The role of dopamine in the locomotor stimulant effects and tolerance to these effects of caffeine.

Current evidence indicates that the acute locomotor stimulant effects of caffeine involve dopamine (DA) receptor activation; however, few studies have investigated the role of DA receptors in mediating the development of tolerance to caffeine. Therefore, the present study was designed to determine the 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 effects of caffeine. Neither nisoxetine nor fluoxetine altered the effects of caffeine. 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 ( approximately 136 mg/kg/day). HAL did not block the development of tolerance to the locomotor stimulant effects of caffeine, but did impair the recovery from tolerance following withdrawal of caffeine. [3H]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. control rats; however, the affinity of [3H]SCH 23390 for these binding sites was unaltered. There were no differences between the caffeine-treated and control rats in number or affinity of [3H]spiperone (DA D(2)) binding sites. These results suggest that, although HAL did not alter the development of tolerance to caffeine, changes in DA D(1) receptors could be one component of the mechanism underlying caffeine-induced tolerance.