and dopaminergic tonus in three rat brain areas with special relevance for the pharmacological effects of neuroleptics. Finally, new pharmacological approaches to the medical treatment of schizophrenia are suggested based on our experimental results. Initially, the effects of the prototypical neuroleptic haloperidol and the atypical neuroleptic clozapine on nerve cell activity in the rat forebrain were investigated by measuring the regional expression of the Fos protein. The Fos protein is regarded as a marker of cellular activity and was measured by use of immunohistochemical techniques i) in the medial prefrontal cortex (PFC), probably involved in the negative symptoms of schizophrenia, ii) in the nucleus accumbens (NAc), probably involved in the positive symptoms of schizophrenia and iii) in the dorsolateral striatum (DLSt), most likely involved in the motoric side effects of neuroleptics. Clozapine increases Fos protein immunoreactivity in the PFC with no or minimal effects in the DLSt. In contrast, haloperidol increases Fos protein immunoreactivity in the DLSt with minor effect in the PFC. Other atypical neuroleptics (risperidone, sertindole and NNC 22-0031) induced a Fos protein expression pattern different from haloperidol: The atypical compounds exhibit a larger ratio between Fos protein expression in PFC and DLSt than measured for haloperidol. These results are in accordance with the reported beneficial effects of clozapine, risperidone and sertindole on negative symptoms of schizophrenia and their lower degree of motoric side effects compared to haloperidol. All neuroleptics induced Fos protein immunoreactivity in the NAc, in accordance with their ability to reduce positive psychotic symptoms in schizophrenics. The microdialysis technique was used to investigate the regional dopaminergic effects of the above mentioned antipsychotic compounds by measuring interstitial levels of the dopamine metabolite dihydroxyphenylacetic acid ([DOPAC]i) in PFC, NAc and DLSt. All antipsychotics tested increased [DOPAC]i in the NAc, whereas the atypical antipsychotics clozapine, risperidone, sertindole and NNC 22-0031--in contrast to haloperidol--preferentially increased [DOPAC]i in PFC compared to DLSt. Also these results are in concordance with the clinical effects of clozapine, risperidone, sertindole and haloperidol and support the hypothesis that reduced dopaminergic tone in the prefrontal cortex relates to the negative symptoms of schizophrenia. All clinically efficacious neuroleptics block central dopamine D2 receptors, which include the dopamine D2, D3 and D4 receptor subtypes. The present thesis characterizes a dopamine D3 receptor agonist, cis-OH-PBZI.