Amphetamine derivatives induce locomotor hyperactivity by acting as indirect serotonin agonists.
Derivatives of amphetamine are potent releasers of both dopamine (DA) and serotonin (5-HT), but the relative contributions of DA and 5-HT release to the behavioral effects of these drugs have not been established. Previously, S-(+)3,4-methylenedioxymethamphetamine (S-(+)MDMA) was found to produce locomotor hyperactivity in rats which was dependent on 5-HT release. The present study found that MBDB (1.25, 2.5, 5.0 or 10.0 mg/kg), the alpha-ethyl derivative of MDMA that produces little or no direct DA release, also induced locomotor hyperactivity that lasted for greater than 60 min after the 5.0 and 10.0 mg/kg doses. MBDB produced spatial patterns of locomotor hyperactivity and suppression of exploratory activity (holepokes and rearings) very similar to the behavioral syndrome produced by MDMA. MBDB-induced hyperactivity was blocked by pretreatment with the selective 5-HT uptake inhibitor fluoxetine (2.5 or 10 mg/kg), suggesting that MBDB produced behavioral effects via uptake-carrier mediated release of 5-HT. Similarly, fluoxetine pretreatment blocked the locomotor hyperactivity produced by S-(+)3,4-methylenedioxyamphetamine (3.0 mg/kg) or p-chloroamphetamine (2.5 mg/kg), supporting a serotonergic basis for the action of these drugs. Tissue levels of 5-HT and its metabolite 5-HIAA were decreased 40 min after administration of S-(+)MDMA (3.0 mg/kg) or MBDB (5.0 mg/kg), and these decreases were prevented by fluoxetine pretreatment. S-(+)MDMA also produced a fluoxetine-sensitive increase of tissue DA levels, suggesting that 5-HT release may indirectly result in increased DA release, although MBDB did not significantly increase DA levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Psychiatry, University of California, San Diego, School of Medicine, La Jolla 92093-0804.
C W
CW
Callaway
M P
MP
Johnson
L H
LH
Gold
D E
DE
Nichols
M A
MA
Geyer
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000502:physiology*; D010133:p-Chloroamphetamine / Q000494:pharmacology
D000662:Amphetamines; D001679:Biogenic Amines; D005473:Fluoxetine; C051570:N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D010133:p-Chloroamphetamine