The role of striatal dopaminergic mechanisms in rotational behavior induced by phencyclidine and phencyclidine-like drugs.

Five drugs similar to phencyclidine (PCP) were tested in rats with brain lesions to see if they cause circling behavior and alter dopamine levels in the striatum. All five drugs caused the rats to turn in circles toward the side of the lesion, which typically indicates increased dopamine on the intact side. But measurements of dopamine in the striatum did not match this expectation. Only PCP itself increased dopamine levels. MK-801 caused strong circling but no dopamine increase. Dexoxadrol also caused circling without raising dopamine. TCP and SKF 10,047 raised dopamine only slightly (16% and 12%) at their peak. The authors conclude these drugs likely act through NMDA receptor blockade rather than by altering dopamine.

Study at a glance

Abstract

Phencyclidine (PCP) and phencyclidine-like drugs (TCP, dexoxadrol, MK-801, and SKF 10,047) were evaluated for their ability to induce rotational behavior in rats with unilateral 6-OHDA lesions of the medial forebrain bundle and for their ability to alter striatal dopamine (DA) overflow with microdialysis procedures. All of the compounds tested produced rotational behavior ipsilateral to the lesion, suggesting that they were enhancing extracellular dopamine in the intact striatum. The microdialysis studies, however, did not support this contention. There appeared to be a complete dissociation between the ability of the five compounds to produce ipsilateral rotations and their ability to enhance extracellular dopamine levels in the striatum. PCP was the only compound able to elicit significant increases in striatal dopamine overflow following i.p. injections and also produce dramatic rotational behavior. MK-801 was the most potent compound in enhancing rotational output while it had no effect at all on striatal dopamine overflow. Dexoxadrol also produced significant rotational output without having any effect on extracellular levels of dopamine following i.p. injections. TCP and SKF 10,047, at doses which produced significant rotational behavior, only elevated dopamine 16% and 12%, respectively, at peak effect. It is most parsimonious to conclude that the effects of PCP-like drugs on nigro-striatal function are mediated through their ability to act as indirect NMDA receptor antagonists and not through their ability to alter striatal dopamine activity.