Differential effects of the antipsychotics haloperidol and clozapine on G protein measures in mononuclear leukocytes of patients with schizophrenia.
OBJECTIVE
Heterotrimeric G proteins play a pivotal role in postreceptor information transduction. These proteins were previously implicated in the pathophysiology and treatment of mood and other neuropsychiatric disorders. Recently we showed that untreated patients with schizophrenia have a significantly elevated dopamine-induced Gs protein function which is correlated with the severity of the psychotic symptoms. In contrast, an inverse picture with reduction in the function and the immunoreactivity of Gs protein was detected in patients with Parkinson's disease. The present study aims at investigating the effect of antipsychotic medications on dopamine-induced Gs protein hyperfunction in schizophrenia comparing the classical antipsychotic haloperidol and the newer antipsychotic clozapine, which is devoid of extrapyramidal side effects, on G protein measures.


METHODS
G protein functional measurements coupled to beta-adrenergic, muscarinic, and dopamine receptors were undertaken through bacterial toxin sensitive, agonist enhanced [3H]-Gpp(NH)p binding capacity, substantiated by quantitative measures of Gs alpha, Gi alpha, and G beta subunit proteins through immunoblot analysis in mononuclear leukocytes obtained from patients with schizophrenia under haloperidol, or clozapine treatments in comparison with untreated patients with schizophrenia and healthy volunteers.


RESULTS
Dopamine-induced Gs hyperfunction characteristic of untreated patients with schizophrenia was not detected under antipsychotic treatment with either haloperidol or clozapine. Haloperidol caused a significant decrease in Gs function and immunoreactivity below normal levels. The extend of reduction in Gs function was found to be correlated with the intensity of extrapyramidal side effects. The pattern of G protein subunits levels in patients with schizophrenia under haloperidol treatment resembles the one obtained in patients with Parkinson's disease.


CONCLUSIONS
In the present study it is shown that G protein measurements in patients with schizophrenia under antipsychotic treatments can be used to biochemically monitor effects of antipsychotic medications in living patients. Moreover, these measurements may be used also for monitoring parkinsonian side effects induced by antipsychotic medications.
Avissar
S
S
Department of Clinical Pharmacology, Ben Gurion University of the Negev, Beer Sheva, Israel. sofia@bgumail.bgu.ac.il
Roitman
G
G
Schreiber
G
G
D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D011943:Receptors, Adrenergic, beta; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D019204:GTP-Binding Proteins; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine