Journal of Neuroscience
January 19, 2005
Dao‐yao He, Nancy N. H. Mcgough, Ajay Ravindranathan et al.
181 citations
Ibogaine, a natural alkaloid with side effects that prevent clinical use, reduces alcohol consumption in rats. In two-bottle choice and operant self-administration tests, ibogaine decreased ethanol intake and also reduced relapse-like drinking. The effect is mediated by glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area (VTA): ibogaine microinjected into the VTA reduced self-administration, systemic ibogaine increased GDNF expression in the midbrain, and in dopaminergic SHSY5Y cells ibogaine activated the GDNF pathway (phosphorylation of Ret and ERK1). Intra-VTA GDNF mimicked ibogaine's effect, while anti-GDNF antibodies blocked it. GDNF in the VTA therefore mediates ibogaine's action on ethanol consumption, suggesting GDNF as a target for alcoholism medications that could avoid ibogaine's side effects.
Journal of Neuroscience
October 6, 2010
Cullen L. Schmid, Laura Bohn
172 citations
Hallucinogens like psilocybin activate serotonin 2A receptors (5-HT2AR) to produce psychoactive effects. Serotonin itself, the natural neurotransmitter, also activates these receptors but does not normally cause hallucinations. This study shows that serotonin triggers a specific signaling pathway involving β-arrestin2, phosphoinositide 3-kinase, Src, and Akt in the frontal cortex of mice, whereas N-methyltryptamines (hallucinogens) do not. In mice lacking β-arrestin2, serotonin-induced head-twitch responses (a behavioral proxy for receptor activation) were greatly reduced unless doses were elevated, and N-methyltryptamines produced stronger responses. Blocking N-methyltransferase prevented serotonin precursor-induced head twitches in knockout mice, suggesting N-methyltryptamines, not serotonin, mediate that response. This agonist-directed signaling bifurcation may inform drug development for conditions like schizophrenia or depression where hallucinations occur.
Journal of Neuroscience
February 29, 2012
Jesse Wood, Yunbok Kim, Bita Moghaddam
164 citations
Schizophrenia is thought to be a disorder of neural coordination, not cellular pathology. In rats, three different psychotomimetic drugs—MK801 (an NMDA receptor antagonist), DOI (a serotonergic hallucinogen), and amphetamine—all disrupted population activity and modulated gamma oscillations in the prefrontal cortex, but through different mechanisms. MK801 increased population activity, DOI decreased it, and amphetamine had little effect. All three drugs reduced correlations between spike-rate and local field potential power specifically in the gamma band, suggesting they disconnect spike-discharge from gamma oscillators. Gamma oscillations support cognitive functions affected in schizophrenia, offering insight into cortical processing deficits.
Journal of Neuroscience
December 1, 1985
K A Yagaloff, Hartig Pr
159 citations
A binding site for lysergic acid diethylamide (LSD) on the rat choroid plexus, a brain structure that produces cerebrospinal fluid, was found to be a new type of serotonergic site. Using a high-resolution autoradiography technique, the site was localized to the epithelial cells of the choroid plexus. The density of this site was 3100 fmol/mg of protein, ten times higher than any other serotonergic site in brain homogenates. The site's pharmacology was distinct from known serotonin receptor types 5-HT1a, 5-HT1b, and 5-HT2. Binding was strongly inhibited by mianserin, serotonin, and (+)-LSD, while other serotonergic, dopaminergic, and adrenergic agents had moderate to weak effects. The site appears to be located on non-neuronal cells.
Journal of Neuroscience
November 15, 1997
Elizabeth O’hearn, Mark E. Molliver
158 citations
Ibogaine, an alkaloid causing hallucinations, tremor, and ataxia, leads to degeneration of Purkinje cells in the rat cerebellum in narrow parasagittal bands, accompanied by activated glial cells. Harmaline, a related alkaloid that excites inferior olivary neurons, produces the same pattern. The authors hypothesized that ibogaine excites inferior olive neurons, causing sustained glutamate release at climbing fiber synapses, mediating excitotoxic Purkinje cell death. Pharmacologically ablating the inferior olive in rats with 3-acetylpyridine before ibogaine administration almost completely prevented Purkinje cell degeneration and glial activation. This demonstrates ibogaine is not directly toxic but depends on an intact olivocerebellar projection. The unique circuitry of this projection provides high synaptic security, making Purkinje cells vulnerable to excitotoxic injury.
Journal of Neuroscience
November 12, 2014
Michael H. Baumann, Ernesto Solis, Lucas R. Watterson et al.
157 citations
The abuse of synthetic psychoactive substances known as "designer drugs" or "new psychoactive substances" (NPS) is increasing rapidly. These drugs are manufactured as legal alternatives to traditional illicit drugs. Synthetic cathinones ("bath salts") and synthetic cannabinoids ("spice") have received substantial media attention. Low recreational doses can produce desirable effects, but high doses or chronic exposure often lead to dangerous medical consequences including psychosis, violent behaviors, tachycardia, hyperthermia, and death. Despite their popularity, there is a paucity of scientific data about these drugs. This review describes the mechanisms of action and neurobiological effects of synthetic cathinones and cannabinoids.
Journal of Neuroscience
December 1, 2000
Jennifer L. Scruggs, Sachin Patel, Michael Bubser et al.
154 citations
A hallucinogenic drug that activates 5-HT2A receptors increases Fos protein expression in the rat somatosensory cortex. This effect depends on 5-HT2A, not 5-HT2C, receptors and requires intact thalamocortical connections. The drug does not act directly on cortical neurons but instead stimulates 5-HT2A receptors on thalamocortical neurons, increasing glutamate release, which then drives Fos expression in cortical neurons via AMPA receptors. Blocking AMPA/KA receptors or lesioning the ventrobasal thalamus reduces the effect. These findings illuminate how hallucinogens produce their effects through a thalamocortical glutamate pathway.
Journal of Neuroscience
September 10, 2018
Francesca Siclari, Giulio Bernardi, Jacinthe Cataldi et al.
148 citations
Dreaming during non-rapid eye movement (NREM) sleep is linked to fewer, smaller, and shallower slow waves and faster spindles, especially in central and posterior brain regions. A minority of very steep, large slow waves in frontal areas, occurring against a background of reduced slow wave activity and accompanied by high-frequency power increases (local microarousals), preceded successful dream recall. The findings suggest that the brain's ability to generate experiences during sleep is reduced when neuronal off-states are present in posterior and central regions, and that dream recall may be aided by intermittent activation of arousal systems during NREM sleep.
Journal of Neuroscience
May 1, 2001
Harry W. Broening, Laronda L. Morford, Sandra L. Inman-Wood et al.
141 citations
MDMA exposure during a period equivalent to the late human third trimester causes lasting learning and memory impairments in rats, while exposure during the early third trimester has little effect. Rats given MDMA on days 11–20 after birth showed dose-related difficulties in sequential learning and spatial learning and memory, but not in swimming or cued learning. Body weight temporarily dropped but recovered to 90–95% of controls. Brain chemical changes were small and did not explain the learning deficits. These findings suggest MDMA may pose a previously unrecognized risk to the developing brain.
Journal of Neuroscience
March 12, 2008
Stéphane Doly, Emmanuel Valjent, Vincent Setola et al.
140 citations
The club drug MDMA (ecstasy) primarily causes serotonin release by reversing the serotonin transporter. This study in mice shows that blocking or removing the 5-HT2B receptor completely stops MDMA-induced hyperactivity and serotonin release in key brain regions (nucleus accumbens and ventral tegmental area). The 5-HT2B receptor acts presynaptically to regulate MDMA-stimulated serotonin release, a previously unknown role. These findings suggest that 5-HT2B receptor antagonists could be promising treatments for MDMA abuse.
Journal of Neuroscience
February 8, 2017
Jason Samaha, Olivia Gosseries, Bradley R. Postle
131 citations
Transcranial magnetic stimulation (TMS) of occipital and posterior parietal cortex can produce visual sensations called phosphenes. Using near-threshold TMS with concurrent EEG, the authors found that prestimulus power and phase in the alpha band (8–13 Hz) predicted occipital TMS phosphenes, while higher-frequency beta-band (13–20 Hz) power (but not phase) predicted parietal TMS phosphenes. TMS-evoked responses related to phosphene perception were similar across sites, showing an early posterior negativity and later parietal positivity, plus low-frequency power increase followed by broadband alpha/beta power decrease. These correlates resemble those of conscious perception of near-threshold visual stimuli. The regionally differential prestimulus predictors suggest distinct frequencies reflect cortical excitability in occipital versus parietal cortex, challenging the assumption that alpha rhythm serves as a general index of cortical excitability.
Journal of Neuroscience
June 3, 2009
Atheir I. Abbas, Prem N. Yadav, Wei-Dong Yao et al.
131 citations
The scaffolding protein PSD-95, known for organizing glutamate receptors at synapses, also critically regulates serotonin 5-HT2A and 5-HT2C receptors. In mice lacking PSD-95, these serotonin receptors show reduced expression, abnormal distribution in dendrites, and impaired signaling. Hallucinogen-induced behaviors and the effects of atypical antipsychotics that target these receptors are disrupted. PSD-95 is essential for normal serotonergic receptor function, expanding its role beyond glutamate signaling.
Journal of Neuroscience
January 16, 2013
Terrell Holloway, José L. Moreno, Adrienne Umali et al.
122 citations
Severe stress during pregnancy in mice alters the expression of two brain receptors linked to schizophrenia: serotonin 5-HT2A increases and metabotropic glutamate mGlu2 decreases in the frontal cortex. These changes correspond to behavioral differences in adult offspring, such as a heightened response to a hallucinogenic drug and reduced antipsychotic-like effects of a mGlu2/3 agonist. Cross-fostering ruled out maternal care as a cause, and similar effects appeared after prenatal immune activation. The findings support the idea that early neurodevelopmental disruptions contribute to schizophrenia risk.
Journal of Neuroscience
February 2, 2011
José L. Moreno, Mitsumasa Kurita, Terrell Holloway et al.
122 citations
Maternal infection with influenza virus in mice alters the expression of serotonin and glutamate receptors in the frontal cortex of adult offspring, leading to behavioral changes relevant to schizophrenia. The 5-HT 2A receptor is upregulated and the mGlu 2 receptor is downregulated. Offspring show increased head-twitch responses to hallucinogens and reduced antipsychotic-like effects of a glutamate agonist, along with altered signaling pathways. These findings suggest a biochemical link between prenatal viral infection and schizophrenia-related behaviors, potentially guiding new treatments.
Journal of Neuroscience
November 1, 2001
Nigel P. Pedersen, W.w. Blessing
120 citations
MDMA (Ecstasy) raises body temperature partly by constricting blood vessels near the skin's surface, which reduces the body's ability to release heat. In conscious rabbits, MDMA caused a dose-dependent increase in body temperature (from about 38.3 to 41.2 °C after 6 mg/kg) along with a sharp drop in ear pinna blood flow (from 29 to 5 cm/sec), indicating cutaneous vasoconstriction. Blocking sympathetic nerves on one side of the head reduced both the temperature rise and the vasoconstriction. This suggests that sympathetically mediated skin vessel narrowing is a key mechanism behind MDMA-induced hyperthermia, and reversing that constriction might help treat life-threatening overheating in humans.
Journal of Neuroscience
December 15, 2001
Evelyn K. Lambe, George K. Aghajanian
111 citations
Blocking potassium channels that contain the Kv1.2 subunit triggers glutamate release in the rat prefrontal cortex, mimicking the effect of serotonin on thalamocortical terminals. The potassium channel blocker α-dendrotoxin (DTX), which selectively targets Kv1.1-, Kv1.2-, and Kv1.6-containing channels, induced excitatory postsynaptic currents (EPSCs) in layer V pyramidal neurons similar to those caused by serotonin acting on 5-HT2A receptors. Both DTX- and serotonin-induced EPSCs were blocked by tetrodotoxin and ω-agatoxin-IVA, suppressed by μ-opiates and thalamic lesions, and showed mutual occlusion, indicating a shared mechanism. This suggests that serotonin triggers glutamate release by inhibiting Kv1.2-containing potassium channels on thalamocortical terminals.
Journal of Neuroscience
January 3, 2023
Panos Zanos, Kyle A. Brown, Polymnia Georgiou et al.
109 citations
Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects, but the role of NMDA receptor activation in these effects is unclear. In male mice, ketamine showed an inverted U-shaped dose-response in antidepressant-sensitive tests, indicating that excessive NMDA receptor inhibition can prevent its antidepressant actions. Pretreatment with other NMDA receptor antagonists blocked ketamine's behavioral effects, upregulation of AMPA receptor subunits, and metaplasticity. The antidepressant-like actions of other rapid-acting compounds were also blocked by NMDA receptor inhibition. Ketamine acted synergistically with an NMDA receptor positive allosteric modulator. The authors conclude that rapid-acting antidepressants share a common downstream NMDA receptor activation-dependent effector mechanism, and promoting NMDA receptor signaling may be an effective antidepressant strategy.
Journal of Neuroscience
October 8, 2003
Mahmoud M. Iravani, Michael S. Jackson, Mikko Kuoppamäki et al.
105 citations
MDMA (ecstasy) reduced dyskinesia and extended the effect of L-DOPA in a single Parkinson's disease patient. In MPTP-treated marmosets primed with L-DOPA, MDMA given alone transiently relieved motor disability but worsened symptoms over 60 minutes. When combined with L-DOPA, MDMA markedly decreased dyskinesia by reducing chorea and, to a lesser extent, dystonia, and lowered locomotor activity to normal levels. MDMA also alleviated dyskinesia induced by the dopamine D2/3 agonist pramipexole. These effects were fully blocked by the serotonin reuptake inhibitor fluvoxamine and partially inhibited by 5-HT1a/b antagonists, indicating MDMA's antidyskinetic action is mediated through serotonin systems.
Journal of Neuroscience
November 23, 2011
Benjamin Di Cara, Roberto Maggio, Gabriella Aloisi et al.
97 citations
MDMA (ecstasy) activates trace amine-1 receptors (TA1Rs), which normally inhibit dopamine and serotonin release. In mice lacking TA1Rs, MDMA caused only hyperthermia (not the biphasic temperature response seen in normal mice), produced larger increases in dopamine levels in the striatum, frontal cortex, and nucleus accumbens, and led to greater locomotion that was blocked by haloperidol. Serotonin release was also amplified in TA1R-deficient mice. A TA1R agonist reduced the dopamine- and serotonin-releasing effects of another drug in normal mice but not in knockout mice. TA1Rs thus limit MDMA's neurochemical and behavioral effects, suggesting they play a regulatory role in the drug's actions.
Journal of Neuroscience
January 21, 2015
Elisa Filevich, Martin Dresler, Timothy R. Brick et al.
89 citations
People who frequently have lucid dreams—dreams in which they know they are dreaming—show structural and functional differences in a brain region linked to self-reflection and thought monitoring. The frontopolar cortex (BA9/10) contained more gray matter in high-lucidity dreamers compared with low-lucidity dreamers, and this same area showed stronger activity during a thought-monitoring task in the high-lucidity group. The findings suggest that lucid dreaming and metacognitive abilities share common neural systems, offering insight into how higher-order consciousness can arise during sleep.
Journal of Neuroscience
May 11, 2011
Philippe Huot, Tom H. Johnston, Katie D. Lewis et al.
83 citations
The drug MDMA, composed of two mirror-image forms (enantiomers), shows promise for treating Parkinson's disease motor complications. R-MDMA reduced peak-dose dyskinesia severity by 33% at 3 mg/kg and 46% at 10 mg/kg, and cut the duration of disabling dyskinesia by 69% (90 minutes) without changing total ON-time. S-MDMA at 1 mg/kg extended total ON-time by 34% (88 minutes) but worsened dyskinesia. The findings suggest that racemic MDMA's simultaneous antidyskinetic and ON-time-extending effects arise from R-MDMA's action on 5-HT2A receptors and S-MDMA's inhibition of serotonin and dopamine transporters.
Journal of Neuroscience
June 19, 2020
Lilian Weber, Andreea O. Diaconescu, Christoph Mathys et al.
82 citations
The auditory mismatch negativity (MMN) is reduced in schizophrenia and can also be reduced by NMDA receptor (NMDAR) antagonists, suggesting impaired predictive coding. This study tested the theory that perceptual inference depends on NMDAR-dependent hierarchical precision-weighted prediction errors (PEs). Using a hierarchical Bayesian model on single-trial EEG data from healthy volunteers given the NMDAR antagonist S-ketamine in a placebo-controlled, double-blind, within-subject design, the analysis showed that low-level PEs (about stimulus transitions) appear early (102-207 ms), while high-level PEs (about transition probability) appear later (152-199 and 215-277 ms). Ketamine significantly diminished high-level PE responses, indicating NMDAR antagonism disrupts inference on abstract statistical regularities and impairs hierarchical Bayesian inference about the world's statistical structure.
Journal of Neuroscience
March 23, 2021
Diego Candia‐rivera, Jitka Annen, Olivia Gosseries et al.
81 citations
Heartbeat-evoked responses (HERs) in resting-state EEG can distinguish between postcomatose patients who are unresponsive and those in a minimally conscious state with 87% accuracy, 96% sensitivity, and 50% specificity. HERs provide more accurate classification than random EEG segments not locked to heartbeats or heart rate variability. HER-based consciousness scores correlate with glucose metabolism in the right superior temporal sulcus and right ventral occipitotemporal cortex. HERs reflect consciousness diagnosis based on brain metabolism better than behavior-based diagnosis (77% validation accuracy). These findings suggest HERs capture a capacity for consciousness that does not necessarily translate into intentional overt behavior.
Journal of Neuroscience
March 19, 2018
Katrin H. Preller, Leonhard Schilbach, Thomas Pokorny et al.
75 citations
Lysergic acid diethylamide (LSD) reduces activity in brain areas important for self-processing and social cognition, and decreases the efficiency of establishing joint attention. These effects are attributable to stimulation of the serotonin 2A receptor (5-HT2AR), as they are blocked by the antagonist ketanserin. The findings point toward the 5-HT2AR system as a potential target for treating social impairments in psychiatric disorders.
Journal of Neuroscience
June 4, 2014
Eugene A. Kiyatkin, A. H. Kim, Ken T. Wakabayashi et al.
47 citations
MDMA (Ecstasy) can cause fatal brain hyperthermia when taken in hot, crowded environments, even at moderate doses that are harmless under cool, quiet conditions. In male rats, MDMA at 9 mg/kg (about one-fifth of the lethal dose) produced only weak brain temperature increases under standard lab conditions (quiet rest, 22–23°C). However, social interaction with another male rat and a warm environment (29°C) dramatically amplified brain hyperthermia. The key mechanism is peripheral vasoconstriction, which prevents heat dissipation through the skin. This shows that doses of MDMA that are nontoxic in cool, quiet settings become highly dangerous under conditions mimicking recreational use at rave parties or other hot, crowded venues.