Pharmacological Studies of the Acute and Chronic Effects of (1)-3,4-Methylenedioxymethamphetamine on Locomotor Activity: Role of 5-Hydroxytryptamine1A and 5-Hydroxytryptamine1B/1D Receptors

The 5-hydroxytryptamine1B/1D (5-HT1B/1D) antagonist 29-methyl49-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127935) and 5-HT1A antagonist N-(2-(4-(2-methoxyphenyl)-1piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635) were used to assess whether hyperactivity induced by 3 mg/kg (1)-3,4-methylenedioxymethamphetamine [(1)-MDMA] is mediated by 5-HT1B/1D and/or 5-HT1A receptors. Activity in the periphery and center of an open field as well as rearing activity were measured in photobeam monitors. (1)-MDMA-induced peripheral and central activities were blocked by GR 127935 (0.3, 0.625, 1.25, and 2.5 mg/kg); central hyperactivity was blocked by 0.1, 0.3, and 0.625 mg/kg GR 127935. WAY 100635 (0.5–2 mg/kg) had little effect on (1)-MDMA-induced activity except for an enhancement of central activity at one dose (0.5 mg/kg). Central activity induced by (1)-MDMA increased from day 1 to day 5 of treatment with (1)-MDMA (3 mg/kg), whereas peripheral, central, and rearing activity significantly increased in (1)-MDMA-treated rats pretreated daily with GR 127935 (2.5 mg/kg). Withdrawal from (1)-MDMA, but not GR 127935 1 (1)-MDMA, pretreatment was associated with heightened hyperactivity induced by the 5-HT1B/1A agonist RU 24969 (2 mg/kg i.p.); treatments were not associated with alterations in 5-HT and 5-hydroxyindoleacetic acid content or turnover in frontal cortex. These data support a role for 5-HT1B/1D in mediating the acute hyperactivity evoked by (1)-MDMA. The development of sensitization to (1)-MDMA was associated with supersensitivity to a 5-HT1B/1A agonist, suggesting that these receptors may contribute to sensitization. However, sensitization to (1)-MDMA developed even under conditions of 5-HT1B/1D receptor blockade, which is somewhat counter to this speculation. Perhaps, under circumstances of continued 5-HT1B/1D blockade, other mechanisms (e.g., dopamine) predominate in the progressive enhancement of behavior with repeated (1)-MDMA treatment. 3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”) elicits a unique constellation of subjective effects that differs from the psychostimulant amphetamine (Peroutka et al., 1988). The behavioral profile for MDMA in animals is also unique in comparison with amphetamine. The hyperactivity induced by MDMA is characterized by increased forward locomotion in the periphery of the chamber, whereas amphetamine evokes hypermotility distributed throughout the entire activity monitor (Gold et al., 1989; Callaway et al., 1990). Decreased investigatory behaviors, e.g., holepokes and rearing activity (Gold et al., 1989; Callaway et al., 1990), and elicitation of the serotonin (5-HT; 5-hydroxytryptamine) syndrome (Spanos and Yamamoto, 1989) are also observed after MDMA administration. The ability of MDMA to release 5-HT because of a 5-HT-MDMA exchange (Rudnick and Wall, 1992) has been proposed to mediate the MDMA-induced 5-HT syndrome (Spanos and Yamamoto, 1989). However, unlike the case for d-amphetamine (Callaway et al., 1990), both the 5-HT and dopamine (DA) systems may mediate hyperactivity induced by MDMA. First, MDMA evokes the release of DA as well as 5-HT in vivo (Yamamoto and Spanos, 1988; White et al., 1994). Second, the pattern of behavior evoked by MDMA is more similar to that induced by substituted amphetamines that enhance 5-HT, but not DA, release than to that evoked by amphetamine, which is predominantly a DA releaser (Callaway et al., 1991). Pretreatment with selective 5-HT reuptake inhibitors, which presumably Received for publication December 3, 1998. 1 Support for this research was provided by the National Institute on Drug Abuse Grants DA 06511, DA 00260, and DA 07287. 2 Present address: Eli Lilly and Company Limited, Lilly Research Center, Erl Wood Manor, Sunninghill Rd., Windlesham, Surrey, U.K., GU20 6PH. ABBREVIATIONS: (1)-MDMA, (1)-3,4-methylenedioxymethamphetamine; 5-HT, 5-hydroxytryptamine; DA, dopamine; GR 127935, 29-methyl-49(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide); WAY 100635, N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; 5-HIAA, 5-hydroxyindole acetic acid; VTA, ventral tegmental area; NAc, nucleus accumbens. 0022-3565/99/2903-0965$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 290, No. 3 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 290:965–973, 1999 965 at A PE T Jornals on July 2, 2017 jpet.asjournals.org D ow nladed from block access of MDMA to the 5-HT transporter, antagonized MDMA-induced, but not amphetamine-induced, hyperactivity (Callaway et al., 1990; Callaway et al., 1991). Furthermore, depletion of 5-HT (Callaway et al., 1990) or DA (Gold et al., 1989; but see Callaway et al., 1990) attenuated MDMAevoked hyperactivity as did antagonists with affinity at either 5-HT or DA receptors (Callaway et al., 1992; Kehne et al., 1996). Thus, MDMA appears to evoke hyperactivity via indirect actions in both the DA and 5-HT systems. Because of the potentially unique contribution of 5-HT to hyperactivity evoked by MDMA, attempts to identify the 5-HT receptors involved have been made. Subsequent to the release of 5-HT, an indirect activation of 5-HT1B receptors has been proposed as important to its behavioral effects (Callaway et al., 1992; Rempel et al., 1993). This conclusion is based on the observation that 5-HT agonists with affinity for 5-HT1B receptors elicit a behavioral profile similar to MDMA and that ligands that function as nonselective 5-HT1B receptor antagonists block the behavioral activation evoked by MDMA. However, many of the antagonists that have been shown to attenuate MDMA-induced activity (e.g., methiothepin and propranolol) also have appreciable affinity for the 5-HT1A receptor (Callaway et al., 1992; Kehne et al., 1996). Furthermore, the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin can induce a prominent forward locomotion that is blocked by 5-HT1A antagonists (Kalkman and Soar, 1990). Thus, both 5-HT1A and 5-HT1B receptors may contribute to the locomotor stimulant effects of MDMA, although this hypothesis has not yet been tested with selective antagonists. Psychostimulants enhance hyperactivity and stereotypy during repeated, intermittent administration (“behavioral sensitization”) (Robinson and Berridge, 1993). Demonstrations of sensitization to MDMA exposure are limited. Rats repeatedly treated with MDMA displayed sensitized hyperactivity (Spanos and Yamamoto, 1989; Dafters, 1995; Kalivas et al., 1998), 5-HT syndrome behaviors (Spanos and Yamamoto, 1989), and hyperthermia (Dafters, 1995). However, the development of sensitization to MDMA is not consistently reported; in fact, tolerance and no effect of repeated treatment with MDMA have been observed (Callaway and Geyer, 1992; McNamara et al., 1995). The present study was designed to analyze the relative importance of 5-HT1B/1D and 5-HT1A receptors in hyperactivity evoked by a low dose of (1)-MDMA; the (1)-MDMA isomer was chosen because of its greater potency in eliciting hyperactivity compared with the (2)-isomer (Paulus and Geyer, 1992). For this investigation, the novel 5-HT1B/1D antagonist 29-methyl-49(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127935; Skingle et al., 1996) and the selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1piperazinylethy]-N-2-pyridinyl-cyclohexanecarboxamide (WAY 100635; Forster et al., 1995) were used. The ability of (1)-MDMA (3 mg/kg/day for 5 days) to evoke behavioral sensitization in the presence or absence of GR 127935 was analyzed as was the sensitivity to hyperactivity evoked by 5-HT1B/1A agonist RU 24969 (Callaway et al., 1992) during withdrawal. The dose regimen of MDMA was chosen as likely to induce behavioral sensitization (Spanos and Yamamoto, 1989) but to be subthreshold for elicitation of the 5-HT syndrome (Spanos and Yamamoto, 1989) and induction of 5-HT neurotoxicity (Kalivas et al., 1998). To assure that this was the case, frontal cortex was collected 24 h after the challenge injection of RU 24969 and assayed for 5-HT and 5-hydroxyindole acetic acid (5-HIAA) content. Materials and Methods