Competitive NMDA receptor antagonists attenuate phencyclidine-induced excitations of A10 dopamine neurons

The binding of phencyclidine (PCP) within the channel gated by the NMDA-receptor complex can be positively or negatively modulated by compounds which facilitate or prevent the interaction of glutamate to the NMDA recognition site. In the present study extracellular recordings were used to evaluate the possibility that the negative modulation of NMDA channel function by the competitive NMDA antagonists (+/-)-CPP (3-((+/-)2-carboxypiperazin-4- yl)propyl-1-phosphonate) and CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylate) could affect the response of A10 dopamine neurons to PCP. Pretreatment with 40 mg/kg of (+/-)-CPP or CGS 19755 completely blocked the low-dose excitatory effects of PCP, whereas 10 mg/kg of CGS 19755 produced only a partial blockade. However, neither CGS 19755 or (+/-)-CPP affected the amount of attenuation of A10 firing occurring with large doses of PCP. (+/-)-CPP and CGS 19755 pretreatment also failed to alter the morphine-induced stimulation of dopamine activity. These findings not only provide further evidence that the low-dose PCP-induced activation of A10 neurons is mediated through the NMDA-ion channel complex, but suggest that some physiological or behavioral effects evoked by PCP might be prevented by treatment with competitive NMDA receptor blockers.