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

In this thesis in vivo microdialysis was used to investigate the effects of cocaine on extracellular dopamine (DA) and serotonin (5-HT) levels in the rat nucleus accumbens (NAc). First, increases of extracellular concentrations of DA and 5-HT were measured in the NAc following the systemic administration of various doses of cocaine. A systemic injection of 25 mg/kg cocaine increased DA and 5-HT levels by 462 ± 102% and 281 ± 35% respectively. Second, DA and 5-HT levels in the NAc were measured in response to infusion of cocaine through the microdialysis probe into the NAc. Cocaine infusion resulted in concentration-dependent increases in both DA and 5-HT levels that were much greater than the maximum increases following systemic cocaine. Infusion of 30 mM cocaine produced an increase in DA and 5-HT levels of 1765 ± 677 and 1306 ± 438% respectively. Third, the mediating effects of DA and 5-HT autoreceptors were examined by systemically administering cocaine during the cocaine infusion. Under these conditions, systemic cocaine activates somatodendritic autoreceptors thus reducing the cocaine infusion-induced increases in extracellular levels of DA and 5-HT. Fourth, to further clarify the effects of the 5-HT somatodendritic autoreceptor, the 5-HT1A receptor, on extracellular levels of DA and 5-HT in response to cocaine, the 5-HT1A receptor antagonist 4-(2′-methoxy-)-phenyl-1-[2 ′-(N-2″-pyridyl)-p-fluorobenzamido (p-MPPF) was administered prior to the systemic cocaine injection both alone and in combination with cocaine infusion. p-MPPF administered prior to systemic cocaine resulted in a greater increase in both DA (1030 ± 321%) and 5-HT (584 ± 106%) levels in the NAc than cocaine alone. p-MPPF administered prior to systemic cocaine during cocaine (1030 ± 321%) and 5-HT (584 ± 106%) levels in the NAc than cocaine alone. p-MPPF administered prior to systemic cocaine during cocaine infusion blocked the systemic cocaine induced decrease in both DA and 5-HT levels. Finally, 5-HT mediation of the DA response to cocaine was investigated by depleting 5-HT with para-chlorophenylalanine (p-CPA) and measuring extracellular DA in response to systemic and local cocaine. p-CPA treatment had no measurable effect on extracellular DA levels in response to systemic or local cocaine. Taken together these studies indicate that the DA and 5-HT response to cocaine is mediated by somatodendritic autoreceptors and the 5-HT1A receptor antagonist p-MPPF blocks this mediation