A COMPARISON BETWEEN CLASSES OF DRUGS HAVING PHENCYCLIDINE-LIKE BEHAVIORAL PROPERTIES ON DOPAMINE EFFLUX INVITRO AND DOPAMINE METABOLISM INVIVO

  • 1 January 1984
    • journal article
    • research article
    • Vol. 231  (2) , 261-269
Abstract
Phencyclidine (PCP) is known to increase the basal efflux of striatal dopamine (DA) in vitro and to enhance haloperidol (HAL)-induced striatal DA metabolism in vivo. This study compared these activities of PCP to several representatives of the arylcycloalkylamine, benzomorphan and substituted dioxolane classes whose behavioral similarities to PCP have been well studied. The affinity of these drugs for the PCP/sigma opiate receptor also was estimated by determining the concentration of these drugs required to inhibit the specific binding of 10 nM [3H]PCP to rat cortical membranes by 50%. Of the arylcycloalkylamines tested on the basal efflux of [3H]DA, it was found that the rank-order effectiveness was as follows: PCP > 1-[1-(naphthyl)cyclohexyl]piperidine HCl (m-amino-PCP) > ketamine .gtoreq. 1-[l-(m-nitrophenyl)cyclohexyl]piperidine HCl (m-nitro-PCP) > N-ethyl-l-phencyclohexylamine (PCE). In vivo it was found that PCP, m-amino-PCP and PCE significantly elevated HAL-induced DA metabolism, whereas ketamine and m-nitro-PCP were without effect. Although each of the benzomorphans tested [N-allylnormetazocine (NANM) and ethylketocyclazocine (EKC)] slightly enhanced the basal efflux of [3H]DA from striatal slices, concentrations of 10 to 30 .mu.M were required to elicit the same magnitude of [3H]DA release caused by 3 .mu.M PCP. Quantitatively similar responses were produced by the substituted dioxolanes tested (etoxadrol, dexoxadrol and levoxadrol). Neither (+)-NANM, (.sbd.)-NANM, (.+-.)-NANM, etoxadrol nor dexoxadrol had any effect on HAL-induced DA metabolism. Both levoxadrol and EKC significantly decreased the ratio of HVA/DA after HAL administration. When assessed for their ability to inhibit [3H]PCP binding, the relative potencies of the agents tested was as follows: m-amino-PCP (2.0), PCE (1.2), PCP (1.0), etoxadrol (0.75), dexoxadrol (0.69), (+)-NANM (0.36), (.sbd.)-NANM (0.16), m-nitro-PCP (0.09), levoxadrol (0.08) and EKC (0.05). These potencies in general are poorly correlated with these agents'' dopaminergic properties, but generally agree with their potencies in behavioral assays of PCP-like properties (particularly in PCP discrimination paradigms). Based on these results it was concluded that the dopaminergic properties of PCP are not it was exerted through an interaction with PCP/sigma receptors. No difference was found in the specific binding of [3H]PCP between the left and right striatum after 6-hydroxydopamine lesions of the left substantia nigra. These data also suggest that the dopaminergic properties of PCP do not underlie its discriminative stimulus properties.