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Behavioral and neurochemical effects of the dopamine transporter ligand 4-chlorobenztropine alone and in combination with cocaine in vivo.
J Pharmacol Exp Ther. 1999 Apr; 289(1):110-22.JP

Abstract

The current studies evaluated the novel diphenylmethoxytropane analog 4-chlorobenztropine (4-Cl-BZT), cocaine, and combinations of the two drugs for their abilities to stimulate locomotor activity, produce cocaine-like discriminative stimulus effects, and elevate extracellular dopamine (DA) in the nucleus accumbens (NAc) as measured by in vivo microdialysis. Peripherally administered cocaine was approximately twice as efficacious as 4-Cl-BZT as a locomotor stimulant and was behaviorally active at a lower dose than was 4-Cl-BZT. Cocaine also was more efficacious than 4-Cl-BZT in producing discriminative-stimulus effects in rats trained to discriminate i.p. injections of 10 mg/kg cocaine from saline. The time course of behavioral activation differed markedly between the two drugs, with much shorter onset and duration of locomotor stimulant effects for cocaine relative to 4-Cl-BZT. Similarly, i.p. cocaine (10 and 40 mg/kg) induced a pronounced, rapid, and short-lived increase in DA in the NAc, whereas i.p. 4-Cl-BZT was effective only at the higher dose and produced a more gradual, modest, and sustained (>/=2 h) elevation in accumbens DA. In contrast to i.p. administration, local infusion of 4-Cl-BZT (1-100 microM) into the NAc through the microdialysis probe elevated extracellular DA to a much greater extent than did local cocaine (nearly 2000% of baseline maximally for 4-Cl-BZT versus 400% of baseline for cocaine) and displayed a much longer duration of action than cocaine. However, when microinjected bilaterally into the NAc at 30 or 300 nmol/side, cocaine remained a more efficacious locomotor stimulant than 4-Cl-BZT. Finally, pretreatment with i.p. 4-Cl-BZT dose dependently enhanced the locomotor stimulant, discriminative stimulus effects, and NAc DA response to a subsequent low-dose i.p. cocaine challenge. The diphenylmethoxytropane analog also facilitated the emergence of stereotyped behavior and convulsions induced by high-dose cocaine. The current results demonstrate that DA transporter ligands that do not share the neurochemical and behavioral profiles of cocaine nevertheless may enhance the effects of cocaine in vivo.

Authors+Show Affiliations

Department of Psychiatry, University of California at San Francisco San Francisco, USA. tollivr@itsa.ucsf.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, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10086994

Citation

Tolliver, B K., et al. "Behavioral and Neurochemical Effects of the Dopamine Transporter Ligand 4-chlorobenztropine Alone and in Combination With Cocaine in Vivo." The Journal of Pharmacology and Experimental Therapeutics, vol. 289, no. 1, 1999, pp. 110-22.
Tolliver BK, Newman AH, Katz JL, et al. Behavioral and neurochemical effects of the dopamine transporter ligand 4-chlorobenztropine alone and in combination with cocaine in vivo. J Pharmacol Exp Ther. 1999;289(1):110-22.
Tolliver, B. K., Newman, A. H., Katz, J. L., Ho, L. B., Fox, L. M., Hsu, K., & Berger, S. P. (1999). Behavioral and neurochemical effects of the dopamine transporter ligand 4-chlorobenztropine alone and in combination with cocaine in vivo. The Journal of Pharmacology and Experimental Therapeutics, 289(1), 110-22.
Tolliver BK, et al. Behavioral and Neurochemical Effects of the Dopamine Transporter Ligand 4-chlorobenztropine Alone and in Combination With Cocaine in Vivo. J Pharmacol Exp Ther. 1999;289(1):110-22. PubMed PMID: 10086994.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Behavioral and neurochemical effects of the dopamine transporter ligand 4-chlorobenztropine alone and in combination with cocaine in vivo. AU - Tolliver,B K, AU - Newman,A H, AU - Katz,J L, AU - Ho,L B, AU - Fox,L M, AU - Hsu,K,Jr AU - Berger,S P, PY - 1999/3/23/pubmed PY - 2001/3/28/medline PY - 1999/3/23/entrez SP - 110 EP - 22 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 289 IS - 1 N2 - The current studies evaluated the novel diphenylmethoxytropane analog 4-chlorobenztropine (4-Cl-BZT), cocaine, and combinations of the two drugs for their abilities to stimulate locomotor activity, produce cocaine-like discriminative stimulus effects, and elevate extracellular dopamine (DA) in the nucleus accumbens (NAc) as measured by in vivo microdialysis. Peripherally administered cocaine was approximately twice as efficacious as 4-Cl-BZT as a locomotor stimulant and was behaviorally active at a lower dose than was 4-Cl-BZT. Cocaine also was more efficacious than 4-Cl-BZT in producing discriminative-stimulus effects in rats trained to discriminate i.p. injections of 10 mg/kg cocaine from saline. The time course of behavioral activation differed markedly between the two drugs, with much shorter onset and duration of locomotor stimulant effects for cocaine relative to 4-Cl-BZT. Similarly, i.p. cocaine (10 and 40 mg/kg) induced a pronounced, rapid, and short-lived increase in DA in the NAc, whereas i.p. 4-Cl-BZT was effective only at the higher dose and produced a more gradual, modest, and sustained (>/=2 h) elevation in accumbens DA. In contrast to i.p. administration, local infusion of 4-Cl-BZT (1-100 microM) into the NAc through the microdialysis probe elevated extracellular DA to a much greater extent than did local cocaine (nearly 2000% of baseline maximally for 4-Cl-BZT versus 400% of baseline for cocaine) and displayed a much longer duration of action than cocaine. However, when microinjected bilaterally into the NAc at 30 or 300 nmol/side, cocaine remained a more efficacious locomotor stimulant than 4-Cl-BZT. Finally, pretreatment with i.p. 4-Cl-BZT dose dependently enhanced the locomotor stimulant, discriminative stimulus effects, and NAc DA response to a subsequent low-dose i.p. cocaine challenge. The diphenylmethoxytropane analog also facilitated the emergence of stereotyped behavior and convulsions induced by high-dose cocaine. The current results demonstrate that DA transporter ligands that do not share the neurochemical and behavioral profiles of cocaine nevertheless may enhance the effects of cocaine in vivo. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/10086994/Behavioral_and_neurochemical_effects_of_the_dopamine_transporter_ligand_4_chlorobenztropine_alone_and_in_combination_with_cocaine_in_vivo_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10086994 DB - PRIME DP - Unbound Medicine ER -