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Hyperthermia Severely Affects the Vascular Effects of MDMA and Metabolites in the Human Internal Mammary Artery In Vitro

January 13, 2017 / MDMA, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a recreational drug used worldwide for its distinctive psychotropic effects. Although important cardiovascular effects, such as increased blood pressure and heart rate, have also been described, the vascular effects of MDMA and metabolites and their correlation with hyperthermia (major side effect of MDMA) are not yet fully understood and have not been previously reported. This study aimed at evaluating the effects of MDMA and its main catechol metabolites, alpha-methyldopamine (α-MeDA), N-methyl-alpha-methyldopamine (N-Me-α-MeDA), 5-(glutathion-S-yl)-alpha-methyldopamine [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][5-(GSH)-α-MeDA] and 5-(glutathion-S-yl)-N-methyl-alpha-methyldopamine [5-(GSH)-N-Me-α-MeDA], on the 5-HT-dependent vasoactivity in normothermia (37 °C) and hyperthermia (40 °C) of the human internal mammary artery (IMA) in vitro. The results showed the ability of MDMA, α-MeDA and N-Me-α-MeDA to exert vasoconstriction of the IMA which was considerably higher in hyperthermic conditions (about fourfold for MDMA and α-MeDA and twofold for N-Me-α-MeDA). The results also showed that all the compounds may influence the 5-HT-mediated concentration-dependent response of IMA, as MDMA, α-MeDA and N-Me-α-MeDA behaved as partial agonists and 5-(GSH)-α-MeDA and 5-(GSH)-N-Me-α-MeDA as antagonists. In conclusion, MDMA abuse may imply a higher cardiovascular risk associated both to MDMA and its metabolites that might be relevant in patients with underlying cardiovascular diseases, particularly in hyperthermia.

Fonseca, D. A., Guerra, A. F., Carvalho, F., Fernandes, E., Ferreira, L. M., Branco, P. S., … & Cotrim, M. D. (2017). Hyperthermia Severely Affects the Vascular Effects of MDMA and Metabolites in the Human Internal Mammary Artery In Vitro. Cardiovascular Toxicology, 1-12. 10.1007/s12012-017-9398-y
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Possible role of biochemiluminescent photons for lysergic acid diethylamide (LSD)-induced phosphenes and visual hallucinations

January 1, 2017 / LSD, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Today, there is an increased interest in research on lysergic acid diethylamide (LSD) because it may offer new opportunities in psychotherapy under controlled settings. The more we know about how a drug works in the brain, the more opportunities there will be to exploit it in medicine. Here, based on our previously published papers and investigations, we suggest that LSD-induced visual hallucinations/phosphenes may be due to the transient enhancement of bioluminescent photons in the early retinotopic visual system in blind as well as healthy people.
Kapócs, G., Scholkmann, F., Salari, V., Császár, N., Szőke, H., & Bókkon, I. (2017). Possible role of biochemiluminescent photons for lysergic acid diethylamide (LSD)-induced phosphenes and visual hallucinations. Reviews in the Neurosciences, 28(1), 77-86. 10.1515/revneuro-2016-0047
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Ketamine accelerates fear extinction via mTORC1 signaling

December 30, 2016 / Anxiety Disorders / PTSD, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Impaired fear extinction contributes to the persistence of post-traumatic stress disorder (PTSD), and can be utilized for the study of novel therapeutic agents. Glutamate plays an important role in the formation of traumatic memories, and in the pathophysiology and treatment of PTSD, highlighting several possible drug targets. Recent clinical studies demonstrate that infusion of ketamine, a glutamate NMDA receptor antagonist, rapidly and significantly reduces symptom severity in PTSD patients. In the present study, we examine the mechanisms underlying the actions of ketamine in a rodent model of fear conditioning, extinction, and renewal. Rats received ketamine or saline 24 h after fear conditioning and were then subjected to extinction-training on each of the following three days. Ketamine administration enhanced extinction on the second day of training (i.e., reduced freezing behavior to cue) and produced a long-lasting reduction in freezing on exposure to cue plus context 8 days later. Additionally, ketamine and extinction exposure increased levels of mTORC1 in the medial prefrontal cortex (mPFC), a region involved in the acquisition and retrieval of extinction, and infusion of the selective mTORC1 inhibitor rapamycin into the mPFC blocked the effects of ketamine on extinction. Ketamine plus extinction also increased cFos in the mPFC and administration of a glutamate-AMPA receptor antagonist blocked the effects of ketamine. These results support the hypothesis that ketamine produces long-lasting mTORC1/protein synthesis and activity dependent effects on neuronal circuits that enhance the expression of extinction and could represent a novel approach for the treatment of PTSD.

Girgenti, M. J., Ghosal, S., LoPresto, D., Taylor, J. R., & Duman, R. S. (2017). Ketamine accelerates fear extinction via mTORC1 signaling. Neurobiology of Disease, 100, 1-8. 10.1016/j.nbd.2016.12.026
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Harmine stimulates proliferation of human neural progenitors

December 6, 2016 / Ayahuasca, Depressive Disorders, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Harmine is the β-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive) derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A), which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY), and an irreversible selective inhibitor of monoamine oxidase (MAO) but not DYRK1A (pargyline). INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation in vitro and antidepressant effects in vivo.

Dakic, V., de Moraes Maciel, R., Drummond, H., Nascimento, J. M., Trindade, P., & Rehen, S. K. (2016). Harmine stimulates proliferation of human neural progenitors. PeerJ, 4, e2727. 10.7717/peerj.2727
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Effects of the Natural β-Carboline Alkaloid Harmine, a Main Constituent of Ayahuasca, in Memory and in the Hippocampus: A Systematic Literature Review of Preclinical Studies

December 5, 2016 / Ayahuasca, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

Harmine is a natural β-carboline alkaloid found in several botanical species, such as the Banisteriopsis caapi vine used in the preparation of the hallucinogenic beverage ayahuasca and the seeds of Syrian rue (Peganum harmala). Preclinical studies suggest that harmine may have neuroprotective and cognitive-enhancing effects, and retrospective/observational investigations of the mental health of long-term ayahuasca users suggest that prolonged use of this harmine-rich hallucinogen is associated with better neuropsychological functioning. Thus, in order to better investigate these possibilities, we performed a systematic literature review of preclinical studies analyzing the effects of harmine on hippocampal neurons and in memory-related behavioral tasks in animal models. We found two studies involving hippocampal cell cultures and nine studies using animal models. Harmine administration was associated with neuroprotective effects such as reduced excitotoxicity, inflammation, and oxidative stress, and increased brain-derived neurotrophic factor (BDNF) levels. Harmine also improved memory/learning in several animal models. These effects seem be mediated by monoamine oxidase or acetylcholinesterase inhibition, upregulation of glutamate transporters, decreases in reactive oxygen species, increases in neurotrophic factors, and anti-inflammatory effects. The neuroprotective and cognitive-enhancing effects of harmine should be further investigated in both preclinical and human studies.

dos Santos, R. G., & Hallak, J. E. (2017). Effects of the Natural β-Carboline Alkaloid Harmine, a Main Constituent of Ayahuasca, in Memory and in the Hippocampus: A Systematic Literature Review of Preclinical Studies. Journal of psychoactive drugs, 49(1), 1-10. 10.1080/02791072.2016.1260189
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Discriminative Stimulus Properties of MDMA: The Role of Serotonin and Dopamine

December 1, 2016 / MDMA, Neuroscience, Papers, Publications / By /

Abstract

Rationale: ±3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) produces unique and complex subjective effects which distinguish it from other recreationally used drugs. An understanding of the neurochemical mechanisms that underlie these effects is important in order to assess the potential for MDMA abuse and to inform researchers exploring of the drug’s therapeutic potential. The present thesis investigated the neurochemical mechanisms underlying the subjective effects of MDMA using drug discrimination procedures in laboratory animals. Despite evidence that training dose can markedly impact the results of drug discrimination studies, the impact of training dose on the discriminative stimulus properties of MDMA has been largely overlooked. The broad aims of these experiments were 1) to test the ability of two different doses of MDMA to support drug discrimination learning, and 2) to determine the role of serotonin (5-HT) and dopamine (DA) neurotransmitter systems in producing the discriminative stimulus effects of each MDMA training dose. 

Methods: Groups of rats were trained to discriminate MDMA (1.5 or 3.0 mg/kg) from saline or to discriminate MDMA (1.5 or 3.0 mg/kg) from amphetamine (0.5 mg/kg) and saline, using two- or three-lever, food-reinforced drug discrimination procedures. The first experiments determined the impact of training dose on the acquisition of the MDMA discrimination. Reliability of the discrimination was assessed by measuring the impact of changes in acquisition criteria. Once the discrimination had been acquired, generalisation tests were carried out in two-lever experiments with the SSRIs, fluoxetine and clomipramine, the 5-HT2 agonists, mCPP and DOI, and the 5-HT1 agonists, 8-OH-DPAT and RU-24969, to investigate the role of 5-HT in the discriminative stimulus effects of 1.5 mg/kg vs 3.0 mg/kg MDMA. Next, the role of DA was investigated in further generalisation test sessions with the DA releasing stimulant, AMPH, the non-selective D1/D2 agonist, apomorphine, the D1 agonist, SKF38393, and the D2 agonist, quinpirole. Finally, experiments were carried out in which the ability of the 5-HT2A antagonist, ketanserin, the 5-HT1B/1D antagonist, GR-127935, the 5-HT1A antagonist, WAY100635, the D1 antagonist, SCH23390, and the D2 antagonist, eticlopride, to attenuate the discriminative stimulus effects of 1.5 mg/kg vs 3.0 mg/kg MDMA was assessed.

Results: A higher training dose of MDMA was associated with a more rapid acquisition of drug discrimination in both the two- and three-lever tasks, and significant differences were observed with respect to the ability of each dose of MDMA to maintain consistently accurate discrimination across both tasks. All of the serotonin agonists that were tested generalised to the discriminative stimulus effects of 1.5 mg/kg MDMA in a two-lever discrimination task. In contrast, only agonists for 5-HT1A or 5-HT2A receptors generalised to the discriminative stimulus effects of 3.0 mg/kg MDMA. Non-selective dopamine agonists generalised to the discriminative stimulus effects of 3.0 mg/kg but not 1.5 mg/kg MDMA, whereas selective D1 and D2 agonists failed to generalise to the discriminative stimulus effects of either training dose. None of the DA or 5-HT antagonists tested had a marked impact of the discrimination of 1.5 mg/kg MDMA whereas administration of a D2 antagonist produced a small but significant attenuation on the discriminative stimulus effects of 3.0 mg/kg MDMA.

Conclusions: The results of the present thesis suggest that the discriminative stimulus effects of MDMA may change both quantitatively and qualitatively as a function of dose. The subjective effects produced by lower doses appear to be mediated primarily via serotonergic mechanisms, whereas higher doses may involve the additional recruitment of dopaminergic mechanisms. These findings have implications for our understanding of MDMA in terms of the drug’s potential for dependence and abuse.

Webster, J. (2016). Discriminative Stimulus Properties of MDMA: The Role of Serotonin and Dopamine. 10063/5622

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Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

December 1, 2016 / MDMA, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate.

Ma, K. H., Liu, T. T., Weng, S. J., Chen, C. F. F., Huang, Y. S., Chueh, S. H., … & Huang, W. S. (2016). Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT. Scientific Reports, 6. 10.1038/srep38695
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Ecstasy research: will increasing observational data aid our understanding of MDMA?

December 1, 2016 / MDMA, Neuroscience, Papers, Psychology, Publications / By /

Abstract

Over the past three decades, millions of dollars have been spent on thousands of studies attempting to better understand the neurotoxic effects of MDMA. All of the clinical studies have recruited people who use ecstasy—a drug that does often but not always contain MDMA. Although most researchers agree that MDMA is the cause of neurocognitive deficits in ecstasy users, this consensus is based on a large body of literature with many limitations.

Amoroso, T. (2016). Ecstasy research: will increasing observational data aid our understanding of MDMA?. The Lancet Psychiatry, 3(12), 1101-1102. 10.1016/S2215-0366(16)30345-5
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Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats

November 30, 2016 / Neuroscience, Papers / By / , , , ,

Abstract

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, ‘foxy’) is one of the most popular tryptamine hallucinogens in the illicit drug market. It produces serious adverse effects, but its pharmacological profile is not well recognized. In vitro data have shown that 5-MeO-DIPT acts as a potent serotonin transporter (SERT) inhibitor and displays high affinity at serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors. In this study, using microdialysis in freely moving rats, we examined the effect of 5-MeO-DIPT on dopamine (DA), serotonin (5-HT), and glutamate release in the rat striatum, nucleus accumbens, and frontal cortex. In search of a possible neurotoxic effect of 5-MeO-DIPT, we measured DA and 5-HT tissue content in the above rat brain regions and also determined the oxidative DNA damage with the comet assay. Moreover, we tested drug-elicited head-twitch response and a forepaw treading induced by 8-OH-DPAT. 5-MeO-DIPT at doses of 5, 10, and 20 mg/kg increased extracellular DA, 5-HT, and glutamate level but the differences in the potency were found between brain regions. 5-MeO-DIPT increased 5-HT and decreased 5-HIAA tissue content which seems to result from SERT inhibition. On the other hand, a decrease in DA, DOPAC, and HVA tissue contents suggests possible adaptive changes in DA turnover or damage of DA terminals by 5-MeO-DIPT. DNA single and double-strand breaks persisted up to 60 days after the treatment, indicating marked neurotoxicity of 5-MeO-DIPT. The induction of head-twitch response and potentiation of forepaw treading induced by 8-OH-DPAT indicate that hallucinogenic activity seems to be mediated through the stimulation of 5-HT2A and 5-HT1A receptors by 5-MeO-DIPT.
Noworyta-Sokołowska, K., Kamińska, K., Kreiner, G., Rogóż, Z., & Gołembiowska, K. (2016). Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats. Neurotoxicity research, 30(4), 606-619. 10.1007/s12640-016-9654-0
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