Tags

Type your tag names separated by a space and hit enter

3'- and 4'-chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys.
Psychopharmacology (Berl). 2000 Jan; 147(4):426-35.P

Abstract

RATIONALE

The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission. Drugs that block dopamine (DA) uptake have generally been found to function as positive reinforcers. Benztropine (BZT) and several of its halogenated analogs have previously been characterized as potent DA-uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine.

OBJECTIVES

The present experiments were designed to examine, in rhesus monkeys, the reinforcing effects of the DA-uptake inhibitor BZT and two chloro-analogs 3'-Cl-BZT and 4'-Cl-BZT, and to compare self-administration and binding profiles.

METHODS

Four rhesus monkeys self-administered cocaine i.v. under a fixed-ratio 10 (FR10) schedule until stable responding was established. Saline, and various doses of cocaine, BZT, and the BZT analogs were then made available for self-administration. Binding of these compounds to monoaminergic and cholinergic sites in monkey brain were determined using standard radioligand binding techniques.

RESULTS

Self-administration was maintained by both 3'-Cl-BZT and 4'-Cl-BZT, but not by BZT. Results suggested that 3'-Cl-BZT and 4'-Cl-BZT were weak positive reinforcers. BZT and analogs bound DA transporters (DAT) with affinities higher than that of cocaine and had affinity for muscarinic binding sites.

CONCLUSIONS

Surprisingly, high affinity at DATs was associated with weak or no reinforcing effects. The mechanism(s) that may underlie this dissociation between DAT actions and reinforcing effects remains to be established. These data support the proposal that a lead for the discovery of a pharmacotherapeutic agent for cocaine abuse may come from this group of compounds.

Authors+Show Affiliations

Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson 39216-4505, USA. WWoolverton@psychiatry.umsmed.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10672637

Citation

Woolverton, W L., et al. "3'- and 4'-chloro-substituted Analogs of Benztropine: Intravenous Self-administration and in Vitro Radioligand Binding Studies in Rhesus Monkeys." Psychopharmacology, vol. 147, no. 4, 2000, pp. 426-35.
Woolverton WL, Rowlett JK, Wilcox KM, et al. 3'- and 4'-chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys. Psychopharmacology (Berl). 2000;147(4):426-35.
Woolverton, W. L., Rowlett, J. K., Wilcox, K. M., Paul, I. A., Kline, R. H., Newman, A. H., & Katz, J. L. (2000). 3'- and 4'-chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys. Psychopharmacology, 147(4), 426-35.
Woolverton WL, et al. 3'- and 4'-chloro-substituted Analogs of Benztropine: Intravenous Self-administration and in Vitro Radioligand Binding Studies in Rhesus Monkeys. Psychopharmacology (Berl). 2000;147(4):426-35. PubMed PMID: 10672637.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3'- and 4'-chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys. AU - Woolverton,W L, AU - Rowlett,J K, AU - Wilcox,K M, AU - Paul,I A, AU - Kline,R H, AU - Newman,A H, AU - Katz,J L, PY - 2000/2/15/pubmed PY - 2000/4/1/medline PY - 2000/2/15/entrez SP - 426 EP - 35 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 147 IS - 4 N2 - RATIONALE: The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission. Drugs that block dopamine (DA) uptake have generally been found to function as positive reinforcers. Benztropine (BZT) and several of its halogenated analogs have previously been characterized as potent DA-uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine. OBJECTIVES: The present experiments were designed to examine, in rhesus monkeys, the reinforcing effects of the DA-uptake inhibitor BZT and two chloro-analogs 3'-Cl-BZT and 4'-Cl-BZT, and to compare self-administration and binding profiles. METHODS: Four rhesus monkeys self-administered cocaine i.v. under a fixed-ratio 10 (FR10) schedule until stable responding was established. Saline, and various doses of cocaine, BZT, and the BZT analogs were then made available for self-administration. Binding of these compounds to monoaminergic and cholinergic sites in monkey brain were determined using standard radioligand binding techniques. RESULTS: Self-administration was maintained by both 3'-Cl-BZT and 4'-Cl-BZT, but not by BZT. Results suggested that 3'-Cl-BZT and 4'-Cl-BZT were weak positive reinforcers. BZT and analogs bound DA transporters (DAT) with affinities higher than that of cocaine and had affinity for muscarinic binding sites. CONCLUSIONS: Surprisingly, high affinity at DATs was associated with weak or no reinforcing effects. The mechanism(s) that may underlie this dissociation between DAT actions and reinforcing effects remains to be established. These data support the proposal that a lead for the discovery of a pharmacotherapeutic agent for cocaine abuse may come from this group of compounds. SN - 0033-3158 UR - https://www.unboundmedicine.com/medline/citation/10672637/3'__and_4'_chloro_substituted_analogs_of_benztropine:_intravenous_self_administration_and_in_vitro_radioligand_binding_studies_in_rhesus_monkeys_ L2 - https://dx.doi.org/10.1007/s002130050012 DB - PRIME DP - Unbound Medicine ER -