Kr. Powell et al., The role of dopamine in the locomotor stimulant effects and tolerance to these effects of caffeine, PHARM BIO B, 69(1-2), 2001, pp. 59-70
Current evidence indicates that the acute locomotor stimulant effects of ca
ffeine involve dopamine (DA) receptor activation; however, few studies have
investigated the role of DA receptors in mediating the development of tole
rance to caffeine. Therefore, the present study was designed to determine t
he degree to which DA receptors mediate the development of tolerance to the
locomotor stimulant effects of caffeine.. Caffeine was examined alone and
in combination with haloperidol (HAL), GBR 12909, nisoxetine and fluoxetine
. HAL dose-dependently and completely blocked the acute effects of caffeine
on locomotor activity, and the highest dose of GBR 12909 enhanced the effe
cts of caffeine. Neither nisoxetine nor fluoxetine altered the effects of c
affeine. HAL was infused via osmotic pumps (0.1 mg/kg/day) during a 14-day
regimen of chronic caffeine administered in a caffeinated drinking solution
(approximate to 136 mg/kg/day). HAL did not block the development of toler
ance to the locomotor stimulant effects of caffeine, but did impair the rec
overy from tolerance following withdrawal of caffeine. [H-3]SCH 23390 (DA D
-1) binding sites were downregulated in the nucleus accumbens and striatum
and were upregulated in the prefrontal cortex of caffeine-treated vs. contr
ol rats; however, the affinity of [H-3]SCH 23390 for these binding sites wa
s unaltered. There were no differences between the caffeine-treated and con
trol rats in number or affinity of [H-3]spiperone (DA D-2) binding sites. T
hese results suggest that, although HAL did not alter the development of to
lerance to caffeine, changes in DA D-1 receptors could be one component of
the mechanism underlying caffeine-induced tolerance. (C) 2001 Elsevier Scie
nce Inc. All rights reserved.