Locomotor stimulation produced by 3,4-methylenedioxymethamphetamine (MDMA) is correlated with dialysate levels of serotonin and dopamine in rat brain

Abstract

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA, or Ecstasy) is an illicit drug that evokes transporter-mediated release of monoamines, including serotonin (5-HT) and dopamine (DA). Here we monitored the effects of MDMA on neurochemistry and motor activity in rats, as a means to evaluate relationships between 5-HT, DA, and behavior. Male rats undergoing in vivo microdialysis were housed in chambers equipped with photobeams for measurement of ambulation (i.e., forward locomotion) and stereotypy (i.e., head weaving and forepaw treading). Microdialysis probes were placed into the n. accumbens, striatum or prefrontal cortex in separate groups of rats. Dialysate samples were assayed for 5-HT and DA by microbore HPLC-ECD. Rats received two i.v. injections of MDMA, 1 mg/kg followed by 3 mg/kg 60 min later; neurochemical and locomotor parameters were measured concurrently. MDMA produced dose-related elevations in extracellular 5-HT and DA in all regions, with the magnitude of 5-HT release always exceeding that of DA release. MDMA-induced ambulation was positively correlated with dialysate DA levels in all regions (P<0.05-0.0001) and with dialysate 5-HT in striatum and cortex (P<0.001-0.0001). Stereotypy was strongly correlated with dialysate 5-HT in all areas (P<0.001-0.0001) and with dialysate DA in accumbens and striatum (P<0.001-0.0001). These data support previous work and suggest the complex spectrum of behaviors produced by MDMA involves 5-HT and DA in a region- and modality-specific manner.

Figure 1

Diagrammatic representation of the placement of microdialysis probes in rat brain for the present study. Anterior-posterior coordinates are noted (Paxinos and Watson, 2005).

Figure 2

Effects of i.v. MDMA administration on dialysate 5-HT (top panel) and DA (bottom panel) in rat n. accumbens. Rats undergoing microdialysis in the accumbens received two injections of MDMA, 1 mg/kg at 0 min followed by 3 mg/kg at 60 min. Data are mean ±SEM for N=6 rats. Baseline 5-HT and DA levels in accumbens were 0.24±0.04 and 2.18±0.40 pg/5 µL. * = P<0.05 compared to 0 min preinjection control.

Figure 3

Correlations between dialysate 5-HT in n. accumbens versus ambulation (top panel) and stereotypy (bottom panel) produced by MDMA. Data points represent raw values from individual rats, obtained from +20 min (first sample after 1 mg/kg) through +120 min (last sample after 3 mg/kg). Pearson correlation coefficients (r) are shown with corresponding P values.

Figure 4

Correlations between dialysate DA in n. accumbens versus ambulation (top panel) and stereotypy (bottom panel) produced by MDMA. Data points represent raw values from individual rats, obtained from +20 min (first sample after 1 mg/kg) through +120 min (last sample after 3 mg/kg). Pearson correlation coefficients (r) are shown with corresponding P values.

Figure 5

Effects of i.v. MDMA administration on dialysate 5-HT (top panel) and DA (bottom panel) in rat striatum. Rats undergoing microdialysis in the striatum received two injections of MDMA, 1 mg/kg at 0 min followed by 3 mg/kg at 60 min. Data are mean ±SEM for N=6 rats. Baseline 5-HT and DA levels in striatum were 0.28±0.05 and 6.28±1.23 pg/5 µL. * = P<0.05 compared to 0 min preinjection control.

Figure 6

Correlations between dialysate 5-HT in striatum versus ambulation (top panel) and stereotypy (bottom panel) produced by MDMA. Data points represent raw values from individual rats, obtained from +20 min (first sample after 1 mg/kg) through +120 min (last sample after 3 mg/kg). Pearson correlation coefficients (r) are shown with corresponding P values.

Figure 7

Correlations between dialysate DA in striatum versus ambulation (top panel) and stereotypy (bottom panel) produced by MDMA. Data points represent raw values from individual rats, obtained from +20 min (first sample after 1 mg/kg) through +120 min (last sample after 3 mg/kg). Pearson correlation coefficients (r) are shown with corresponding P values.

Figure 8

Effects of i.v. MDMA administration on dialysate 5-HT (top panel) and DA (bottom panel) in rat prefrontal cortex. Rats undergoing microdialysis in prefrontal cortex received two injections of MDMA, 1 mg/kg at 0 min followed by 3 mg/kg at 60 min. Data are mean ±SEM for N=5 rats. Baseline 5-HT and DA levels in cortex were 0.24±0.05 and 0.25±0.03 pg/5 µL. * = P<0.05 compared to 0 min preinjection control.

Figure 9

Correlations between dialysate 5-HT in prefrontal cortex versus ambulation (top panel) and stereotypy (bottom panel) produced by MDMA. Data points represent raw values from individual rats, obtained from +20 min (first sample after 1 mg/kg) through +120 min (last sample after 3 mg/kg). Pearson correlation coefficients (r) are shown with corresponding P values.

Figure 10

Correlations between dialysate DA in prefrontal cortex versus ambulation (top panel) and stereotypy (bottom panel) produced by MDMA. Data points represent raw values from individual rats, obtained from +20 min (first sample after 1 mg/kg) through +120 min (last sample after 3 mg/kg). Pearson correlation coefficients (r) are shown with corresponding P values.