Examining the Role of Oxytocinergic Signaling and Neuroinflammatory Markers in the Therapeutic Effects of MDMA in a Rat Model for PTSD

Abstract

MDMA-assisted psychotherapy has shown potential as an effective treatment for post-traumatic stress disorder (PTSD). Preclinical studies involving rodents have demonstrated that MDMA can facilitate the extinction of fear memories. It has been noted that MDMA impacts oxytocin neurons and pro-inflammatory cytokines. Thus, the aim of this study was to explore the role of oxytocinergic signaling and neuroinflammatory markers in the therapeutic effects of MDMA. To achieve this, male rats were subjected to a model of PTSD involving exposure to shock and situational reminders. MDMA was microinjected into the medial prefrontal cortex (mPFC) before extinction training, followed by behavioral tests assessing activity levels, anxiety, and social function. Our findings indicate that MDMA treatment facilitated fear extinction and mitigated the shock-induced increase in freezing, as well as deficits in social behavior. Shock exposure led to altered expression of the gene coding for OXT-R and neuroinflammation in the mPFC and basolateral amygdala (BLA), which were restored by MDMA treatment. Importantly, the OXT-R antagonist L-368,899 prevented MDMA's therapeutic effects on extinction and freezing behavior. In conclusion, MDMA's therapeutic effects in the PTSD model are associated with alterations in OXT-R expression and neuroinflammation, and MDMA's effects on extinction and anxiety may be mediated by oxytocinergic signaling.

Keywords: MDMA; PTSD; fear extinction; neuroinflammation; oxytocin.

Figure 1

The impact of MDMA on behavior in rats subjected to shock and reminders. In comparison to the No Shock–Veh and the Shock–MDMA groups, the Shock–Veh group exhibited (a) increased latency to enter the dark compartment on Ext1–Ext4, (b) decreased distance travelled in the OFT, (c) increased freezing levels in the OFT, and (d) decreased discrimination index in the social preference test, (e) with no difference in discrimination index in the social recognition test. Ext: extinction; OFT: open field test; SP: social preference; SR: social recognition. *, p < 0.05, **, p < 0.01, ***, p < 0.001. n = 8 for all groups.

Figure 2

The effects of MDMA on mRNA expression of OXT-R, IL-1β, IL-6, and TNF-α in the mPFC and BLA in rats subjected to shock and reminders. In comparison to the No Shock–Veh and Shock–MDMA groups, the Shock–Veh group exhibited (a) decreased OXT-R expression in the mPFC, (b) increased OXT-R expression in the BLA, (c) decreased IL-1β expression in the mPFC, (d) increased IL-1β expression in the BLA, (e) increased IL-6 expression in the mPFC, and (f) decreased IL-6 expression in the BLA, (g) with no significant differences in the expression of TNF-α in the mPFC (h) and increased TNF-α expression in the BLA in the Shock–Veh group. *, p < 0.05, **, p < 0.01, ***, p < 0.001. n = 5–8.

Figure 3

The effects of the oxytocin receptor antagonist L-368,899 on the behavior of shocked rats. (a) Extinction: The Shock–MDMA group exhibited decreased latency to enter the dark compartment compared to the Shock–Veh group on Ext1–Ext4 and compared to the Shock–L-368,899 group on Ext1–Ext2. Importantly, the Shock–L-368,899–MDMA group exhibited increased latency to enter the dark compartment on Ext 4 compared to the Shock–MDMA group. (b) In the OFT, in comparison to the Shock–Veh group, the Shock–MDMA group showed increased distance travelled (c) and decreased freezing. Importantly, the Shock–MDMA group showed decreased freezing compared to the Shock–L-368,899 and Shock–L-368,899–MDMA groups. (d) In social preference, the Shock–MDMA group exhibited increased social preference compared to the Shock–Veh group. (e) In social recognition, the Shock–MDMA group showed increased discrimination compared to the Shock–L-368,899 group. Ext: extinction; OFT: an open field test. *, p < 0.05, **, p < 0.01, n = 7.

Scheme 1

A diagram illustrating the experimental design.