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Science

ISSN 0036-8075; 1095-9203;

57 papers in the library · 13,974 citations · publishing 1954-2026

Papers

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

Science August 19, 2010 Nanxin Li, Boyoung Lee, Rongjian Liu et al. 2,875 citations

Ketamine, a drug that blocks NMDA receptors, rapidly activates the mTOR pathway in the prefrontal cortex of rats, increasing synaptic signaling proteins and the number and function of new spine synapses. Blocking mTOR signaling prevented ketamine from inducing synaptogenesis and behavioral antidepressant-like responses in depression models. These effects reverse the synaptic deficits caused by stress and may explain ketamine's fast antidepressant action in treatment-resistant depressed patients, which contrasts with the weeks or months needed for standard medications.

DOI: 10.1126/science.1190287 Full text Ketamine Antidepressant Prefrontal cortex Pi3k/akt/mtor pathway +11

Synaptic Dysfunction in Depression: Potential Therapeutic Targets

Science October 4, 2012 1,613 citations

Depression involves shrinkage of brain regions that regulate mood and cognition, such as the prefrontal cortex and hippocampus, along with reduced neuronal synapses in those areas. Typical antidepressants can reverse some of these deficits but work slowly and have limited effectiveness. Ketamine, a drug that blocks N-methyl-D-aspartate receptors, rapidly (within hours) improves symptoms in patients who do not respond to standard antidepressants. In basic studies, ketamine quickly promotes the formation of new synapses and reverses the synaptic damage caused by chronic stress. These findings suggest that maintaining healthy mood circuit connections is central to depression and its treatment, forming the basis of a synaptogenic hypothesis.

DOI: 10.1126/science.1222939

NMDA Antagonist Neurotoxicity: Mechanism and Prevention

Science December 6, 1991 850 citations

Drugs that block NMDA glutamate receptors, such as PCP and ketamine, protect the brain from damage in conditions like stroke, but they also cause psychotic-like symptoms in humans and damage neurons in the rat cerebral cortex. This damage can be prevented by certain anticholinergic drugs or by diazepam and barbiturates, which act on GABA receptors and also suppress the psychotic symptoms caused by ketamine. These findings suggest it may be possible to block the unwanted side effects of NMDA antagonists, making them more useful as neuroprotective treatments.

DOI: 10.1126/science.1835799

Structural Features for Functional Selectivity at Serotonin Receptors

Science March 21, 2013 Daniel Wacker, Chong Wang, Vsevolod Katritch et al. 689 citations

Serotonin receptors are targets for drugs treating depression, obesity, and migraine headaches. Crystal structures of two serotonin receptor subtypes bound to antimigraine medications or a precursor of LSD reveal how subtle differences in ligand binding cause substantial differences in receptor signaling and biological responses. The structures show that the same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which receptor it binds.

DOI: 10.1126/science.1232808 Lysergic acid diethylamide Serotonin Functional selectivity G protein-coupled receptor +7

Physiological Effects of Transcendental Meditation

Science March 27, 1970 Robert K. Wallace 659 citations

During the practice of transcendental meditation, oxygen consumption and heart rate decreased, skin resistance increased, and electroencephalogram patterns showed specific frequency changes. These physiological shifts distinguish the meditative state from ordinary waking consciousness and suggest potential practical applications.

DOI: 10.1126/science.167.3926.1751 Transcendental meditation Transcendental number Consciousness Heart rate +7

Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase

Science December 6, 2007 M. Margarita Behrens, Sameh S. Ali, Diep N. Dao et al. 590 citations

Repeated exposure to the anesthetic ketamine, which blocks NMDA receptors, causes a lasting increase in superoxide in the brain by activating NADPH oxidase in neurons. This increase in superoxide leads to dysfunction of fast-spiking inhibitory interneurons in the prefrontal cortex, specifically reducing their expression of parvalbumin and the GABA-producing enzyme GAD67—changes that mirror those seen in schizophrenia. Lowering superoxide production prevented these effects on inhibitory interneurons. The findings suggest that targeting NADPH oxidase could offer a new approach for treating ketamine-induced psychosis.

DOI: 10.1126/science.1148045 Ketamine Nadph oxidase Parvalbumin Inhibitory postsynaptic potential +10

The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator

Science February 13, 2009 Dominique Fontanilla, Molly Johannessen, Abdol R. Hajipour et al. 528 citations

The sigma-1 receptor, once mistaken for an opioid receptor, binds many synthetic compounds but not opioid peptides and is now considered an orphan receptor. Its pharmacophore includes an alkylamine core also found in the endogenous compound N,N-dimethyltryptamine (DMT). DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion channels in both native cardiac myocytes and heterologous cells expressing sigma-1 receptors. DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.

DOI: 10.1126/science.1166127 Full text Sigma-1 receptor Sigma receptor Hallucinogen Pharmacology +7

Structural Basis for Molecular Recognition at Serotonin Receptors

Science March 22, 2013 Chong Wang, Yi Jiang, Jinming Ma et al. 522 citations

Two research teams independently determined the crystal structures of two serotonin receptors bound to antimigraine drugs or a precursor of LSD. The structures show that subtle differences in how ligands bind to these receptors lead to substantial differences in the signals generated and the resulting biological responses. The same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which specific receptor it binds to.

DOI: 10.1126/science.1232807 Serotonin 5-HT Receptor Migraine Pharmacology +6

Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors

Science February 16, 2023 467 citations

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-HT2ARs is essential for psychedelic-induced cortical plasticity, but it is unclear why some 5-HT2AR agonists promote neuroplasticity while others do not. Using molecular and genetic tools, the authors demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms. This work emphasizes location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.

DOI: 10.1126/science.adf0435 Full text

Lysergic Acid Diethylamide: Sensitive Neuronal Units in the Midbrain Raphe

Science August 16, 1968 George K. Aghajanian, Warren E. Foote, Michael Sheard 406 citations

Injections of d-lysergic acid diethylamide (LSD) into the midbrain cause a reversible halt in the spontaneous firing of neurons that contain serotonin. The dose needed is at or below the level that produces noticeable behavioral changes. This inhibition of serotonin-containing neurons may explain the drug's effect of reducing serotonin metabolism.

DOI: 10.1126/science.161.3842.706 Lysergic acid diethylamide Serotonin Serotonergic Midbrain +9

Hallucinogenic Amphetamine Selectively Destroys Brain Serotonin Nerve Terminals

Science September 6, 1985 G.a. Ricaurte, Guy K. Bryan, L. Strauss et al. 367 citations

The amphetamine analog MDA, which has hallucinogenic effects, causes long-lasting reductions in serotonin levels, serotonin uptake sites, and a serotonin metabolite in rat brains. Morphological evidence suggests these changes result from degeneration of serotonin nerve terminals. These findings indicate MDA is toxic to serotonin neurons in rats and raise concerns about whether MDA and similar hallucinogenic amphetamines could cause serotonin neurotoxicity in humans.

DOI: 10.1126/science.4023719 Serotonin Amphetamine Hallucinogen Neuroscience +2

Diverse Psychotomimetics Act Through a Common Signaling Pathway

Science November 21, 2003 Per Svenningsson, Eleni T. Tzavara, Robert Carruthers et al. 312 citations

Three drug classes—dopaminergic agonists (e.g., D-amphetamine), serotonergic agonists (e.g., LSD), and glutamatergic antagonists (e.g., PCP)—produce schizophrenia-like effects in animals. A common signaling pathway involving the protein DARPP-32 mediates these effects. DARPP-32 is phosphorylated or dephosphorylated at three sites, leading to synergistic inhibition of protein phosphatase-1 and regulation of downstream effectors GSK-3, CREB, and c-Fos. In mice lacking DARPP-32 or with point mutations at its phosphorylation sites, the drugs' effects on sensorimotor gating and repetitive movements were strongly reduced, indicating DARPP-32's essential role in these psychotomimetic actions.

DOI: 10.1126/science.1089681 Serotonergic Creb Amphetamine Protein kinase a +10

Structure-based discovery of nonhallucinogenic psychedelic analogs

Science January 27, 2022 Dongmei Cao, Jing Yu, Huan Wang et al. 306 citations

Drugs targeting the human serotonin 2A receptor (5-HT2AR) are used for neuropsychiatric diseases, but many have hallucinogenic effects. Structures of 5-HT2AR complexed with psilocin, LSD, serotonin, and lisuride reveal that serotonin and psilocin show a second binding mode. This insight enabled design of the psychedelic IHCH-7113 and several 5-HT2AR β-arrestin–biased agonists that displayed antidepressant-like activity in mice without hallucinogenic effects. These structures provide a foundation for designing safe, nonhallucinogenic psychedelic analogs with therapeutic potential.

DOI: 10.1126/science.abl8615 Psilocybin Lysergic acid diethylamide Serotonin Hallucinogen +5

Enzymatic Formation of Psychotomimetic Metabolites from Normally Occurring Compounds

Science August 4, 1961 Julius Axelrod 183 citations

An enzyme that N-methylates serotonin and tryptamine into the psychotomimetic compounds bufotenine and N,N-dimethyltryptamine has been identified. This enzyme is highly concentrated in rabbit lung and also acts on phenylethylamine derivatives including tyramine, phenylethylamine, mescaline, and dopamine.

DOI: 10.1126/science.134.3475.343 Mescaline Psilocybin Serotonin Psychotomimetic +9

RETRACTED: Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy")

Science September 27, 2002 George A. Ricaurte, Jie Yuan, George Hatzidimitriou et al. 179 citations

The recreational drug MDMA (ecstasy) is widely believed to selectively damage serotonin neurons in animals and possibly humans. However, nonhuman primates given several sequential doses of MDMA—a pattern similar to human use—developed severe damage to brain dopamine neurons, along with milder serotonin damage. This dopamine loss was linked to increased vulnerability to movement problems. The findings suggest that recreational MDMA users may unknowingly risk developing neuropsychiatric disorders related to dopamine or serotonin deficiency, either as young adults or later in life.

DOI: 10.1126/science.1074501 MDMA Ecstasy Serotonergic Serotonin +9

2,5-Dimethoxy-4-methyl-amphetamine (STP): A New Hallucinogenic Drug

Science November 3, 1967 Solomon H. Snyder, Louis A. Faillace, Leo E. Hollister 146 citations

In two independent trials with normal volunteers, 2,5-dimethoxy-4-methyl-amphetamine (the active chemical in the hallucinogenic drug STP) produced mild euphoria at low doses. Doses above 3 milligrams caused pronounced hallucinogenic effects lasting about 8 hours, similar to those from hallucinogenic doses of lysergic acid diethylamide, mescaline, and psilocybin. The compound is chemically related to both mescaline and amphetamine, about 100 times more potent as a hallucinogen than mescaline, and only one-thirtieth as potent as lysergic acid diethylamide. Chlorpromazine did not accentuate its psychological effects.

DOI: 10.1126/science.158.3801.669 Mescaline Lysergic acid diethylamide Psilocybin Hallucinogen +4

LSD and Genetic Damage

Science April 30, 1971 Norman I. Dishotsky, William D. Loughman, Robert E. Mogar et al. 145 citations

Pure LSD ingested in moderate doses does not damage chromosomes in vivo, cause detectable genetic damage, or act as a teratogen or carcinogen in humans. In vitro studies showed chromatid breakage only at concentrations and exposure durations unachievable in humans, with no dose-response relation. Among 126 subjects given pure LSD, only 14.29% had elevated chromosome aberrations, versus 48.91% of 184 users of illicit LSD. Chromosome damage correlated with general drug abuse, not LSD alone. LSD is a weak mutagen effective only at extremely high doses. No cause-and-effect relation with neoplasia has been demonstrated, and case reports of leukemia are rare. Pure LSD is not teratogenic in humans, though illicit LSD use was linked to spontaneous abortions.

DOI: 10.1126/science.172.3982.431 In vivo Chromosome aberration Dna damage Toxicology +4

Chromosomal Abnormalities in Leukocytes from LSD-25 Users

Science July 21, 1967 S. T. Irwin, José Egozcue 139 citations

Chromosomal abnormalities were significantly more frequent in leukocytes from LSD-25 users (six out of eight) than in nonuser controls (one out of nine). The two users without damage had the lowest estimated average dose. Damaged cells were observed in samples taken between 1 day and 6 months after the last dose.

DOI: 10.1126/science.157.3786.313 Lysergic acid diethylamide Andrology Genetics Molecular biology +3

Lysergic Acid Diethylamide- and Mescaline-Induced Attenuation of the Effect of Punishment in the Rat

Science May 21, 1976 Ronald I. Schoenfeld 118 citations

Lysergic acid diethylamide (LSD), at doses as low as 1 microgram per kilogram of body weight, reduced the suppressive effect of electric shock on rats' licking behavior. Mescaline produced a similar attenuation of punishment, while dimethyltryptamine and Δ9-tetrahydrocannabinol did not. Drugs that interfere with serotonin-containing neurons, cyproheptadine and α-propyldopacetamide, had comparable behavioral effects, suggesting that LSD and mescaline may attenuate punishment by decreasing the activity of these neurons.

DOI: 10.1126/science.192.4241.801 Mescaline Lysergic acid diethylamide Serotonin Licking +4