In a separate set of experiments, we measured the response to systemic injections of cocaine of DA released from dendrites in the VTA simultaneously with ACh released from terminals projecting from the pontomesencephalic cholinergic nuclei. Figure 4 shows that both ACh and DA increased robustly following 20 mg/kg cocaine. The time course of the ACh response was less phasic and the increase lasted longer than the DA response. Importantly, we have found identical responses (both in quality and time course) of DA and ACh to methamphetamine using microdialysis in the VTA of C57BL6 mice [62]. We also sought to determine if the increase in VTA DA following cocaine was dependent on cholinergic activity. We found that blockade of nicotinic cholinergic receptors (nAChR) within the VTA (using the nAChR antagonist mecamylamine; MEC) prevented the cocaine-induced increase in somatodendritic DA output (Fig. 5). These results collectively demonstrate that psychostimulants potently activate the cholinergic projections to the VTA and may be important finding for understanding the mechanism of ACh/DA interactions in the VTA.
