The present study examined the effects of chronic stress and subsequent MDMA treatment on gene transcription in the rat hippocampus. The key findings are the following: (1) MDMA alone increases the expression of genes in several gene ontology categories, including protein folding and unfolded protein binding, (2) MDMA upregulates the genes for several heat shock proteins, (3) MDMA negatively affects the expression of genes related to axon sheaths and tissue remodeling in stressed rats, (4) chronic stress alters gene expression within the circadian rhythm pathway, and this effect is absent in rats treated subsequently with MDMA, and (5) the number of stress-responsive genes is lessened by MDMA treatment.
The genetic responses to repeated stress included over two hundred genes that were either up- or downregulated. The reduction in the number of these genes by consecutive MDMA administration implies the potential for a drug-induced amelioration of the stress response. Among the genetic adaptations to stress, transcripts in the KEGG pathway for circadian rhythm were downregulated in response to chronic, unpredictable stress. One prominent clinical characteristic of stress disorder, particularly PTSD, in humans is abnormalities in the circadian rhythms of several physiological responses such as cortisol, blood pressure, and sleep [38
]. In the present study, the suppressive effect of stress on gene transcription within the KEGG pathway for circadian rhythm was not manifest in stressed rats treated subsequently with MDMA. There is evidence that MDMA may affect sleep cycles [41
], implying that it could have the potential to reverse or reduce stress-induced sleep disturbance. MDMA has been shown to be beneficial in treating the symptoms of PTSD [2
]. While it is not yet known whether this clinical response is related to a restoration of circadian rhythms, the anxiolytic drug prazosin can reduce stress-induced sleep disturbances [42
], providing a rationale for non-antidepressant restoration of the circadian rhythm. In general, MDMA is under discussion for the treatment of anxiety disorders [43
]. This drug significantly altered the pattern of stress-induced gene induction and suppression. It remains to be determined whether the ability of MDMA to alter the genetic response to stress is of significance in the clinical response of PTSD patients to MDMA.
One component of the psychopharmacology of MDMA is that human abusers of the drug report enhanced sensory perceptions. In the present study, MDMA administration to chronically stressed rats exhibited an upregulation of related gene categories associated with sensory perception when compared to stressed rats not given MDMA. These findings suggest that MDMA may exert persistent effects on sensory perception that outlast the acute effects of the drug on neurotransmitter release.
Exposure to prior chronic stress impacted the genetic responses to MDMA. Notably, gene categories of tissue regeneration, axon ensheathment, myelin sheath, and cytokine-cytokine receptor interaction were significantly downregulated following MDMA treatment to rats exposed to chronic stress when compared to unstressed rats given MDMA or to stressed rats not given MDMA. Hence, chronic stress appears to augment the deleterious effects of MDMA on the neuronal structure. Callahan et al. [44
] have concluded that MDMA produces structural damage to axonal transport mechanisms in multiple brain regions. The susceptibility to that damage or the intensity of the damage may be enhanced consecutively to stressing experiences. Although the identity of neurons affected by the combination of stress and MDMA is unknown, it is of interest that chronic, unpredictable stress augments the persistent deficits in serotonergic neurons produced by MDMA [30
The gene expression changes observed in this study are consistent with the existing literature. The MDMA-induced alterations in gene ontology categories are consistent with transcriptional events associated with drug-induced neuronal damage. Genes related to protein folding and unfolded protein binding were upregulated 24 hours following MDMA treatment. Gene transcripts for heat shock proteins were notably upregulated following MDMA administration. This finding is consistent with previous reports that MDMA increases heat shock protein mRNAs in the mouse striatum [16
] and heat shock protein levels in several brain regions [45
]. The effects of MDMA on heat shock protein gene expression are viewed as a response to cellular stress that may accompany MDMA-induced hyperthermia and/or oxidative stress.
Treatment with MDMA also increased gene expression in GO categories related to cell signaling (e.g., neuropeptide signaling pathway and calmodulin-dependent protein kinase activity). This finding is in accord with the reports of Thiriet et al. [48
] and Salzmann et al. [16
] in which MDMA was shown to increase transcription for several proteins belonging to signal transduction pathways. These changes can be viewed, most likely, as a consequence of 5-HT receptor activity subsequent to the MDMA-induced increase in extracellular 5-HT in the hippocampus [49
The use of psychedelic drugs to treat emotional disorders has been controversial due to the intrinsic neurotoxicity of these agents [1
]. The evaluation of such therapies largely depends, in the short term, on cognitive and psychological evaluations that may be particularly susceptible to placebo effects or interpretive differences. The supplementation of clinical studies with ex vivo molecular assessments may aid in providing mechanistic insights. The present investigation of hippocampal gene expression profiles has elucidated the potential of MDMA to ameliorate the genetic response to chronic unpredictable stress and to reverse stress-induced sleep disorders. However, it has also found evidence that the toxicity of MDMA on nerve sheaths may be increased in individuals previously exposed to stressful experiences.