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Assessment of the influence of histaminergic actions on cocaine-like effects of 3alpha-diphenylmethoxytropane analogs.
J Pharmacol Exp Ther. 2005 Nov; 315(2):631-40.JP

Abstract

Previous studies demonstrated that analogs of benztropine (BZT) possess high affinity for the dopamine (DA) transporter (DAT) but generally have behavioral effects different from those of cocaine, suggesting either unique actions at the DA transporter or that another action of these drugs interferes with cocaine-like effects. Because the parent compound has histamine-antagonistic effects, the affinity of its analogs for histamine H(1), H(2), and H(3) receptors were compared with DA transporter affinity to assess whether those differences predicted the amount of cocaine-like activity. All of the compounds displaced [(3)H]mepyramine from H(1), [(125)I]iodoaminopotentidine from H(2), and [(3)H]N-alpha-methylhistamine from H(3) histamine receptors with affinities ranging from 15.7 to 37,600, 218 to >4430, and 4040 to >150,000 nM, respectively. Affinities at histamine H(1) receptors were, respectively, approximately 25- or 300-fold greater than those at H(2) or H(3) histamine receptors. Relative affinities for H(1) and DAT binding did not reliably predict the degree of cocaine-like stimulation of locomotor activity. In addition, interactions of various histaminic agents with cocaine assessed whether an action at any of the histamine sites could interfere with cocaine-like effects. None of the histaminic agents fully substituted for cocaine in rats trained to discriminate 10 mg/kg cocaine from saline nor did any of the compounds antagonize or otherwise diminish the discriminative stimulus effects of cocaine. The results suggest that affinity for histamine receptors cannot account for the diminished cocaine-like effects of the BZT analogs and suggest alternatively that these compounds have actions different from those of cocaine but likely mediated by their interaction with the DAT.

Authors+Show Affiliations

Psychobiology, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16055673

Citation

Campbell, Vera C., et al. "Assessment of the Influence of Histaminergic Actions On Cocaine-like Effects of 3alpha-diphenylmethoxytropane Analogs." The Journal of Pharmacology and Experimental Therapeutics, vol. 315, no. 2, 2005, pp. 631-40.
Campbell VC, Kopajtic TA, Newman AH, et al. Assessment of the influence of histaminergic actions on cocaine-like effects of 3alpha-diphenylmethoxytropane analogs. J Pharmacol Exp Ther. 2005;315(2):631-40.
Campbell, V. C., Kopajtic, T. A., Newman, A. H., & Katz, J. L. (2005). Assessment of the influence of histaminergic actions on cocaine-like effects of 3alpha-diphenylmethoxytropane analogs. The Journal of Pharmacology and Experimental Therapeutics, 315(2), 631-40.
Campbell VC, et al. Assessment of the Influence of Histaminergic Actions On Cocaine-like Effects of 3alpha-diphenylmethoxytropane Analogs. J Pharmacol Exp Ther. 2005;315(2):631-40. PubMed PMID: 16055673.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Assessment of the influence of histaminergic actions on cocaine-like effects of 3alpha-diphenylmethoxytropane analogs. AU - Campbell,Vera C, AU - Kopajtic,Theresa A, AU - Newman,Amy Hauck, AU - Katz,Jonathan L, Y1 - 2005/07/29/ PY - 2005/8/2/pubmed PY - 2006/1/13/medline PY - 2005/8/2/entrez SP - 631 EP - 40 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 315 IS - 2 N2 - Previous studies demonstrated that analogs of benztropine (BZT) possess high affinity for the dopamine (DA) transporter (DAT) but generally have behavioral effects different from those of cocaine, suggesting either unique actions at the DA transporter or that another action of these drugs interferes with cocaine-like effects. Because the parent compound has histamine-antagonistic effects, the affinity of its analogs for histamine H(1), H(2), and H(3) receptors were compared with DA transporter affinity to assess whether those differences predicted the amount of cocaine-like activity. All of the compounds displaced [(3)H]mepyramine from H(1), [(125)I]iodoaminopotentidine from H(2), and [(3)H]N-alpha-methylhistamine from H(3) histamine receptors with affinities ranging from 15.7 to 37,600, 218 to >4430, and 4040 to >150,000 nM, respectively. Affinities at histamine H(1) receptors were, respectively, approximately 25- or 300-fold greater than those at H(2) or H(3) histamine receptors. Relative affinities for H(1) and DAT binding did not reliably predict the degree of cocaine-like stimulation of locomotor activity. In addition, interactions of various histaminic agents with cocaine assessed whether an action at any of the histamine sites could interfere with cocaine-like effects. None of the histaminic agents fully substituted for cocaine in rats trained to discriminate 10 mg/kg cocaine from saline nor did any of the compounds antagonize or otherwise diminish the discriminative stimulus effects of cocaine. The results suggest that affinity for histamine receptors cannot account for the diminished cocaine-like effects of the BZT analogs and suggest alternatively that these compounds have actions different from those of cocaine but likely mediated by their interaction with the DAT. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16055673/Assessment_of_the_influence_of_histaminergic_actions_on_cocaine_like_effects_of_3alpha_diphenylmethoxytropane_analogs_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16055673 DB - PRIME DP - Unbound Medicine ER -