GUANINE-NUCLEOTIDE-BINDING PROTEINS IN BIPOLAR AFFECTIVE-DISORDER - EFFECTS OF LONG-TERM LITHIUM TREATMENT

Background: This study examines recent suggestions from a number of in vestigators that signal-transducing guanine nucleotide-binding (G) pro teins may be involved in the pathophysiology of bipolar affective diso rder and may represent molecular targets for lithium's mood-stabilizin g actions. Methods: We used selective antibodies to quantitate the lev els of the G protein alpha subunits that regulate adenylate cyclase ac tivity (G alpha(s) and G alpha(i2)) and phosphoinositide turnover (G a lpha(q/11)). We also quantitated levels of pertussis toxin-catalyzed p hosphate 32-labeled adenosine diphosphate ([P-32]ADP) ribosylation in platelet and leukocyte membranes from a group of 14 untreated (predomi nantly manic) patients with bipolar affective disorder, 20 lithium-tre ated euthymic patients with bipolar affective disorder, and 11 healthy controls. Results: In both tissues, the immunolabeling of the 45-kd f orm of G alpha(s) was higher in the bipolar affective disorder group c onsidered as a whole (treated or untreated) compared with controls, ef fects that reached statistical significance in the leukocyte membranes . There were no significant differences in the immunolabeling of G alp ha(i1/2), G alpha(q/11), or pertussis toxin-catalyzed [P-32]ADP ribosy lation in either tissue in the untreated bipolar affective disorder gr oup compared with controls. In both tissues, lithium-treated subjects demonstrated lower levels of G alpha(q/11) and higher levels of pertus sis toxin-catalyzed [P-32]ADP-ribosylation, which reached significance in the platelet membranes. Conclusions: Our results are complementary to the previously reported findings of elevated G alpha(s) levels in postmortem brain tissue from patients with bipolar affective disorder and in mononuclear leukocytes obtained from depressed patients with bi polar (but not unipolar) affective disorder. The significantly higher levels of pertussis toxin-catalyzed [P-32]ADP ribosylation in the subj ects receiving long-term lithium-treatment replicates our findings in rat cortex and in healthy volunteers and adds to the growing body of e vidence implicating G alpha(i) as a target of lithium's actions.