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 σ-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 σ-ligand, and U50,488H, a κ-opiate, failed to produce any stimulation of firing. Also, pretreatment with haloperidol, a potent σ-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 σ-psychotomimetics is mediated by the PCP receptor, not the haloperidol-sensitive σ-receptor, with potencies directly correlated to their activity as non-competitive N-methyl-d-aspartate (NMDA) antagonists.