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Relations between stimulation of mesolimbic dopamine and place conditioning in rats produced by cocaine or drugs that are tolerant to dopamine transporter conformational change.
Psychopharmacology (Berl). 2013 Sep; 229(2):307-21.P

Abstract

RATIONALE

Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT inhibitors. Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT. In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change.

METHODS

We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place conditioning in rats among cocaine and four BZT analogs with Cl substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring.

RESULTS

Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux. Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, i.p.), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine. Despite this equilibration, none of the BZT analogs tested produced significant place conditioning.

CONCLUSIONS

The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT. In contrast, BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse.

Authors+Show Affiliations

Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., NIDA suite 200, Baltimore, MD 21224, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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, N.I.H., Intramural

Language

eng

PubMed ID

23612854

Citation

Tanda, Gianluigi, et al. "Relations Between Stimulation of Mesolimbic Dopamine and Place Conditioning in Rats Produced By Cocaine or Drugs That Are Tolerant to Dopamine Transporter Conformational Change." Psychopharmacology, vol. 229, no. 2, 2013, pp. 307-21.
Tanda G, Li SM, Mereu M, et al. Relations between stimulation of mesolimbic dopamine and place conditioning in rats produced by cocaine or drugs that are tolerant to dopamine transporter conformational change. Psychopharmacology (Berl). 2013;229(2):307-21.
Tanda, G., Li, S. M., Mereu, M., Thomas, A. M., Ebbs, A. L., Chun, L. E., Tronci, V., Green, J. L., Zou, M. F., Kopajtic, T. A., Newman, A. H., & Katz, J. L. (2013). Relations between stimulation of mesolimbic dopamine and place conditioning in rats produced by cocaine or drugs that are tolerant to dopamine transporter conformational change. Psychopharmacology, 229(2), 307-21. https://doi.org/10.1007/s00213-013-3109-6
Tanda G, et al. Relations Between Stimulation of Mesolimbic Dopamine and Place Conditioning in Rats Produced By Cocaine or Drugs That Are Tolerant to Dopamine Transporter Conformational Change. Psychopharmacology (Berl). 2013;229(2):307-21. PubMed PMID: 23612854.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Relations between stimulation of mesolimbic dopamine and place conditioning in rats produced by cocaine or drugs that are tolerant to dopamine transporter conformational change. AU - Tanda,Gianluigi, AU - Li,Su Min, AU - Mereu,Maddalena, AU - Thomas,Alexandra M, AU - Ebbs,Aaron L, AU - Chun,Lauren E, AU - Tronci,Valeria, AU - Green,Jennifer L, AU - Zou,Mu-Fa, AU - Kopajtic,Theresa A, AU - Newman,Amy Hauck, AU - Katz,Jonathan L, Y1 - 2013/04/24/ PY - 2012/12/07/received PY - 2013/04/05/accepted PY - 2013/4/25/entrez PY - 2013/4/25/pubmed PY - 2014/4/1/medline SP - 307 EP - 21 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 229 IS - 2 N2 - RATIONALE: Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT inhibitors. Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT. In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change. METHODS: We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place conditioning in rats among cocaine and four BZT analogs with Cl substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring. RESULTS: Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux. Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, i.p.), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine. Despite this equilibration, none of the BZT analogs tested produced significant place conditioning. CONCLUSIONS: The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT. In contrast, BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/23612854/Relations_between_stimulation_of_mesolimbic_dopamine_and_place_conditioning_in_rats_produced_by_cocaine_or_drugs_that_are_tolerant_to_dopamine_transporter_conformational_change_ L2 - https://dx.doi.org/10.1007/s00213-013-3109-6 DB - PRIME DP - Unbound Medicine ER -