title: Regulation of G proteins and adenylyl cyclase in brain regions of caffeine-tolerant and -dependent mice.
abstract: Regulation of post-receptor signaling provides a mechanism of adaptation to chronic psychotropic drug treatment. In this study, the regulation of guanine nucleotide binding proteins (G proteins) and G protein-stimulated adenylyl cyclase activity was examined in brain regions of caffeine-tolerant and -dependent mice. Chronic caffeine doses were administered 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 with plasma caffeine concentrations. In behavioral studies, the stimulant effects of acute caffeine on motor activity were significantly diminished in a dose-dependent manner after chronic caffeine, suggesting the 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 Gialpha1,2 and Gialpha3 subunits were significantly reduced by 20.2% and 11.1%, respectively, in caffeine tolerant/dependent mice (caffeine 125 mg kg-1 day-1 vs. vehicle controls). Decreases in inhibitory G protein subunit concentrations 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 cortical Gsalpha 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 cyclase to oppose this effect via G protein regulation.
authors.affiliation: Department of Psychiatry and Human Behavior, Veterans Affairs Medical Center, 830 Chalkstone Avenue, Providence, RI 02912, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Leite-Morris
authors.forename: G B
authors.initials: GB
authors.lastname: Kaplan
authors.forename: J G
authors.initials: JG
authors.lastname: Smith
authors.forename: M T
authors.initials: MT
authors.lastname: Sears
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006165:Guanylyl Imidodiphosphate / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009994:Osmolar Concentration; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D006165:Guanylyl Imidodiphosphate; D002110:Caffeine; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases