MDMA and the Brain: A Short Review on the Role of Neurotransmitters in the Cause of Neurotoxicity

Mustafa, Nor Suliana; Bakar, Nor Hidayah Abu; Mohamad, Nasir; Adnan, Liyana Hazwani Mohd; Fauzi, Nurul Farah Aina Md; Thoarlim, Abdulsoma; Omar, Syed Hadzrullathfi Syed; Hamzah, Mohd Shafiee; Yusoff, Zawawi; Jufri, Mahdi; Ahmad, Rashid

doi:10.32598/bcn.9.10.485

Cited by 12 publications

(13 citation statements)

References 31 publications

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“…However, it is unclear whether the cause is associated with SERT neuron recovery or other causes. Future longitudinal studies are recommended to investigate the serotonin level in blood or cerebrospinal fluid [55] or behavior tests.…”

Section: Discussionmentioning

confidence: 99%

Amitriptyline Accelerates SERT Binding Recovery in a Rat 3,4-Methylenedioxymethamphetamine (MDMA) Model: In Vivo 4-[18F]-ADAM PET Imaging

Tsai

Chiu

Kuo

et al. 2022

IJMS

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Numerous studies have confirmed that 3,4-Methylenedioxymethamphetamine (MDMA) produces long-lasting changes to the density of the serotonin reuptake transporter (SERT). Amitriptyline (AMI) has been shown to exert neuroprotective properties in neuropathologic injury. Here, we used a SERT-specific radionuclide, 4-[18F]-ADAM, to assess the longitudinal alterations in SERT binding and evaluate the synergistic neuroprotective effect of AMI in a rat MDMA model. In response to MDMA treatment regimens, SERT binding was significantly reduced in rat brains. Region-specific recovery rate (normalized to baseline) in the MDMA group at day 14 was 71.29% ± 3.21%, and progressively increased to 90.90% ± 7.63% at day 35. AMI dramatically increased SERT binding in all brain regions, enhancing average ~18% recovery rate at day 14 when compared with the MDMA group. The immunochemical staining revealed that AMI markedly increased the serotonergic fiber density in the cingulate and thalamus after MDMA-induction, and confirmed the PET findings. Using in vivo longitudinal PET imaging, we demonstrated that SERT recovery was positively correlated with the duration of MDMA abstinence, implying that lower SERT densities in MDMA-induced rats reflected neurotoxic effects and were (varied) region-specific and reversible. AMI globally accelerated the recovery rate of SERT binding and increased SERT fiber density with possible neuroprotective effects.

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Section: Discussionmentioning

confidence: 99%

Amitriptyline Accelerates SERT Binding Recovery in a Rat 3,4-Methylenedioxymethamphetamine (MDMA) Model: In Vivo 4-[18F]-ADAM PET Imaging

Tsai

Chiu

Kuo

et al. 2022

IJMS

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“…The results also indicated that the SERT self-recovery in rat brain after MDMA-induction was time-dependent and returned to 70.7% ± 3.96% of baseline values at day 28. The regions of low or mid-self-recovery rate were the most affected region by MDMA [4,45].…”

Section: Discussionmentioning

confidence: 99%

“…However, it is unclear whether the cause is associated with the SERT neurons recovery or other causes. Future longitudinal studies are recommended to investigate the serotonin level in blood or cerebrospinal uid [45] or behavior tests.…”

Section: Discussionmentioning

confidence: 99%

Amitriptyline Accelerates SERT Binding Recovery Rate in MDMA-Induced Rat Model: In Vivo 4-[18F]-ADAM PET Imaging

Yeh

Chiu

Kuo

et al. 2021

Preprint

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Background Numerous studies have confirmed that 3, 4-Methylenedioxymethamphetamine (MDMA) produces long-lasting changes to the serotonergic system and decreases the density of the serotonin reuptake transporter (SERT). However, amitriptyline (AMI) is a potent neuroprotector that can cause devastating neuropathologic injury. Use of 4-[18F]-ADAM, a SERT-specific radionuclide as a molecular imaging agent, facilitates longitudinal, non-invasive assessment of SERT activity/expression post-MDMA. We used 4-[18F]-ADAM PET imaging to access the longitudinal alteration of SERT binding and evaluate the synergistic neuroprotective effect of MDMA and SERT inhibition by AMI in rat model.Materials and Methods The adult male Sprague–Dawley (SD) rats are grouped into four according to drug administration (Group 1: saline, Group 2: MDMA 10mg/kg i.p., Group 3: MDMA 10mg/kg i.p. with AMI 5 mg/kg i.p., Group 4: AMI 5 mg/kg i.p.). All drugs were administrated twice daily for 4 successive days (Day 1 to Day 4). Post-drug 4-[18F]-ADAM PET scans were performed on day 14, day 21 and day 28 to measure the SERT occupancy/recovery. After the last PET imaging, SERT-positive cells were measured quantitatively using immunochemical staining.Results In response to MDMA treatment regimens, SERT binding was significantly reduced in rat brain. Recovery rate (normalized to baseline) in the MDMA group, at day 14 was 64.34% ± 2.05%, progressively increased to 70.70% ± 3.96% at day 28. Recovery rate in the MDMA group varies based on region-specific. AMI dramatically increased SERT binding in all brain regions, enhancing average ~24% recovery rate at day 14 when compared with the MDMA group (MDMA 64.34% ± 2.05% vs. MDMA+ AMI 87.76% ± 2.98%), reaching 84.38% ± 2.05% at day 28. The immunochemical staining revealed that MDMA treatment reduced SERT immunoactivity densities in all brain regions, whereas AMI markedly increased the serotonergic fiber density after MDMA-induction that confirmed the PET findings.Conclusions Using in vivo longitudinal PET imaging, we demonstrated that SERT recovery was positively correlated with the duration of MDMA abstinence, implying the lower SERT densities in MDMA-induced rats reflected neurotoxic effects, varied region-specific, and reversible. AMI globally accelerated the recovery rate of SERT binding and increased SERT fiber density with possible neuroprotective effects.

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“…Unfortunately, MDMA rebranded as “Ecstasy,” became popular as a recreational drug in the club scene of the 1980's and by 1985 had been designated as a Schedule I compound with high abuse potential without any known medical use ( 14 ). As of 2004, a reported 11 million people in the United States had experimented with MDMA at some point in their lives ( 69 ). By 2011, the number of Americans reporting experimentation with MDMA increased to 14.5 million ( 10 ).…”

Section: Mdmamentioning

confidence: 99%

A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy

Sottile

Vida

2022

Front. Psychiatry

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Post-traumatic stress disorder (PTSD) is a devastating psychiatric disorder afflicting millions of people around the world. Characterized by severe anxiety, intrusive thoughts, pervasive nightmares, an assortment of somatic symptoms, associations with severe long-term health problems, and an elevated risk of suicide, as much as 40–70% of patients suffer from refractory disease. 3,4-Methylenedioxy-methamphetamine (MDMA), like classic psychedelics such as psilocybin, have been used to enhance the efficacy of psychotherapy almost since their discovery, but due to their perceived potential for abuse and inclusion on USFDA (United States Food and Drug Administration) schedule 1, research into the mechanism by which they produce improvements in PTSD symptomology has been limited. Nevertheless, several compelling rationales have been explored, with the pro-social effects of MDMA thought to enhance therapeutic alliance and thus facilitate therapist-assisted trauma processing. This may be insufficient to fully explain the efficacy of MDMA in the treatment of psychiatric illness. Molecular mechanisms such as the MDMA mediated increase of brain-derived neurotrophic factor (BDNF) availability in the fear memory learning pathways combined with MDMA's pro-social effects may provide a more nuanced explanation for the therapeutic actions of MDMA.

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MDMA and the Brain: A Short Review on the Role of Neurotransmitters in the Cause of Neurotoxicity

Cited by 12 publications

References 31 publications

Amitriptyline Accelerates SERT Binding Recovery in a Rat 3,4-Methylenedioxymethamphetamine (MDMA) Model: In Vivo 4-[18F]-ADAM PET Imaging

Amitriptyline Accelerates SERT Binding Recovery in a Rat 3,4-Methylenedioxymethamphetamine (MDMA) Model: In Vivo 4-[18F]-ADAM PET Imaging

Amitriptyline Accelerates SERT Binding Recovery Rate in MDMA-Induced Rat Model: In Vivo 4-[18F]-ADAM PET Imaging

A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy

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