McGregor IS, Gurtman CG, Morley KC, Clemens KJ, Blokland A, Li KM, Cornish JL, Hunt GE (2003) Increased anxiety and "depressive" symptoms months after MDMA ("ecstasy") in rats: drug-induced hyperthermia does not predict long-term outcomes. Psychopharmacology 17: 17
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MDMA effects on anxiety, object memory and forced swim performance after MDMA given at low versus high ambient temperature (16 deg. C versus 28 deg. C) were assessed in rats, with all subjects given 4 hourly doses 5 mg/kg MDMA for two consecutive days. Non-social anxiety was measured 8 to 10 weeks post-drug via emergence test (measure time spent in "hide box" versus in the more anxiety-provoking open space). Two days after emergence test, social anxiety was measured through observing number and type of social interactions between the subject and a novel rat. 16 to 18 weeks post-drug, forced swim test performance (used as a behavioral test of antidepressant efficacy in rats) was assessed in half the rats in all conditions. The forced swim test measures time spent swimming versus time spent immobile and counts escape attempts. Memory was assessed in half the rats in all conditions 10 to 12 weeks post-drug via object-recognition test (longer timer spent with novel object indicative of functioning object memory). Sixteen to 18 weeks post-drug, and 4 days post-forced swim, neurochemical analyses were performed on olfactory bulb, prefrontal cortex, striatum, hippocampus and amygdala from the 32 rats given the forced swim test. Levels of serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid (5HIAA), and dopamine (DA) were performed via HLPC, and serotonin and dopamine transporter levels were measured via binding with radioactively labeled drugs. Administering MDMA at 16 deg. C produced hypothermia, while administering MDMA at 28 deg C produced hyperthermia, yet MDMA treated rats in either low or high ambient temperature were more active than rats receiving vehicle. On day 2, rats receiving vehicle at 28 deg. C were less active than vehicle-treated rats kept at 16 deg C, but MDMA-treated rats showed differences in activity associated with ambient temperature. Rats given MDMA in both low and high ambient temperatures had fewer social interactions and spent less time interacting with the novel rat than did rats receiving vehicle at either ambient temperature. Likewise, rats given MDMA at 16 or 28 deg C took longer to emerge from the "hide box" and spent less time in the open field than rats in either vehicle-treated condition. MDMA pre-treatment at 16 deg C decreased novel object preference, (a sign of object memory), and rats given MDMA at 28 deg C showed even less of a novel object preference than rats given MDMA at 16 deg C, though the two groups did not differ in novel object inspection time. Rats in all conditions performed similarly on the first two days of forced swim challenge, but on day 3, MDMA-treated rats in both low and high ambient temperature conditions spent more time immobile and less time climbing than vehicle-treated rats. Pre-frontal, striatal, hippocampal and amygdalar levels of 5-HT and 5-HIAA were lower in both groups of MDMA treated rats than in controls. A temperature affect for striatal 5-HT was not confirmed after further analysis. Administering MDMA at higher ambient temperature reduced hippocampal and amygdalar 5-HIAA to levels below those seen in rats given MDMA at lower ambient temperatures. MDMA also lowered levels of striatal dopamine, even when administered at low ambient temperature. In general, the researchers found that MDMA pretreatment increased anxiety and "depression-like" effects, reduced object memory, and reduced brain serotonin and dopamine regardless of whether MDMA was administered in a high or low ambient temperature. However administering MDMA at 28 (versus 16) deg C further reduced hippocampal 5-HIAA levels and performance on the object recognition. Hence it is possible that long-term effects of MDMA dose regimen on anxiety, memory and neurochemistry are separable in rats. This is the first report of long-term effects on the forced-swim test in MDMA-treated rats, and also one of the first reports of dopamine toxicity in rats. It is important to note that studies in non-human primates and rodents usually fail to find changes in cognitive function after MDMA-pretreatment (see Baggott et al. 2001) with cognitive impairment most often seen in developmental studies, (e.g. Broening et al. 2001; Morley-Fletcher et al. 2002; Williams et al. 2003). It is more common to find an association between drug use in general and psychological problems such as anxiety or depression in humans (for example Lieb et al. 2002; Morgan et al. 2002; Thomasius et al. 2003). Nevertheless, findings may be some of the first to examine the behavioral effects of hyperthermia in rodents, and it appears that impairment in object memory, but not anxiety or "depression," are attenuated by reducing hyperthermia through lower ambient temperature.

 
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