Non-competitive N-methyl-D-aspartate antagonists are potent activators of ventral tegmental A10 dopamine neurons

The response of ventral tegmental (VTA) A10 dopamine neurons to a series of compounds covering the spectrum from high-affinity phencyclidine receptor ligands (MK-801, PCP) to high-affinity sigma-receptor ligands [+)-pentazocine, DTG) was measured using single-unit extracellular recording techniques in the rat. Dose-response comparisons revealed that MK-801 was 3, 6, 19 and 119 times more potent at activating A10 neurons than PCP, (+)-SKF-10,047, ketamine and (+)-pentazocine, respectively. DTG (1,3-di-o-tolylguanidine), the most selective sigma-ligand, and U50,488H, a kappa-opiate, failed to produce any stimulation of firing. Also, pretreatment with haloperidol, a potent sigma-receptor ligand, did not prevent MK-801-induced excitations. Thus, the activation of the A10-mesolimbic-mesocortical dopamine pathways by PCP, PCP-like drugs and sigma-psychotomimetics is mediated by the PCP receptor, not the haloperidol-sensitive sigma-receptor, with potencies directly correlated to their activity as non-competitive N-methyl-D-aspartate (NMDA) antagonists.