Effects of the selective 5-HT2A receptor antagonist MDL 100,907 on MDMA-induced locomotor stimulation in rats.
(+/-)3,4-Methylenedioxymethamphetamine (MDMA) releases dopamine and serotonin in vivo and stimulates locomotor activity. Previous work demonstrated that MDMA-stimulated dopamine release could be reduced by the selective 5-HT2A receptor antagonist [R-(+)-a- (2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinem ethanol] (MDL 100,907). In the present study MDL 100,907 significantly reduced MDMA-stimulated locomotion without affecting basal levels of locomotion. Other agents with 5-HT2A antagonist activity (ritanserin, clozapine, MDL 28,133A, or methiothepin), as well as agents that block 5-HT1A-(propranolol), D2-(haloperidol), or D1 receptors (SCH 23390) also reduced MDMA-stimulated locomotion. Intraventricularly administered 5,7-dihydroxytryptamine decreased regional 5-HT levels and attenuated MDMA-stimulated locomotion. These data support the conclusion that serotonin released onto 5-HT2A receptors contributes to MDMA-stimulated locomotion and suggest that MDMA-stimulated locomotion may be useful as an in vivo behavioral measure of 5-HT2A antagonism. The data also support previous reports of contributions of 5-HT1A, D1 and D2 receptors to MDMA-stimulated locomotion. A preliminary time-course analysis indicating time-dependent contributions of different receptors to MDMA-stimulated locomotion suggests the potential utility of this model for characterizing potential atypical antipsychotic compounds.
Kehne
J H
JH
Hoechst Marion Roussel, Inc., Cincinnati, OH 45215, USA.
Ketteler
H J
HJ
McCloskey
T C
TC
Sullivan
C K
CK
Dudley
M W
MW
Schmidt
C J
CJ
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology*; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013268:Stimulation, Chemical
D018492:Dopamine Antagonists; D005464:Fluorobenzenes; D010880:Piperidines; D017981:Receptors, Neurotransmitter; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D016713:Ritanserin; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D008719:Methiothepin; C079049:volinanserin; D003024:Clozapine; D018817:N-Methyl-3,4-methylenedioxyamphetamine