Guanine nucleotide binding (
G) proteins play a pivotal role in postreceptor information transduction. An important characteristic of
G proteins is their increased
guanine nucleotide binding following agonist stimulation, which in turn leads to their activation. We have developed a method that enables the measurement of early events in signal transduction beyond receptors, through activated receptor-coupled
guanine nucleotide exchange on
G proteins. Using this method,
lithium was recently demonstrated to inhibit the coupling of both
muscarinic cholinergic and
beta-adrenergic receptors to
pertussis toxin-sensitive and
cholera toxin-sensitive
G proteins, respectively, thus suggesting alteration of the function of
G protein by
lithium, as the single site for both the antimanic and
antidepressant effects of this
drug. One of the most puzzling aspects of the ability of
lithium to ameliorate the manic-depressive condition is its relatively selective action upon the central nervous system (CNS). It was previously shown that
lithium selectively attenuated the function of Gs
proteins in the CNS. In the present study, we show that inhibition by
lithium of
muscarinic receptor-coupled
G protein function is also selective to the CNS. The clinical profile of
lithium,
carbamazepine, and electroconvulsive treatment (ECT), agents that are effective in the prevention and treatment of bipolar
affective disorder, differs from that of purely
antidepressant drugs.
Antidepressant drugs are effective in the acute treatment and prevention of depression only, and can even precipitate hypomanic or manic "switches," or "rapid cycling" between
mania and depression. We have investigated and compared the effects of chronic antibipolar and
antidepressant treatments on receptor-coupled
G protein function. Antibipolar treatments (
lithium,
carbamazepine, ECT) attenuate both receptor-coupled Gs and non-Gs (i.e., Gi, Go)
proteins function; in contrast, only Gs
protein function is inhibited by
antidepressant drugs [either tricyclics or
monoamine oxidase (
MAO) inhibitors]. Moreover, an integral
adrenergic neuronal system is required for
antidepressant inhibition of Gs
protein function, as pretreatment with the noradrenergic
neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) specifically abolishes the effects of
antidepressant drugs on Gs
protein, whereas antibipolar
drug effects on
G protein function are unaffected by
DSP-4. Our results suggest that attenuation of
beta-adrenergic receptor-coupled Gs
protein function, which is common to both
antidepressant and antibipolar treatments, may be the mechanism underlying their
antidepressant therapeutic efficacy.(ABSTRACT TRUNCATED AT 400 WORDS)