Molecular Psychiatry
May 13, 2026
Fukang Zhang, Shuyuan Fan, Shiqi Li et al.
Exposure to 60% nitrous oxide (N2O), but not 30%, induced conditioned place preference (CPP) reward behavior in rodents and increased the excitability and glutamatergic transmission of dopamine neurons in the ventral tegmental area (VTA). N2O specifically elevated homocysteine levels in the deep cerebellar nuclei (DCN), but blocking homocysteine production did not reduce the rewarding behavior or glutamatergic transmission. Instead, N2O directly enhanced AMPA receptor-mediated glutamatergic transmission and increased activity in both DCN and VTA dopamine neurons. Inhibiting the DCN-VTA circuit via optogenetic long-term depression or chemogenetic inhibition of VTA dopamine neurons reduced N2O-induced CPP. Attenuating N2O-induced potentiation of the DCN-VTA circuit may offer a therapeutic strategy for N2O-related reward behavior.
Molecular Psychiatry
April 1, 2026
Qiang Li, Jingyu Liu, Godfrey D Pearlson et al.
Psychotic disorders like schizophrenia and bipolar disorder involve disruptions in the brain's information processing. Using resting-state fMRI and information-theoretic metrics, the authors show that the psychotic brain exhibits states of randomness across both spatial and temporal dimensions. They found a disruption in the balance between redundant and synergistic information, termed brainquake, indicating instability and disorganization in brain networks. Aberrant information interactions were observed in cortical and subcortical intrinsic connectivity networks, particularly in sensorimotor, visual, temporal, default mode, and fronto-parietal networks, as well as hippocampal and amygdalar regions. These findings suggest profound alterations in the brain's complexity and organizational states.
Molecular Psychiatry
March 1, 2026
Wilf Gardner, David H. Sarrazin, Martin Balzinger et al.
Disruptions in sleep, circadian rhythms, and neural plasticity are closely linked to depression. Using a mouse model of stress-induced depression, the authors found altered sleep architecture, impaired sleep homeostasis, and disrupted day-night oscillations of glutamatergic plasticity markers Homer1a and synaptic AMPAR expression in the medial prefrontal cortex (mPFC). Sleep deprivation (SD) and ketamine, both rapid-acting antidepressants, exerted opposing effects on mPFC circadian gene expression: SD enhanced negative clock loop genes (Per, Cry), while ketamine downregulated them. Targeted deletion of the core clock gene Bmal1 in mPFC excitatory neurons disrupted sleep-wake architecture and abolished the behavioral and molecular response to SD. Pharmacological activation of the clock repressor REV-ERB suppressed SD's antidepressant effects. The mPFC molecular clock is essential for sleep consolidation and homeostasis and mediates SD's behavioral effects.
Molecular Psychiatry
December 1, 2025
Yuanpeng Li, Hongyuan Li, Hongshuang Wang et al.
Psychedelics, especially psilocybin, show promise as treatments for substance use disorders (SUDs) including alcohol, nicotine, heroin, and cocaine. They may work by disrupting maladaptive neural circuits, promoting neuroplasticity, and enabling psychological insights that address root causes. Clinical trials indicate psilocybin-assisted therapy can significantly reduce substance use and improve mental health outcomes. However, legal barriers, safety concerns, and the need for more rigorous research remain. The outlook is cautiously optimistic, with potential to transform SUD therapy.
Molecular Psychiatry
September 1, 2023
Thomas Desmidt, Paul-Armand Dujardin, Frédéric Andersson et al.
A single one-hour session of a 50:50 nitrous oxide/oxygen mixture (EMONO) rapidly alters functional connectivity in the default mode network and increases brain tissue pulsations in depressed women who respond to the treatment. Among 20 women with treatment-resistant depression, 45% showed at least a 50% reduction in depression scores one week after exposure. Responders exhibited decreased connectivity between the subgenual anterior cingulate cortex and the precuneus, and a larger early increase in brain tissue pulsations, which may enhance drug delivery. Non-responders and healthy controls showed different connectivity changes. The findings suggest potential cerebral mechanisms and markers for antidepressant response to nitrous oxide.
Molecular Psychiatry
January 1, 2023
Gilly Wolf, Sandeep Singh, Karin Blakolmer et al.
Negative symptoms of schizophrenia, which cause long-term disability and respond poorly to antipsychotic drugs, are linked to cortical atrophy and cell loss. Psychedelic drugs, which show promise for other psychiatric conditions and enhance neuroplasticity in preclinical studies, might help treat these pathological changes. The main risk is inducing or worsening psychosis. Strategies to mitigate this risk include using non-hallucinogenic derivatives, sub-psychedelic or microdosing, harnessing entourage effects in psychedelic mushroom extracts, and blocking 5-HT2A receptor-mediated hallucinogenic effects. Preclinical studies with appropriate animal models are needed before careful clinical trials can proceed.
Molecular Psychiatry
September 1, 2005
P Seeman, F Ko, T Tallerico
Phencyclidine, ketamine, dizocilpine, and LSD all show higher affinity for the high-affinity state of the dopamine D2 receptor (D2High) than for the NMDA receptor. Phencyclidine had a Ki of 2.7 nM at D2High versus 313 nM at the NMDA receptor; ketamine had a Ki of 55 nM at D2High versus 3100 nM at NMDA sites; dizocilpine had a Ki of 0.3 nM at D2High versus a Kd of 1.8 nM at NMDA; LSD had a Ki of 2 nM at D2High. Because these psychotomimetics are more potent at D2High, their psychotomimetic action likely involves D2 agonism. In vivo, these drugs test a combined hyperdopamine and hypoglutamate theory of psychosis.