Pharmacological Studies of the Acute Effects of (+)-3,4-Methylenedioxymethamphetamine on Locomotor Activity, Role of 5-HT1B/1D and 5-HT2 Receptors

Abstract

The role of serotonin 5-HT 2 receptors (5-HT 2 R) in the hyperactivity induced by ( ϩ )-3,4-methylenedioxymethamphetamine (( ϩ )-MDMA; 3 mg/kg) was investigated. Hyperactivity induced by ( ϩ )-MDMA was robustly potentiated by the 5-HT 2B/2C R antagonist SB 206553 (1.0, 2.0, and 4.0 mg/kg). Administration of the 5-HT 1B/1D R antagonist GR 127935 (2.5 mg/kg) or the 5-HT 2A R antagonist M100907 (1.0 mg/kg) partially suppressed the potentiated hyperactivity seen following SB 206553 plus ( ϩ )-MDMA; a blockade to activity levels seen with ( ϩ )-MDMA alone was observed following the combination of GR 127935 plus M100907. A modest potentiative interaction was seen when SB 206553 was combined with the DA releaser amphetamine (0.5 mg/kg) or amphetamine plus the 5-HT releaser fenfluramine (4.0 mg/ kg). SB 206553 (1-4 mg/kg), GR 127935 (2.5 mg/kg) and M100907 (1 mg/kg) did not alter spontaneous activity upon administration singly or in combination. These data suggest that activation of 5-HT 2C R exerts a strong inhibitory influence on the hyperactivity induced by ( ϩ )- receptors; 5-HT 2A receptors; 5-HT 2C receptors; M100907; MDL 100907; MDMA; 3,4-Methylenedioxymethamphetamine; SB 206553; Serotonin 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a commonly abused amphetamine derivative that evokes a unique set of stimulant, emotional and perceptual effects distinguishable from the parent drug amphetamine (Greer and Tolbert 1986). The mechanisms of action of both amphetamine and MDMA are based upon their ability to reverse monoamine reuptake transporters resulting in monoamine release from nerve terminals (Rudnick and Wall 1992). Amphetamine is selective for the release of dopamine (DA) via the DA reuptake transporter (Crespi et al. 1997), while MDMA has greater affinity for the serotonin (5-hydroxytryptamine; 5-HT) transporter (SERT) (Battaglia et al. 1988;Crespi et al. 1997). The ratio of 5-HT release to DA release is much greater for MDMA than for amphetamine (Crespi et al. 1997), although MDMA, like amphetamine, does release a larger amount of DA than 5-HT (Gudelsky and Nash 1996;White et al. 1994;Yamamoto and Spanos 1988). There are also similarities and stark contrasts when comparing the overt behaviors expressed upon the administration of these two drugs. Both drugs increase locomotor activity in rodents, but amphetamine-induced activity is amplified throughout the activity monitor, while MDMA-induced activity occurs predominantly in the periphery of the chamber (Callaway et al. 1990;. MDMA also produces aspects of the "5-HT syndrome" (Spanos and Yamamoto 1989) and decreased investigatory behavior . A large body of literature suggests that accumulation of DA in the synapse is a crucial mediator of the behavioral effects of psychostimulants such as amphetamine and cocaine (Kelly et al. 1975;Robledo et al. 1992). Dopamine antagonists (Kehne et al. 1996) and DA depletion with the DA neurotoxin 6-hydroxydopamine ) have been noted to attenuate the behavioral effects of MDMA. However, several lines of evidence ...

α1-Adrenergic receptors mediate the locomotor response to systemic administration of (±)-3,4-methylenedioxymethamphetamine (MDMA) in rats

“…Consistent with previous reports (Geyer et al 1987), we observed that animals spent more time (>40%) in central than peripheral regions of the chamber following administration of 2 mg/kg (+)-amphetamine. By contrast, several studies from different laboratories have reported observing more peripheral than central activity following (+)-MDMA administration (McCreary et al 1999;Bankson and Cunningham 2002;Gold et al 1988;Callaway et al 1990). In the present experiments, however, locomotor activity was nearly evenly distributed between the central and peripheral areas of the chamber following administration of 5 mg/kg (±)-MDMA.…”

Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

“…MDMA releases dopamine both directly and indirectly through 5-HT release (Callaway et al 1990;Koch and Galloway 1997;Schmidt et al 1992;Yamamoto and Spanos 1988). Both 5-HT 1B and 5-HT 2 receptors can influence the MDMA locomotor response, although both stimulatory and inhibitory effects have been reported (Bankson and Cunningham 2002;Kehne et al 1996;McCreary et al 1999;Schmidt et al 1992). Estrogen enhances basal, stimulated, and stimulant-induced dopamine release as well as both dopamine and serotonin receptors (see reviews by Becker 1999;Cyr et al 2002).…”

“…Multiple mechanisms could contribute to this enhanced response including greater changes in dopamine signaling, upregulation of serotonin receptors like that occurring after other manipulations that deplete serotonin, or some adaptation that is specific for MDMA (Dringenberg et al 1995;Gately et al 1985;Nestler 2004). The augmented response in females could reflect a sex-specific receptor upregulation facilitated by estrogen-facilitated 5-HT 2 receptor synthesis (Bankson and Cunningham 2002;Cyr et al 2002;Reneman et al 2000).…”

3,4-N-Methlenedioxymethamphetamine-Induced Hypophagia is Maintained in 5-HT1B Receptor Knockout Mice, but Suppressed by the 5-HT2C Receptor Antagonist RS102221

“…Likewise, several studies have excluded the possibility that nonspecific behavioral changes, such as hyperlocomotion and even sedation, may account for the hypophagic responses to 5-HT 1B , 5-HT 2A , 5-HT 2B , or 5-HT 2C receptor agonists ( Kitchener and Dourish, 1994; Lee and Simansky, 1997;Hewitt et al, 2002;Clifton et al, 2000Clifton et al, , 2003. The fact that 5-HT 2C receptors may contribute to MDMA-induced hyperlocomotion has been questioned in one study using rats (Bankson and Cunningham, 2002). This investigation reported that SB206553, a 5-HT 2C receptor antagonist, enhanced the motor effects of MDMA in the rat (Bankson and Cunningham, 2002).…”

“…The fact that 5-HT 2C receptors may contribute to MDMA-induced hyperlocomotion has been questioned in one study using rats (Bankson and Cunningham, 2002). This investigation reported that SB206553, a 5-HT 2C receptor antagonist, enhanced the motor effects of MDMA in the rat (Bankson and Cunningham, 2002). Such a discrepancy may likely be due to dose-or species-specific differences since an acute administration of 3.3 mg/kg MDMA did not stimulate locomotion in mice (Scearce-Levie et al, 1999), but did in rats ( Bankson and Cunningham, 2002).…”