Considerable evidence suggests that Phencyclidine and possibly other non-competitive NMDA antagonists may exert some of their pharmacological actions through dopamine. This series of studies was designed to evaluate the participation of dopamine in the actions of these compounds. Rats lesioned unilaterally in the dopamine nigra-striatal pathways rotated ipsilaterally to the lesion when injected with PCP, TCP, AND SKF 10,047, MK-801 and dexoxedral. Only PCP and TCP, however, produced a significant elevation of extracellular dopamine in the striatum as assessed with microdialysis procedures. Unanesthetized rats injected systemically with either PCP, MK-801, or amphetamine exhibited profound rotational behavior ipsilateral to a lesion of the nigra-striatal dopamine pathway. Only PCP and amphetamine, however, were able to elevate dopamine in the contralateral striatum as assessed with microdialysis. PCP also produced a dose-dependent increase in extracellular dopamine in the striatum as well as nucleus accumbens and frontal cortex following systemic injections. These effects were Ca++-dependent, suggesting the involvement of an exocytotic process. MK-801, on the other hand, was entirely ineffective in altering dopamine in the n. accumbens. Blockade of NMDA function alone is not sufficient to account for increases in dopamine produced by PCP. In addition, it does not appear that the locomotor stimulatory effects of MK-801 are determined through activation of dopamine mechanisms.
