REGULATION OF G-PROTEINS AND ADENYLYL-CYCLASE IN BRAIN-REGIONS OF CAFFEINE-TOLERANT AND CAFFEINE-DEPENDENT MICE

Regulation of post-receptor signaling provides a mechanism of adaptati on to chronic psychotropic drug treatment. In this study, the regulati on of guanine nucleotide binding proteins (G proteins) and G protein-s timulated adenylyl cyclase activity was examined in brain regions of c affeine-tolerant and -dependent mice. Chronic caffeine doses were admi nistered via mini-osmotic pumps over 7 days at 0, 42, 85 and 125 mg kg (-1) day(-1). These chronic caffeine doses were linearly correlated wi th plasma caffeine concentrations. In behavioral studies, the stimulan t effects of acute caffeine on motor activity were significantly dimin ished in a dose-dependent manner after chronic caffeine, suggesting th e development of tolerance. Abrupt discontinuation of chronic caffeine treatment (at 85 and 125 mg kg(-1) day(-1)) produced a dose-dependent and reversible reduction in motor activity 24 h later, suggestive of a caffeine withdrawal syndrome. Utilizing quantitative immunoblotting methods, we found that hippocampal G(i alpha 1,2) and G(i alpha 3) sub units were significantly reduced by 20.2% and 11.1%, respectively, in caffeine tolerant/dependent mice (caffeine 125 mg kg(-1) day(-1) vs, v ehicle controls). Decreases in inhibitory G protein subunit concentrat ions in hippocampus were accompanied by a significant increase (by 21% ) in hippocampal G protein function, as measured by guanine nucleotide -stimulated adenylyl cyclase activity, in caffeine-treated mice. This same caffeine treatment also produced significant decreases in cortica l G,, subunits of 14.0%. Since short-term caffeine treatment has been shown to reduce adenylyl cyclase activity, chronic caffeine treatment could produce adaptive increases in G protein-stimulated adenylyl cycl ase to oppose this effect via G protein regulation. (C) 1998 Elsevier Science B.V. All rights reserved.