Differences in the locomotor-activating effects of indirect serotonin agonists in habituated and non-habituated rats.

3,4-Methylenedioxymethamphetamine (MDMA) is a derivative of amphetamine that increases the non-exocytotic release of serotonin (5-HT), dopamine (DA), and norepinephrine (Nichols et al., 1982, 1986; Baumann et al., 2008). MDMA, a popular drug of abuse for several decades, can induce stimulation, heightened mood, empathy, feelings of closeness to others, and minor perceptual alterations (Vollenweider et al., 2002). Although there are similarities between the effects of MDMA and psychostimulants such as amphetamine, qualitative differences exist as well (Gouzoulis-Mayfrank et al., 1999). It has been proposed that MDMA belongs to a novel class of psychoactive compounds known as entactogens (Nichols, 1986; Nichols et al., 1986; Nichols and Oberlender, 1990). In support of this distinction, it appears that the effects of MDMA are mediated primarily by increases in 5-HT release (Callaway et al., 1990; Liechti et al., 2000a,b), whereas amphetamine acts largely via effects on DA efflux (Kelly et al., 1975). MDMA and related compounds produce a distinct profile of behavioral effects in rats, including locomotor hyperactivity, thigmotaxis, and a reduction in the frequency of investigatory rearings and holepokes (Gold et al., 1998; Callaway et al., 1990, 1991). MDMA-induced hyperactivity is markedly attenuated by 5-HT uptake inhibitors (Callaway et al., 1990, 1991), indicating that the effects of MDMA are dependent on carrier-mediated release of 5-HT. There is extensive evidence that the 5-HT1B receptor is responsible for mediating the behavioral effects of MDMA. For example, the 5-HT1A/1B agonist RU 24969 produces effects that are qualitatively similar to those of MDMA (Rempel et al., 1993), and RU 24969 and MDMA produce cross-tolerance (Callaway and Geyer, 1992). Furthermore, the locomotor-activating effects of MDMA are blocked by the selective 5-HT1B/1D antagonist {"type":"entrez-nucleotide","attrs":{"text":"GR127935","term_id":"238377770","term_text":"GR127935"}}GR127935 and attenuated in 5-HT1B knockout mice (McCreary et al., 1999; Scearce-Levie et al., 1999; Fletcher et al., 2002). There is also evidence that 5-HT2A receptors (Ball and Rebec, 2005; Kehne et al., 1996; Fletcher et al., 2002), D1 and D2 dopaminergic receptors (Bubar et al., 2004; Risbrough et al., 2006), and α1 adrenergic receptors (Selken and Nichols, 2007) contribute to the MDMA-induced locomotor response. During the course of a series of pilot behavioral experiments with MDMA, we found evidence that the drug does not increase locomotor activity in animals tested in a familiar environment (data not shown). This finding was surprising because several other groups have reported that racemic MDMA and the more active enantiomer S-(+)-MDMA produced robust hyperactivity in rats habituated to the test chambers (Kehne et al., 1996; McCreary et al., 1999; Bankson and Cunningham, 2002; Fletcher et al., 2002). Given these discrepant observations, we conducted a series of experiments to determine whether habituation alters the behavioral response to MDMA. Parallel studies were conducted with α-ethyltryptamine (AET), a 5-HT releasing agent (Baker et al., 1980) that produces an MDMA-like behavioral profile in rats (Krebs and Geyer, 1993; Glennon, 1993). While most drugs with MDMA-like effects are based on the phenethylamine structure, AET is derived from tryptamine and thus more related structurally to 5-HT; hence, studies with AET were included to assess the generality of any findings with MDMA. In rodents, the baseline level of activity (Iuvone and Van Hartesveldt, 1977), as well as the behavioral response to serotonergic ligands (Singleton and Marsden, 1981; Lu and Nagayama, 1996; Darmani, 1998), varies over the diurnal light/dark cycle. Most investigators have tested MDMA in rats housed on a standard light cycle (i.e., behavioral testing occurred during the light phase), whereas our studies with MDMA were conducted in rats housed on a reversed light cycle. To determine whether the effects of MDMA are influenced by the phase of the light/dark cycle, we also conducted parametric studies with MDMA in habituated and non-habituated rats housed under a standard or a reversed light-dark cycle.