A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine efflux in vitro and dopamine metbolism in vivo

L. D. Snell, Z. L. Mueller, L. Gannon, P. B. Silverman, K. M. Johnson

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)261-269
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume231
Issue number2
StatePublished - 1984
Externally publishedYes

Fingerprint

Phencyclidine
Dopamine
Pharmaceutical Preparations
Haloperidol
Corpus Striatum
piperidine
In Vitro Techniques
Benzomorphans
Ethylketocyclazocine
sigma Receptors
Ketamine
Dioxolanes

ASJC Scopus subject areas

  • Pharmacology

Cite this

A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine efflux in vitro and dopamine metbolism in vivo. / Snell, L. D.; Mueller, Z. L.; Gannon, L.; Silverman, P. B.; Johnson, K. M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 231, No. 2, 1984, p. 261-269.

Research output: Contribution to journalArticle

@article{cba4bf6fafad44d6a20b8de0cf28e855,
title = "A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine efflux in vitro and dopamine metbolism in vivo",
abstract = "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.",
author = "Snell, {L. D.} and Mueller, {Z. L.} and L. Gannon and Silverman, {P. B.} and Johnson, {K. M.}",
year = "1984",
language = "English (US)",
volume = "231",
pages = "261--269",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=0021684925&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0021684925&partnerID=8YFLogxK

M3 - Article

VL - 231

SP - 261

EP - 269

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -