Amphetamine derivatives induce locomotor hyperactivity by acting as indirect serotonin agonists.

Summary

MBDB, a derivative of amphetamine that releases little or no dopamine, caused rats to become hyperactive and suppressed their exploratory behaviors, similar to the effects of MDMA. This hyperactivity lasted over 60 minutes at higher doses. Pretreatment with fluoxetine, a serotonin reuptake inhibitor, blocked MBDB-induced hyperactivity, indicating that the behavioral effects depend on serotonin release rather than dopamine release. Fluoxetine also blocked hyperactivity from related drugs S-(+)3,4-methylenedioxyamphetamine and p-chloroamphetamine. Tissue measurements showed decreased serotonin and its metabolite 5-HIAA after MBDB or S-(+)MDMA, which was prevented by fluoxetine. S-(+)MDMA increased dopamine levels in a fluoxetine-sensitive manner, suggesting serotonin release may indirectly influence dopamine.

Study at a glance

Abstract

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)