Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan.
The behavioral effects of 5-methoxy-6-methyl-2-aminoindan (MMAI) were examined using the drug discrimination procedure and direct observation for classification of the characteristic syndrome induced by MMAI. The stimulus effects of MMAI were studied in 5 different groups of rats trained to discriminate MMAI (1.71 mg/kg; 8 microM/kg), MDMA (3,4-methylenedioxymethamphetamine; 1.75 mg/kg; 7.6 microM/kg), (+)-MBDB ((+)-N-methylamino-(1,3-benzodioxo-5-yl)-2-butanamine; 1.75 mg/kg; 7.18 microM/kg), (+)-amphetamine (1 mg/kg; 5.4 microM/kg), or LSD ((+)-lysergic acid diethylamide tartrate; 0.08 mg/kg; 186 nM/kg) from saline. In substitution tests in rats trained to discriminate MMAI from saline, all the compounds which fully mimicked MMAI were serotonin (5-hydroxytryptamine, 5-HT) releasing agents. This substitution is symmetrical for MDMA and (+)-MBDB. Nevertheless, the dose-response curve of MMAI is parallel to those of (+)-fenfluramine (m-trifluoromethyl-N-ethylamphetamine) and p-chloroamphetamine. The results also show that MMAI lacks amphetamine-like and LSD-like discriminative stimulus effects, suggesting that MMAI is neither a psychostimulant nor a hallucinogen. Tests of the discriminability of MMAI after 5-HT depletion with the selective serotonin synthesis inhibitor, p-chlorophenylalanine (2 x 200 mg/kg i.p., pretreatment 72 h before test), showed only saline appropriate responding. Prolonged block (ca. 1 week) of the MMAI cue by p-chlorophenylalanine further supports the conclusion that endogenous 5-HT is essential for MMAI discrimination. Fluoxetine (10 mg/kg) or paroxetine (2.5 mg/kg), both selective 5-HT uptake inhibitors, reduced the discriminability of MMAI to 40% and 50%, respectively. None of the antagonists (ketanserin, methiothepin, pindolol, yohimbine, haloperidol) used in antagonism tests inhibited the stimulus properties of MMAI. These results and data from radioligand binding studies support the conclusion that direct activation or inhibition of known neurotransmitter receptors did not play a significant role in the discriminative cue of MMAI. The administration of 5, 10, or 20 mg/kg of MMAI to rats induced a behavioral syndrome consisting of hypolocomotion with accompanying catalepsy-like posture, turning, Straub tail, flat body posture, and suppressed sleeping time. In general, this is qualitatively similar to what is seen after administration of 5-HT precursors or 5-HT receptor agonists. In conclusion, the data from the drug discrimination study and the behavioral syndrome induced by MMAI suggest that MMAI is a potential selective releaser of serotonin.
Marona-Lewicka
D
D
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.
Nichols
D E
DE
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000661:Amphetamine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004193:Discrimination Learning; D004305:Dose-Response Relationship, Drug; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D013237:Stereoisomerism
D007189:Indans; D012702:Serotonin Antagonists; C051570:N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine; C068879:5-methoxy-6-methyl-2-aminoindan; D015104:3,4-Methylenedioxyamphetamine; D000661:Amphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine