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Effects of Long-term Lithium Treatment

Husseini K. Manji, MD, FRCPC; Guang Chen, MD; Hady Shimon; John K. Hsiao, MD; William Z. Potter, MD, PhD; Robert H. Belmaker, MD

Arch Gen Psychiatry. 1995;52(2):135-144.

Abstract
Background
This study examines recent suggestions from a number of investigators that signal-transducing guanine nucleotide-binding (G) proteins may be involved in the pathophysiology of bipolar affective disorder and may represent molecular targets for lithium's mood-stabilizing actions.

Methods
We used selective antibodies to quantitate the levels of the G protein subunits that regulate adenylate cyclase activity (G_s and G_i2) and phosphoinositide turnover (G_q/11). We also quantitated levels of pertussis toxin—catalyzed phosphate 32—labeled adenosine diphosphate ([³²P] ADP) ribosylation in platelet and leukocyte membranes from a group of 14 untreated (predominantly manic) patients with bipolar affective disorder, 20 lithium-treated euthymic patients with bipolar affective disorder, and 11 healthy controls.

Results
In both tissues, the immunolabeling of the 45-kd form of G_s was higher in the bipolar affective disorder group considered as a whole (treated or untreated) compared with controls, effects that reached statistical significance in the leukocyte membranes. There were no significant differences in the immunolabeling of G_i2/2, G_q/11, or pertussis toxin—catalyzed [³²P]ADP ribosylation in either tissue in the untreated bipolar affective disorder group compared with controls. In both tissues, lithium-treated subjects demonstrated lower levels of G_q/11 and higher levels of pertussis toxin—catalyzed [³²P]ADP-ribosylation, which reached significance in the platelet membranes.

Conclusions
Our results are complementary to the previously reported findings of elevated G_s levels in postmortem brain tissue from patients with bipolar affective disorder and in mononuclear leukocytes obtained from depressed patients with bipolar (but not unipolar) affective disorder. The significantly higher levels of pertussis toxin—catalyzed [³²P] ADP ribosylation in the subjects receiving long-term lithium-treatment replicates our findings in rat cortex and in healthy volunteers and adds to the growing body of evidence implicating G_i as a target of lithium's actions.

Author Affiliations
From the Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, Md (Drs Manji, Chen, Hsiao, and Potter), and Ben-Gurion University of the Negev, Beersheva, Israel (Ms Shimon and Dr Belmaker).

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