The 5-HT2 receptor antagonist, MDL 28,133A, disrupts the serotonergic-dopaminergic interaction mediating the neurochemical effects of 3,4-methylenedioxymethamphetamine.
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.
Schmidt
C J
CJ
Marion Merrell Dow Research Institute, Cincinnati, OH 45215.
Black
C K
CK
Taylor
V L
VL
Fadayel
G M
GM
Humphreys
T M
TM
Nieduzak
T R
TR
Sorensen
S M
SM
D015104:3,4-Methylenedioxyamphetamine / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism*; D004594:Electrophysiology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D019805:alpha-Methyltyrosine
D008781:Methyltyrosines; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C072859:MDL 28133A; D012701:Serotonin; D007980:Levodopa; D015104:3,4-Methylenedioxyamphetamine; D019805:alpha-Methyltyrosine; D004298:Dopamine