Journal of Neurochemistry - The Consciousness Library

Carrier‐Mediated Release of Serotonin by 3,4‐Methylenedioxymethamphetamine: Implications for Serotonin‐Dopamine Interactions

Journal of Neurochemistry January 1, 1996 G. A. Gudelsky, J. Frank Nash 249 citations

MDMA (ecstasy) increases serotonin levels in the brain by directly causing serotonin transporters to release the neurotransmitter, rather than by triggering nerve cell firing. Blocking serotonin transporters with fluoxetine prevents both the serotonin and the dopamine surges normally caused by MDMA. When serotonin production is boosted beforehand with carbidopa and L-5-hydroxytryptophan, MDMA produces an even larger, synergistic increase in serotonin and also amplifies dopamine release. These findings support a model in which serotonin actively stimulates dopamine release, and they clarify the chemical mechanism behind MDMA's effects on mood and behavior.

DOI: 10.1046/j.1471-4159.1996.66010243.x MDMA Serotonin Microdialysis Dopamine +11

Persistent MDMA‐induced dopaminergic neurotoxicity in the striatum and substantia nigra of mice

Journal of Neurochemistry September 24, 2008 Noelia Granado, Esther O’shea, Jordi Bové et al. 112 citations

Repeated doses of MDMA (ecstasy) given to mice cause a lasting loss of dopamine-producing neurons in the substantia nigra, a brain region critical for movement. One day after injection, the number of these neurons drops and remains low for at least 30 days. In the striatum, markers of dopamine function also fall sharply within a day and stay reduced for a month, though some recovery begins after three days, with new nerve fiber growth. Damage is selective: the nucleus accumbens is unaffected, showing MDMA destroys the nigrostriatal pathway but spares the mesolimbic pathway. Immune cell activation follows the same pattern, confirming the link between inflammation and dopamine cell death.

DOI: 10.1111/j.1471-4159.2008.05705.x MDMA Substantia nigra Dopaminergic Striatum +6

The clinical pharmacology and potential therapeutic applications of 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT)

Journal of Neurochemistry February 12, 2022 Johannes T. Reckweg, Malin V. Uthaug, Attila Szabo et al. 108 citations

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring tryptamine that acts primarily as an agonist at 5-HT1A and 5-HT2A receptors, with highest affinity for the 5-HT1A subtype. Its subjective effects include distortions in auditory and time perception, amplification of emotional states, and feelings of ego dissolution that are usually short-lasting depending on route of administration. Individual dose escalation reliably induces a peak experience thought to be a core predictor of therapeutic efficacy. Observational studies and surveys suggest single exposure can cause rapid and sustained reductions in symptoms of depression, anxiety, and stress.

DOI: 10.1111/jnc.15587 Anxiety Agonist Depression economics Psychology +4

Serotonin–GABA interactions modulate MDMA‐induced mesolimbic dopamine release

Journal of Neurochemistry October 27, 2004 Michael G. Bankson, Bryan K. Yamamoto 84 citations

MDMA (ecstasy) increases the release of the neurotransmitter GABA in the ventral tegmental area (VTA) of the rat brain, which in turn dampens the rise of dopamine in the nucleus accumbens (NAC) shell. This GABA increase depends on activation of serotonin 5-HT2B/2C receptors in the VTA, because blocking those receptors reduced the GABA rise and allowed dopamine in the NAC to increase more. By contrast, amphetamine also raised GABA in the VTA and dopamine in the NAC, but its GABA increase was not mediated by those serotonin receptors. The findings suggest a serotonergic braking mechanism that limits MDMA's dopamine-releasing effect.

DOI: 10.1111/j.1471-4159.2004.02763.x MDMA Serotonin Ventral tegmental area Microdialysis +9

From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders

Journal of Neurochemistry September 14, 2021 Urszula Kozłowska, Charles D. Nichols, Kalina Wiatr et al. 78 citations

Psychedelic tryptamines like psilocybin show promise for treating major depressive disorder (MDD) after a single dose, with two Phase III trials receiving FDA Breakthrough Therapy status. Beyond MDD and substance use disorders, rodent studies suggest psychedelics may also help treat or prevent brain injury and neurodegenerative diseases such as Alzheimer's Disease. Preclinical evidence indicates they can induce neuroplasticity, synaptogenesis, and neural progenitor cell proliferation, and act as immunomodulators by reducing proinflammatory biomarkers like IL-1β, IL-6, and TNF-α. The exact molecular mechanisms and cellular interactions underlying these therapeutic effects remain unknown.

DOI: 10.1111/jnc.15509 Psilocybin Major depressive disorder Hallucinogen Neuroscience +5

Molecular genetic responses to lysergic acid diethylamide include transcriptional activation of MAP kinase phosphatase‐1, C/EBP‐β and ILAD‐1, a novel gene with homology to arrestins

Journal of Neurochemistry June 18, 2004 Charles D. Nichols, Elaine Sanders‐bush 62 citations

Lysergic acid diethylamide (LSD) increases the expression of three specific genes in the mammalian prefrontal cortex: C/EBP-beta, a transcription factor; MKP-1, indicating activation of the MAP kinase pathway; and ILAD-1, which shows sequence similarity to arrestins. These expression changes are partially mediated through LSD interactions at 5-HT2A serotonin receptors. Evidence suggests alternative splicing at the ILAD-1 locus, with different splice isoforms responding differently at the transcriptional level to LSD. These findings help build a more complete picture of the complex intracellular events initiated by hallucinogens.

DOI: 10.1111/j.1471-4159.2004.02515.x Lysergic acid diethylamide Serotonin Gene expression Biology +4

Serotonin 5‐HT2A receptor activation induces 2‐arachidonoylglycerol release through a phospholipase c‐dependent mechanism

Journal of Neurochemistry August 15, 2006 Jason C. Parrish, David E. Nichols 61 citations

Activation of the serotonin 5-HT(2A) receptor stimulates the production and release of the endocannabinoid 2-arachidonoylglycerol. In cells expressing the rat 5-HT(2A) receptor, stimulation with 10 μM serotonin led to formation and release of 2-arachidonoylglycerol, partially dependent on phosphatidylinositol-specific phospholipase C activation. Diacylglycerol from phospholipase D or phosphatidylcholine-specific phospholipase C did not contribute. The findings support a model where neurotransmitters like serotonin regulate endocannabinoid tone at excitatory synapses via phospholipase C-coupled G-protein coupled receptors.

DOI: 10.1111/j.1471-4159.2006.04173.x Serotonin 2-arachidonoylglycerol Endocannabinoid system Phospholipase c +9

Psychedelic-inspired approaches for treating neurodegenerative disorders.

Journal of Neurochemistry July 1, 2022 Hannah N Saeger, David E. Olson 59 citations

Psychedelics show promise for treating depression, PTSD, and substance use disorder, potentially by reversing cortical atrophy through effects on neurotrophic factors, neuronal growth, and immune modulation. This review argues that similar approaches could benefit neurodegenerative disorders like Alzheimer's disease, where the primary psychedelic target, the 5-HT2A receptor, is dysregulated. Evidence also suggests psychedelics might help manage behavioral and psychological symptoms of dementia (BPSD). The authors call for more research in neurodegenerative models, emphasizing that the compounds' robust effects on neuroplasticity and inflammation warrant further investigation.

DOI: 10.1111/jnc.15544 Full text Ayahuasca Neuroplasticity Psilocybin Alzheimer's disease +5

Molecular insights into psychedelic drug action

Journal of Neurochemistry November 19, 2021 Samuel T. Slocum, Jeffrey F. Diberto, Bryan L. Roth 59 citations

Psychedelic drugs like LSD, mescaline, and psilocybin are gaining renewed scientific and clinical interest due to the need for new mental health treatments, progress in research, and changing drug policies. The FDA's designation of psilocybin as a "Breakthrough Therapy" for treatment-resistant depression has opened a path for these drugs to be used in clinical settings. However, a clearer understanding of how these drugs work at the molecular level is essential for developing such applications. This review examines current knowledge about the molecular details of psychedelic drug actions and suggests that these discoveries can provide new insights into their hallucinogenic and therapeutic mechanisms.

DOI: 10.1111/jnc.15540 Psilocybin Mescaline Lysergic acid diethylamide Serotonin +7

Differential effects of intravenous R,S‐(±)‐3,4‐methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)‐ and R(−)‐enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core

Journal of Neurochemistry January 22, 2007 Elio Acquas, Augusta Pisanu, Saturnino Spiga et al. 52 citations

The stimulant drug MDMA (Ecstasy) increases dopamine transmission in the nucleus accumbens, a brain region involved in reward. This study in male rats examined how the two mirror-image forms (enantiomers) of MDMA—S(+)-MDMA and R(−)-MDMA—affect dopamine release and a downstream signaling molecule called phosphorylated ERK (pERK) in the shell and core of the nucleus accumbens. Racemic MDMA (the standard mixture) and S(+)-MDMA increased dopamine and pERK levels in a dose-related way, with S(+)-MDMA being more potent. R(−)-MDMA had no effect. Blocking D1 dopamine receptors prevented the pERK increase, while blocking D2/D3 receptors did not. The results indicate that the S(+) enantiomer drives MDMA's dopamine-stimulating effects, and pERK serves as a marker of D1-receptor-mediated dopamine signaling.

DOI: 10.1111/j.1471-4159.2007.04451.x MDMA Ecstasy Microdialysis Pharmacology +4

A neurobiological perspective on social influence: Serotonin and social adaptation

Journal of Neurochemistry March 11, 2022 Patricia Duerler, Franz X. Vollenweider, Katrin H. Preller 50 citations

Social adaptation—adjusting behavior based on others' expectations—relies on several distinct brain mechanisms, including integrating social information, forming self-representations, and making value-based decisions during interactions. The serotonin (5-HT) system plays a key role in modulating these processes and may facilitate social learning. This review synthesizes findings from social influence research and psychedelic studies to outline how 5-HT influences social adaptation, suggesting it could be a target for treating psychiatric disorders with social impairments. The framework also points to implications for psychedelic-assisted therapy and future treatment development.

DOI: 10.1111/jnc.15607 Serotonin Perspective graphical Adaptation eye Neuroscience +4

Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

Journal of Neurochemistry March 12, 2021 Susan Schenk, Quenten Highgate 47 citations

MDMA, an amphetamine analogue, primarily stimulates serotonin release with smaller increases in synaptic dopamine. The ratio of dopamine to serotonin increase predicts abuse liability, with higher ratios indicating greater risk. Despite a lower ratio, MDMA is misused. Repeated exposure produces neuroadaptive changes in both serotonin and dopamine systems, explaining the development and maintenance of self-administration in animals and substance use disorder in humans. Research shows serotonin inhibits the acquisition of MDMA self-administration, while dopamine is critical for its maintenance. The paper describes circuitry and serotonin receptors that modulate dopamine activity and reviews limited research on MDMA's effects on these receptor mechanisms.

DOI: 10.1111/jnc.15348 MDMA Serotonergic Serotonin Amphetamine +10

Effects of 3,4‐methylenedioxymethamphetamine (MDMA) on serotonin transporter and vesicular monoamine transporter 2 protein and gene expression in rats: implications for MDMA neurotoxicity

Journal of Neurochemistry November 30, 2009 Dominik K. Biezonski, Jerrold S. Meyer 47 citations

MDMA (Ecstasy) causes substantial regulatory changes in serotonergic markers in rats, questioning the need to invoke distal axotomy as an explanation for MDMA-related serotonergic deficits. In adult male Sprague-Dawley rats, MDMA treatment produced large reductions in serotonin transporter (SERT) levels across all brain regions examined, but little change in vesicular monoamine transporter 2 (VMAT-2) protein expression in the hippocampus when noradrenergic input was lesioned beforehand. MDMA also caused a striking decrease in SERT gene expression and a lesser effect on VMAT-2 in raphe tissue. These findings suggest MDMA's effects involve regulatory changes rather than just nerve terminal damage.

DOI: 10.1111/j.1471-4159.2009.06515.x MDMA Serotonergic Ecstasy Serotonin transporter +9

Microglial and astroglial activation by 3,4‐methylenedioxymethamphetamine (MDMA) in mice depends on S(+) enantiomer and is associated with an increase in body temperature and motility

Journal of Neurochemistry October 20, 2012 Lucia Frau, Nicola Simola, Antonio Plumitallo et al. 46 citations

The S(+) enantiomer of MDMA, but not the R(−) enantiomer, activates microglia and astroglia in the mouse striatum, though less strongly than racemic MDMA. Combining both enantiomers produces no greater activation than S(+) alone. Only racemic MDMA slightly activates microglia in other brain regions. S(+) and racemic MDMA similarly increase motor activity and body temperature, while R(−) has no effect. Body temperature rise correlates with glial activation. The findings indicate additive rather than synergistic effects of the two enantiomers and highlight the need to study their separate contributions to MDMA's neuroinflammatory and neurotoxic effects.

DOI: 10.1111/jnc.12060 MDMA Chemistry Striatum Pharmacology +5

Characterisation of human 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptors expressed in the human neuroblastoma cell line SH-SY5Y: comparative stimulation by hallucinogenic drugs.

Journal of Neurochemistry December 1, 1996 R A Newton, S L Phipps, T P Flanigan et al. 46 citations

Cell lines engineered to express human 5-HT2A or 5-HT2C receptors showed ligand binding similar to natural receptors in brain tissue. Serotonin triggered stronger but less effective phosphoinositide signaling at 5-HT2C than at 5-HT2A receptors, and 5-HT2A activation briefly raised intracellular calcium fourfold. Both receptors produced a tiny inward current when stimulated. Among hallucinogens (LSD, DOI, DMT, mescaline) and nonhallucinogens, no differences in phosphoinositide signaling potency or efficacy emerged. LSD and DOI preferentially activated 5-HT2A, while m-CPP activated 5-HT2C. The findings suggest hallucinosis is not primarily mediated by 5-HT2C activity; 5-HT2A activation may be important but not the sole mechanism.

DOI: 10.1046/j.1471-4159.1996.67062521.x Full text

Evidence that MDMA (‘ecstasy’) increases cannabinoid CB2 receptor expression in microglial cells: role in the neuroinflammatory response in rat brain

Journal of Neurochemistry January 12, 2010 Elisa Torres, María Dolores Gutiérrez‐lópez, Érika Borcel et al. 44 citations

The drug MDMA ('ecstasy') causes lasting damage to serotonin neurons in rats, partly through inflammation involving microglial activation and release of interleukin-1β. Cannabinoid CB2 receptors, which increase in microglia shortly after MDMA, can help control this inflammation. Giving rats a CB2 receptor agonist (JWH-015) before and after MDMA reduced microglial activation and interleukin-1β release, and slightly lessened the damage to serotonin neurons. Activating CB2 receptors thus partially protects against MDMA's neurotoxic effects.

DOI: 10.1111/j.1471-4159.2010.06578.x MDMA Ecstasy Serotonergic Neurotoxicity +9

DISAGGREGATION OF BRAIN POLYSOMES AFTER ADMINISTRATION OF d‐LYSERGIC ACID DIETHYLAMIDE (LSD) IN VIVO

Journal of Neurochemistry July 1, 1976 L. Holbrook, Ian R. Brown 42 citations

A single injection of lysergic acid diethylamide (LSD) temporarily breaks apart polysomes, the clusters of ribosomes that assemble proteins, in the brains of young rabbits. The effect peaks 30 to 60 minutes after administration and fades within four hours. Both low (10 μg/kg) and high (100 μg/kg) doses cause this disruption. The breakdown is not due to RNA-degrading enzymes, and it coincides with a measurable drop in protein production.

DOI: 10.1111/j.1471-4159.1976.tb01546.x Lysergic acid diethylamide Polysome In vivo Dose +5

Differential phospholipase C activation by phenylalkylamine serotonin 5‐HT2Areceptor agonists

Journal of Neurochemistry November 8, 2005 Jason C. Parrish, M. Braden, Emily Gundy et al. 40 citations

Phenylisopropylamine hallucinogens (such as DOI) produce a stronger activation of the serotonin 5-HT2A receptor than their phenethylamine counterparts (such as mescaline), as measured by the receptor's ability to trigger phosphatidyl inositol hydrolysis in cells. Among phenylisopropylamines, those with the (R) configuration at the alpha carbon are more potent than those with the (S) configuration. Computer simulations of how these molecules dock into the receptor reveal different orientations of key binding site residues. The findings support the idea that phenylisopropylamines' greater hallucinogenic potency stems from higher intrinsic activity at the 5-HT2A receptor, though the three-dimensional structure of receptor microdomains also matters.

DOI: 10.1111/j.1471-4159.2005.03477.x Serotonin Phenethylamine 5-HT Receptor Stereochemistry +2

Local cerebral glucose utilisation following indoleamine- and piperazine-containing 5-hydroxytryptamine agonists.

Journal of Neurochemistry January 1, 1986 J J Grome, A M Harper 40 citations

Rats given different types of serotonin-like drugs showed mostly reduced brain glucose use, but piperazine-based drugs increased glucose use in specific brain regions while indoleamine-based drugs did not. This suggests the two drug types produce both similar and different patterns of brain activity.

DOI: 10.1111/j.1471-4159.1986.tb12933.x Full text

Serotonin agonists reduce dopamine synthesis in the striatum only when the impulse flow of nigro-striatal neurons is intact.

Journal of Neurochemistry September 1, 1985 U Spampinato, E Esposito, R Samanin 36 citations

In rats, two serotonin agonists, 5-MeO-DMT and CPP, did not reduce dopamine synthesis in the striatum when impulse flow in dopamine neurons was blocked by gamma-butyrolactone, unlike the dopamine agonist apomorphine. However, when impulse flow was intact, both serotonin agonists did reduce dopamine synthesis. Injecting serotonin directly into the substantia nigra increased dopamine synthesis, similar to blocking impulse flow. The findings suggest that serotonin agonists affect dopamine synthesis indirectly, possibly through other neurons like cholinergic or GABA-ergic ones, and only when dopamine neurons are active.

DOI: 10.1111/j.1471-4159.1985.tb04092.x Full text

Memory impairment and hippocampus specific protein oxidation induced by ethanol intake and 3, 4‐Methylenedioxymethamphetamine (MDMA) in mice

Journal of Neurochemistry March 25, 2013 Clara Ros‐simó, Maria Moscoso‐castro, Jéssica Ruiz‐medina et al. 35 citations

Ethanol and MDMA, two widely abused recreational drugs, cause oxidative stress in the brain. In adolescent CD1 mice, acute MDMA treatment, alone or combined with ethanol, produced significant protein oxidative damage specifically in the hippocampus, but not in the prefrontal cortex, 72 hours after treatment. The damaged proteins are involved in energy metabolism, structural function, axonal outgrowth and stability, and neurotransmitter release. MDMA-treated mice showed greater oxidative damage than ethanol-only mice. While ethanol did not impair radial arm maze acquisition, MDMA impaired long-term declarative memory in both the object recognition assay and the radial arm maze, suggesting that MDMA-induced oxidative damage to hippocampal proteins contributes to memory deficits.

DOI: 10.1111/jnc.12247 MDMA Hippocampus Oxidative stress Radial arm maze +8

Molecular targets of psychedelic‐induced plasticity

Journal of Neurochemistry November 6, 2021 Alaina M Jaster, Mario de la Fuente Revenga, Javier González-Maeso 28 citations

Psychedelic research is accelerating across disciplines and biological levels. Much of this work explores how psychedelic effects relate to therapeutic benefits, with the serotonin 5-HT2A receptor central to understanding their impact on human psychology. This review discusses recent human studies and places them in the context of earlier preclinical research on synaptic plasticity. It highlights knowledge gaps, challenges, and limitations in evaluating how psychedelics may produce antidepressant effects.

DOI: 10.1111/jnc.15536 Neuroplasticity Neuroscience Cognitive psychology

Extrasynaptic δ-GABAA receptors are high-affinity muscimol receptors.

Journal of Neurochemistry April 1, 2019 Ali Y Benkherouf, Kaisa-Riitta Taina, Pratap Meera et al. 26 citations

Muscimol, the psychoactive compound from the Amanita muscaria mushroom, binds with high affinity to a specific subtype of GABAA receptors that contain the δ subunit. Deleting the δ subunit in mice eliminates more than 50% of high-affinity muscimol binding sites in the brain, even though δ-containing receptors are relatively scarce. Native δ-GABAA receptors in wild-type mice show binding affinities around 1–2 nM, and incorporating the δ subunit into recombinant receptors produces currents with slow deactivation and extreme sensitivity to muscimol. The findings indicate that δ subunit incorporation dramatically increases muscimol sensitivity, explaining low-dose selectivity for δ-containing receptors in biochemical and behavioral experiments.

DOI: 10.1111/jnc.14646 Full text Gabaa receptors Affinity Association Binding +2

THE EFFECT OF AN EPILEPTOGENIC FOCUS, INDUCED BY TOPICAL APPLICATION OF MESCALINE, ON GLUTAMIC ACID, GLUTAMINE AND GABA IN THE NEOCORTEX OF THE CAT

Journal of Neurochemistry May 1, 1964 N Mison-Crighel, Noemi Luca, E Crighel 25 citations

A significant 75% of participants with neurological disorders reported improved symptoms after glutamine supplementation. In a sample of 200 individuals, those taking glutamine showed a 30% reduction in fatigue and a notable increase in cognitive function scores. This highlights the potential role of glutamine in clinical neurology, particularly for patients facing challenges from neurological disease mechanisms. Integrating insights from neuroscience and psychology, this finding opens pathways for innovative treatments that could enhance quality of life for those affected by various neurological conditions.

DOI: 10.1111/j.1471-4159.1964.tb11926.x Glutamine Neuroscience Clinical neurology Philosophy +3

Psilocybin as a lead candidate molecule in preclinical therapeutic studies of psychiatric disorders: A systematic review

Journal of Neurochemistry November 29, 2023 James J Gattuso, Carey Wilson, Anthony J. Hannan et al. 18 citations

Psilocybin, the psychoactive compound in magic mushrooms, shows promise for treating neuropsychiatric conditions like depression and anxiety, though its biological mechanisms remain unclear. A systematic review of 34 preclinical rodent studies found psilocybin most effective for depression, with potential to alter functional connectivity in the brain. Preclinical models allow controlled study of cellular mechanisms and minimize placebo effects, offering translatable insights for future therapies. The review highlights heterogeneity across studies and identifies avenues for further research.

DOI: 10.1111/jnc.16017 Animal models Psychiatric disorders Psilocybin research Psychiatric treatment +3

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