The influence of tetrodotoxin (TTX) and calcium on the increase of extracellular dopamine (DA) levels in the nucleus accumbens (NAcc), evoked by the systemic administration of nicotine, cocaine and d-amphetamine, have been studied in conscious, freely moving rats using in vivo microdialysis. TTX (10(-6) M), administered via the dialysis probe, completely abolished (P < 0.01) the elevations in extracellular DA, DOPAC and HVA seen following nicotine (0.4 mg/kg SC). The removal of calcium with the inclusion of diaminoethanetetraacetic acid (EDTA 10(-4) M) in the Ringer solution was also associated with inhibition (P < 0.01) of the nicotine-induced changes in these parameters. The systemic administration of cocaine (15 mg/kg IP) and d-amphetamine (0.5 mg/kg SC) caused elevations in extracellular DA (P < 0.01) accompanied by significant decreases (P < 0.01) in HVA levels. DOPAC levels were also significantly (P < 0.01) lowered by d-amphetamine treatment. The presence of TTX and removal of calcium with addition of EDTA completely abolished the changes in NAcc DA and HVA induced by cocaine. TTX had no influence on the d-amphetamine evoked responses in NAcc DA. However, the metabolites, which were markedly reduced by the TTX, were not further decreased by the systemic administration of d-amphetamine. NAcc DA was significantly (P < 0.01) raised following d-amphetamine in the absence of calcium and presence of EDTA. However, this was significantly (P < 0.01) attenuated in comparison to that seen in the presence of calcium. The results support the conclusion that, at the dose tested, nicotine evokes increases in extracellular NAcc DA levels by calcium and impulse-dependent mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)