Chronic Lithium Treatment Impairs Phosphatidylinositol Hydrolysis in Membranes from Rat Brain Regions

Membranes prepared from rat brain regions were used to measure the receptor-coupled and/or guanine nucleotide-binding protein (G protein)-mediated hydrolysis of exogenous [³H]phosphatidylinositol ([³H]PI). Guanosine 5′-O-(3-thiotriphosphate) (GTPγS) and NaF (in the presence of AlCl₃) caused concentration-dependent stimulations of [³H]PI hydrolysis, supporting the conclusion that G proteins mediating [³H]PI hydrolysis can be activated in this preparation. Neither of these responses was altered by in vitro incubation with 8 mM LiCl, but both were reduced in hippocampal, striatal, and cortical membranes from rats that had been treated with lithium for 4 weeks compared with controls. Two cholinergic agonists, carbachol and pilocarpine, induced no hydrolysis of [³H]PI unless GTPγS was also present, in which case each equally stimulated [³H]PI hydrolysis above that obtained with GTPγS alone. In the presence of GTPγS several excitatory amino acid agonists stimulated [³H]PI hydrolysis to an extent similar to that of carbachol. After chronic lithium treatment, [³H]PI hydrolysis stimulated by carbachol was significantly attenuated, but the response to quisqualate was unaffected. Therefore, lithium added in vitro does not have an effect on cholinergic receptor- or G protein-mediated [³H]PI hydrolysis, but each of these is reduced by chronic lithium treatment. Because exogenous [³H]PI was provided as the substrate, it is evident that the inhibitory effect of chronic lithium treatment cannot be due to substrate depletion. Impaired function of G proteins appears to be the most likely mechanism accounting for attenuated [³H]PI hydrolysis after chronic administration of lithium.