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The 5-HT2 receptor antagonist, MDL 28,133A, disrupts the serotonergic-dopaminergic interaction mediating the neurochemical effects of 3,4-methylenedioxymethamphetamine.
Eur J Pharmacol. 1992 Sep 22; 220(2-3):151-9.EJ

Abstract

The selective 5-HT2 receptor antagonist MDL 28,133A dose dependently-blocked the long-term deficits in rat brain 5-HT concentrations produced by the substituted amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). This protective effect of MDL 28,133A could be abolished by coadministration of the dopamine precursor, L-dihydroxyphenylalanine (L-DOPA). Electrophysiological experiments demonstrated that the ability of MDL 28,133A to block the MDMA-induced slowing of A9 dopaminergic neurons was also sensitive to L-DOPA administration. Both sets of experiments suggest an interaction of MDL 28,133A at the level of dopamine synthesis. Consistent with this explanation, MDL 28,133A antagonized the MDMA-induced stimulation of dopamine synthesis in vivo. MDMA-induced 5-HT release did not reduce the firing rate of dopaminergic neurons as assessed by dopamine depletion following synthesis inhibition with alpha-methyl-p-tyrosine (alpha-MPT). This indicates that the effect of 5-HT2 receptor antagonists on MDMA-induced dopamine synthesis is not due simply to the removal of an inhibitory serotonergic input followed by an increase in dopamine cell firing and autoreceptor activation. MDL 28,133A was also shown to be without effect on the sensitivity of terminal dopamine autoreceptors. The results are consistent with the hypothesis that 5-HT2 receptors are permissive for the stimulation of dopamine synthesis necessary to support MDMA-induced transmitter efflux.

Authors+Show Affiliations

Marion Merrell Dow Research Institute, Cincinnati, OH 45215.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

1425989

Citation

Schmidt, C J., et al. "The 5-HT2 Receptor Antagonist, MDL 28,133A, Disrupts the Serotonergic-dopaminergic Interaction Mediating the Neurochemical Effects of 3,4-methylenedioxymethamphetamine." European Journal of Pharmacology, vol. 220, no. 2-3, 1992, pp. 151-9.
Schmidt CJ, Black CK, Taylor VL, et al. The 5-HT2 receptor antagonist, MDL 28,133A, disrupts the serotonergic-dopaminergic interaction mediating the neurochemical effects of 3,4-methylenedioxymethamphetamine. Eur J Pharmacol. 1992;220(2-3):151-9.
Schmidt, C. J., Black, C. K., Taylor, V. L., Fadayel, G. M., Humphreys, T. M., Nieduzak, T. R., & Sorensen, S. M. (1992). The 5-HT2 receptor antagonist, MDL 28,133A, disrupts the serotonergic-dopaminergic interaction mediating the neurochemical effects of 3,4-methylenedioxymethamphetamine. European Journal of Pharmacology, 220(2-3), 151-9.
Schmidt CJ, et al. The 5-HT2 Receptor Antagonist, MDL 28,133A, Disrupts the Serotonergic-dopaminergic Interaction Mediating the Neurochemical Effects of 3,4-methylenedioxymethamphetamine. Eur J Pharmacol. 1992 Sep 22;220(2-3):151-9. PubMed PMID: 1425989.
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TY - JOUR T1 - The 5-HT2 receptor antagonist, MDL 28,133A, disrupts the serotonergic-dopaminergic interaction mediating the neurochemical effects of 3,4-methylenedioxymethamphetamine. AU - Schmidt,C J, AU - Black,C K, AU - Taylor,V L, AU - Fadayel,G M, AU - Humphreys,T M, AU - Nieduzak,T R, AU - Sorensen,S M, PY - 1992/9/22/pubmed PY - 1992/9/22/medline PY - 1992/9/22/entrez SP - 151 EP - 9 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 220 IS - 2-3 N2 - The selective 5-HT2 receptor antagonist MDL 28,133A dose dependently-blocked the long-term deficits in rat brain 5-HT concentrations produced by the substituted amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). This protective effect of MDL 28,133A could be abolished by coadministration of the dopamine precursor, L-dihydroxyphenylalanine (L-DOPA). Electrophysiological experiments demonstrated that the ability of MDL 28,133A to block the MDMA-induced slowing of A9 dopaminergic neurons was also sensitive to L-DOPA administration. Both sets of experiments suggest an interaction of MDL 28,133A at the level of dopamine synthesis. Consistent with this explanation, MDL 28,133A antagonized the MDMA-induced stimulation of dopamine synthesis in vivo. MDMA-induced 5-HT release did not reduce the firing rate of dopaminergic neurons as assessed by dopamine depletion following synthesis inhibition with alpha-methyl-p-tyrosine (alpha-MPT). This indicates that the effect of 5-HT2 receptor antagonists on MDMA-induced dopamine synthesis is not due simply to the removal of an inhibitory serotonergic input followed by an increase in dopamine cell firing and autoreceptor activation. MDL 28,133A was also shown to be without effect on the sensitivity of terminal dopamine autoreceptors. The results are consistent with the hypothesis that 5-HT2 receptors are permissive for the stimulation of dopamine synthesis necessary to support MDMA-induced transmitter efflux. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/1425989/The_5_HT2_receptor_antagonist_MDL_28133A_disrupts_the_serotonergic_dopaminergic_interaction_mediating_the_neurochemical_effects_of_34_methylenedioxymethamphetamine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/0014-2999(92)90743-N DB - PRIME DP - Unbound Medicine ER -