Autoregulation and monoamine interactions in the ventral tegmental area in the absence and presence of cocaine: a microdialysis study in freely moving rats.

Extracellular levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were measured simultaneously by microdialysis in the ventral tegmental area (VTA) of conscious rats, and locomotor activity was monitored. Extracellular NE, DA and 5-HT was increased by both local infusion (30 microM) and i.p. injection (20 and 40 mg/kg) of cocaine with 5-HT responding most rapidly. DA was the only amine that showed a significantly higher increase to the systemic cocaine dose of 40 mg/kg than 20 mg/kg, and a higher response to local cocaine (30 microM) than systemic cocaine (20 mg/kg). In the following experiments, the monoamine autoreceptor antagonists idazoxan (alpha-2, 100 microM), sulpiride (D2 DA/D3 DA, 10 microM) and methiothepin (5-HT1/5-HT2, 20 microM) were focally applied into the VTA before cocaine application. Idazoxan or methiothepin increased only local cocaine-induced NE or 5-HT output, whereas sulpiride increased both local and systemic cocaine-induced DA output, consonant with the importance of somatodendritic monoamine autoreceptors in addition to accumbens-VTA feedback pathways. Both idazoxan and methiothepin increased the basal output of all three amines without modifying cocaine (30 microM or 20 mg/kg)-induced output of DA/5-HT or NE/DA, whereas sulpiride promoted cocaine-induced NE output without modifying basal NE/5-HT output and cocaine-induced 5-HT output, implying complex interactions between monoamines. Idazoxan or methiothepin depressed, whereas sulpiride stimulated cocaine (20 mg/kg)-induced motor activity. The analysis of behavioral/neurochemical relationships revealed a negative correlation between dialysate NE output and motor activity in the cocaine alone and idazoxan/cocaine groups, and a positive correlation between dialysate DA output and motor activity in the sulpiride/cocaine and methiothepin/cocaine groups.