Effects of competitive N-methyl-d-aspartate antagonists on midbrain dopamine neurons: An electrophysiological and behavioral comparison to phencyclidine

Electrophysiological and behavioral methods were used to evaluate and compare the effects of the competitive N-methyl-d-aspartate (NMDA) receptor Mocker, NPC 12626, with the non-competitive NMDA antagonist, phencyclidine (PCP), on the activity of mesolimbic dopamine neurons. NPC 12626 (50 mg/kg, i.p.) produced a degree of locomotor hyperactivity comparable to that seen with PCP (5 mg/kg). However, 6-hydroxydopamine lesions of the nucleus accumbens blocked the PCP-induced hyperactivity but not the behavioral activation evoked by NPC 12626. Single-unit extracellular recordings from ventral tegmental A₁₀ dopamine neurons also found marked differences between the competitive and non-competitive NMDA antagonists. Intravenous injections of NPC 12626 and CGS 19755 in doses up to 60 mg/kg failed to change A₁₀ activity. This was in contrast to the striking bimodal dose-dependent increase-decrease in firing rate elicited by PCP. The absence of an effect of NPC 12626 on a₁₀ neurons was not evidently related to a lack of access to central sites since NPC pretreatment (40 mg/kg, i.v.) completely antagonized the neurotoxicity caused by intrastriatal injection of quinolinic acid, an NMDA agonist, but not that caused by the non-NMDA compound, kainic acid. Thus, competitive NMDA antagonists do not share PCP's properties of activating mesolimbic dopaminergic systems, and as such they may be devoid of the potent psychotomimetic effects or the abuse liability associated with non-competitive NMDA receptor Mockers such as PCP.