Alpha1-adrenergic receptors mediate the locomotor response to systemic administration of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) in rats

Abstract

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) increases locomotor activity when administered to rats. Although the published pharmacology of MDMA has focused almost exclusively on the roles of serotonin and dopamine, in vitro studies indicate that MDMA induces serotonin and norepinephrine release with equal potency. The present experiments tested the hypothesis that blockade of alpha(1)-adrenoceptors with systemic or local administration of the antagonist prazosin would attenuate the locomotor response to systemic administration of (+/-)-MDMA. Pretreatment with systemic prazosin (0.5 mg/kg) or microinjections into either the prefrontal cortex or ventral tegmental area completely blocked the locomotor stimulant effects of 5 mg/kg (+/-)-MDMA, assessed using a computerized Behavioral Pattern Monitor. Prazosin was more potent in blocking the locomotor stimulant effects of (+/-)-MDMA than a 2 mg/kg dose of (+)-amphetamine that produced a similar locomotor activity increase. These results indicate that activation of alpha(1)-adrenoceptors in both the prefrontal cortex and ventral tegmental areas modulates the locomotor response to MDMA.

Figure 1

Illustration of the time course of effect of 2 mg/kg (+)-amphetamine hydrochloride on rat total locomotor activity (n = 6) and effect of systemic prazosin (0.50 or 1.0 mg/kg; n = 6 each) pretreatment. Data were recorded every five minutes and are shown as raw untransformed activity counts.

Figure 2

The effect of systemic prazosin administration on rat spontaneous locomotor activity. Photo beam breaks were recorded during the 30 minutes following saline or prazosin treatment, and prior to administration of amphetamine or MDMA. Thus, the pretreatment data are pooled, and are expressed as a percent of baseline locomotor activity. Saline n = 30, 0.5 mg/kg prazosin n = 21, 1.0 mg/kg prazosin n = 6. The effect of prazosin alone on locomotor activity was not significant (p > 0.05).

Figure 3

Effect of prazosin pretreatment (1 mg/kg) on (A.) 2 mg/kg (+)-amphetamine- (n = 6) and, (B.) 5 mg/kg MDMA-induced (n = 6) increased locomotor activity. Photo beam breaks were recorded in 5 minute intervals, averaged over 15 min bins, and normalized to percent of baseline (see methods).

Figure 4

The effect of systemic prazosin administration on the locomotor response to 2 mg/kg (+)-amphetamine. Pretreatment with 0.5 or 1.0 mg/kg prazosin produced a significant overall effect on the locomotor response to (+)-amphetamine (F_(2,12) = 12.63; p < 0.01). Significant deceases in (+)-amphetamine-induced hyperactivity were observed in animals pretreated with 0.5 mg/kg (* p < 0.05) and 1.0 mg/kg (**p < 0.01) of prazosin. Number of animals used for each treatment n = 6.

Figure 5

The effect of systemic prazosin administration on the locomotor response to MDMA. In animals pretreated with 0.5 mg/kg prazosin, the hyperlocomotion generated by 5 mg/kg MDMA was significantly reduced (*p < 0.01), and this effect was not significantly different from prazosin-saline alone; saline-MDMA n = 14, prazosin-MDMA n = 6. * p<0.05 vs saline.

Figure 6

Figure 6A. Locomotor activity was significantly increased by systemic administration of 5 mg/kg MDMA compared to saline (p < 0.001). The response to MDMA was significantly reduced in animals receiving intra-PFC injections of prazosin (*p < 0.01). Number of animals used for each treatment: n = 11 for saline-saline, n = 6 for saline-MDMA and prazosin-MDMA. Figure 6B. Locomotor activity was significantly increased by 5 mg/kg MDMA compared to saline (p < 0.001). The locomotor response elicited by MDMA was significantly attenuated by intra-VTA injections of prazosin (*p < 0.01). Number of animals used for each treatment: n = 9 for saline-saline, N = 6 for saline-MDMA and prazosin-MDMA.

Figure 7

Comparison of locomotor activity in central versus peripheral areas of the activity chamber (see methods). (A.) The effect of saline on central vs peripheral activity. There was no significant difference between the time spent in the central vs peripheral part of the chamber, although there was a trend to spend more time in the peripheral region of the chamber (p = 0.06). (B.) The effect of (+)-amphetamine on central versus peripheral activity. Following administration of 2 mg/kg of (+)-amphetamine, animals spent significantly more time in the central area of the test chamber than in the peripheral area (*p < 0.01). Number of animals for each treatment n = 6. (C.) The effect of MDMA on central versus peripheral activity. There was no significant difference (p > 0.05) between time spent in central versus peripheral areas of the chamber after administration of 5 mg/kg MDMA (n = 5).

Figure 8

Representative locomotor activity patterns in the behavioral pattern monitor for (A) saline, (B) 2 mg/kg (+)-amphetamine, (C) 5 mg/kg MDMA, and (D) 5 mg/kg MDMA after pretreatment with 0.5 mg/kg prazosin.