TY - JOUR
T1 - A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine efflux in vitro and dopamine metbolism in vivo
AU - Snell, L. D.
AU - Mueller, Z. L.
AU - Gannon, L.
AU - Silverman, P. B.
AU - Johnson, K. M.
PY - 1984
Y1 - 1984
N2 - Phencyclidine [(l-phenylcyclohexyl) piperidine] (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 arylcyloalkylamine, 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, we found the rank-order effectiveness to be as follows: PCP > 1-[l-(naphthyl)cyclohexyl]piperidine HCl (m-amino-PCP) > ketamine ≥ 1-[l-(m-nitrophenyl)cyclohexyl]piperidine HCl (m-nitro-PCP) > N-ethyl-l-phencyclohexylamine (PCE). However, in vivo we 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 μM were required to elicit the same magnitude of [3H]DA release caused by 3 μM PCP. Quantitatively similar responses were produced by the substituted dioxolanes tested (etoxadrol, dexoxadrol and levoxadrol). Neither (+)-NANM, (-)-NANM, (±)-NANM, etoxadrol nor dexoxadrol had any effect on HAL-induced DA metabolism. On the other hand, both levoxadrol and ECK 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 found to be as follows: m-amino-PCP (2.0), PCE (1.2), PCP (1.0), etoxadrol (0.75), dexoxadrol (0.69), (+)-NANM (0.36), (-)-NANM (0.16), m-nitro-PCP (0.09), levoxadrol (0.008) 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 we concluded that the dopaminergic properties of PCP are not exerted through an interaction with PCP/sigma receptors. In support of this conclusion, we found no difference 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.
AB - Phencyclidine [(l-phenylcyclohexyl) piperidine] (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 arylcyloalkylamine, 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, we found the rank-order effectiveness to be as follows: PCP > 1-[l-(naphthyl)cyclohexyl]piperidine HCl (m-amino-PCP) > ketamine ≥ 1-[l-(m-nitrophenyl)cyclohexyl]piperidine HCl (m-nitro-PCP) > N-ethyl-l-phencyclohexylamine (PCE). However, in vivo we 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 μM were required to elicit the same magnitude of [3H]DA release caused by 3 μM PCP. Quantitatively similar responses were produced by the substituted dioxolanes tested (etoxadrol, dexoxadrol and levoxadrol). Neither (+)-NANM, (-)-NANM, (±)-NANM, etoxadrol nor dexoxadrol had any effect on HAL-induced DA metabolism. On the other hand, both levoxadrol and ECK 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 found to be as follows: m-amino-PCP (2.0), PCE (1.2), PCP (1.0), etoxadrol (0.75), dexoxadrol (0.69), (+)-NANM (0.36), (-)-NANM (0.16), m-nitro-PCP (0.09), levoxadrol (0.008) 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 we concluded that the dopaminergic properties of PCP are not exerted through an interaction with PCP/sigma receptors. In support of this conclusion, we found no difference 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.
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M3 - Article
C2 - 6092611
AN - SCOPUS:0021684925
SN - 0022-3565
VL - 231
SP - 261
EP - 269
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -