guanylyl-imidodiphosphate and Substance-Withdrawal-Syndrome

Rats receiving amphetamine (5 mg/kg, i.p. once daily) for 14 continuous days develop behavioral sensitization to a subsequent amphetamine challenge (1 mg/kg) at withdrawal days 8 to 10. The present study was aimed at investigating whether there are changes in binding or functions of striatal D2 dopamine receptors in amphetamine-sensitized rats. The results indicated that the Bmax value of D2 receptors in the ventral striatum decreased 40% and 52% 7 and 10 days after amphetamine withdrawal, respectively, without changes in their binding affinities (Kd). During this withdrawal period, the D(2/3) receptor agonist-induced (a) locomotor activation (bromocriptine, 5 mg/kg, i.p. or quinpirole, 1 mg/kg, i.p.) and (b) inhibition of forskolin-enhanced adenylyl cyclase activity (bromocriptine, 50 or 150 microM) in the ventral striatum were both suppressed as compared with saline controls. The decreases in D2 receptor function were unrelated to the coupled G-proteins, since none of the G alpha i-3, G alpha o or G alpha q in the ventral striatum exhibited quantitative differences between control and amphetamine sensitized rats. Collectively, these results demonstrate that intermittent amphetamine administration for a period of 14 days leads to diminished D2 receptor expression and functions in the ventral striatum at late withdrawal periods. The decrease of D2 receptors might reflect cellular mechanisms underlying the expression of amphetamine sensitization.

Topics: Adenylyl Cyclases; Amphetamine; Analysis of Variance; Animals; Bromocriptine; Colforsin; Corpus Striatum; Cyclic AMP; Drug Administration Schedule; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Injections, Intraperitoneal; Male; Motor Activity; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Stereotyped Behavior; Substance Withdrawal Syndrome; Time Factors

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.

Topics: Adenylyl Cyclases; Animals; Behavior, Animal; Brain; Caffeine; Dose-Response Relationship, Drug; Drug Tolerance; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Male; Mice; Mice, Inbred Strains; Motor Activity; Osmolar Concentration; Substance Withdrawal Syndrome; Substance-Related Disorders; Tissue Distribution

Topics: Animals; Dihydroalprenolol; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Humans; Isoproterenol; Kinetics; Male; Morphine Dependence; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Subcellular Fractions; Substance Withdrawal Syndrome