Suppression of behavioral activity by norfenfluramine and related drugs in rats is not mediated by serotonin release.
Fenfluramine, a phenalkylamine with serotonin (5-HT) releasing properties, decreases motor activity in rats. The following studies assessed the contribution of 5-HT release to the behavioral effects of fenfluramine and norfenfluramine using a behavioral pattern monitor that simultaneously assesses locomotor and investigatory behavior. First, both fenfluramine and its active metabolite d-norfenfluramine dose-dependently reduced locomotor and investigatory activity. The norfenfluramine-induced reduction in activity was not antagonized by pretreatment with the 5-HT uptake inhibitor fluoxetine or the 5-HT synthesis inhibitor p-chlorophenylalanine, drugs that reduce drug-induced 5-HT release. Second, the d- and l-enantiomers of norfenfluramine were nearly equipotent at reducing behavioral activity, although d-norfenfluramine is more potent as a 5-HT releasing agent. Third, p-chloroamphetamine, a drug that shares the 5-HT releasing properties of fenfluramine produced locomotor hyperactivity in the same paradigm. Previous studies indicate that other 5-HT releasing phenalkylamines have behavioral effects resembling those of p-chloroamphetamine rather than those of fenfluramine. Finally, a structurally related drug, 4-methoxy-5-methyl-aminoindan (MMAI), produced dose-dependent reductions in behavioral activity that are similar to the effects of fenfluramine. The behavioral effects of MMAI were not antagonized by fluoxetine or by the 5-HT receptor antagonist methiothepin. These data suggest that the decrease in activity induced by fenfluramine, norfenfluramine and the related drug MMAI is not related to 5-HT release.
Callaway
C W
CW
Department of Psychiatry, UCSD School of Medicine, La Jolla 92093-0804.
Wing
L L
LL
Nichols
D E
DE
Geyer
M A
MA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D010134:Fenclonine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009642:Norfenfluramine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013237:Stereoisomerism
D007189:Indans; D012702:Serotonin Antagonists; D005473:Fluoxetine; C068879:5-methoxy-6-methyl-2-aminoindan; D009642:Norfenfluramine; D012701:Serotonin; D008719:Methiothepin; D010134:Fenclonine