Effects of cocaine on extracellular dopamine and serotonin levels in the nucleus accumbens

Although the rewarding effects of cocaine are generally attributed to its ability to increase dopamine (DA) transmission, cocaine demonstrates approximately equal affinity for dopamine and serotonin (5-HT) transporters in vitro. However, there have been few direct systematic comparisons of the effects of cocaine on DA and 5-HT transmission in vivo. The present experiments compared the effects of systemic cocaine administration, local cocaine infusion and the systemic administration of cocaine during infusion on extracellular levels of DA and 5-HT in the nucleus accumbens (NAc). In vivo microdialysis in awake unrestrained rats was used to measure the effects of systemic administration and local infusion of cocaine on extracellular DA and 5-HT levels simultaneously in the NAc. Systemic cocaine (10-25 mg/kg, IP) dose-dependently increased DA and 5-HT levels, but the increase in DA was larger than for 5-HT at 18 mg/kg. Infusion of cocaine (0.1-10.0 mM) into the NAc increased both DA and 5-HT levels, but the effect on DA was larger than 5-HT at 0.1 and 3 mM cocaine. The influence of cocaine on DA and 5-HT somatodendritic autoreceptors was examined when cocaine (25 mg/kg) was administered systemically during cocaine infusion. The increase in DA and 5-HT levels during cocaine infusion was attenuated by the systemic injection of cocaine during cocaine infusion, but the decrease of 5-HT was greater than that for DA. Cocaine produced a larger impact on DA than 5-HT neurotransmission under specific conditions. A series of physiological mechanisms, i.e. terminal density, neurotransmitter interactions and somatodendritic regulation, are discussed as factors responsible for facilitating cocaine's effects on DA relative to 5-HT.