Ka. Leitemorris et al., REGULATION OF G-PROTEINS AND ADENYLYL-CYCLASE IN BRAIN-REGIONS OF CAFFEINE-TOLERANT AND CAFFEINE-DEPENDENT MICE, Brain research, 804(1), 1998, pp. 52-62
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
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