Neuropharmacology
January 21, 2026
Ana Domi, Erika Lucente, Davide Cadeddu et al.
1 citation
Psilocin, the active metabolite of psilocybin, induces a long-lasting decrease in excitatory synaptic strength in the prefrontal cortex of rats, an effect that is independent of sex. This synaptic depression originates presynaptically and is not mediated by 5-HT2A or metabotropic glutamate group 2 receptors, but instead involves enhanced GABAergic inhibition. The effect is partially blocked by a 5-HT1A receptor antagonist and fully blocked by a TrkB receptor antagonist. These sustained changes in synaptic activity may relate to reduced prefrontal connectivity observed in humans and could affect cognitive function.
Neuropharmacology
October 15, 2025
Marion Hendrickx, Antoine Dampierre, Emmanuel Drouin
1 citation
In 1930, four years before their official publication, psychiatrists Henri Claude and Henri Ey treated a patient, Madame Louise Françoise R., with mescaline at Sainte-Anne hospital in Paris. They administered subcutaneous injections of 20-40 mg, doses now considered sub-threshold, far below the later recognized effective range of 250-500 mg. The experiment was exploratory, using mescaline as a functional probe to observe psychopathological mechanisms rather than as a cure. The patient experienced colored visions, depersonalization, and the observation that "mescaline releases but does not create fantasies." A few days later, she received malariotherapy, an archetypal shock therapy, which was followed by clinical improvement.
Neuropharmacology
September 15, 2026
Taisiia Prosvirova, Wiktoria Podolecka, Jacek Wróbel et al.
Ketamine rapidly reorganizes fast brain rhythms differently across cortical networks. In freely moving rats, neocortical gamma power increased broadly, while the olfactory bulb showed suppressed gamma alongside robust high-frequency oscillations (HFO; 130-180 Hz). Local blockade of non-NMDA glutamate receptors in the olfactory bulb suppressed ketamine-enhanced HFO in the bulb, ventral striatum, and prefrontal cortex without affecting neocortical gamma, indicating separate circuit mechanisms. Within the bulb, a kainate receptor antagonist markedly reduced HFO, while AMPA receptor blockade had minimal effect. Blocking GABA-A receptors reduced HFO power while increasing gamma power, showing that fast inhibition is necessary for HFO expression. The findings suggest that tonic kainate-dependent depolarization recruits interneurons to generate an inhibitory network rhythm that drives HFO propagation through olfactory-limbic circuits.
Neuropharmacology
June 6, 2026
Devin P. Hagarty, Adam Dawoud, Alfonso Brea Guerrero et al.
Ketamine is approved for treatment-resistant depression and is being tested for substance use disorder and PTSD, but its addictive potential raises safety concerns. The nucleus accumbens (NAc), a brain reward hub, is involved in how drug-related cues become salient. The NAc contains two types of medium spiny neurons (MSNs): those expressing dopamine 1 receptors (D1R) and those expressing dopamine 2 receptors (D2R). Using DREADD technology in transgenic rats, the authors found that D1R-expressing MSNs, but not D2R-expressing ones, play a key role in reinstatement of seeking behavior triggered by ketamine-associated cues. This identifies a cell-type specific mechanism in ketamine's addictive properties.
Neuropharmacology
June 1, 2026
Nehal G. Fahmy, Nada M. Kamel, Mahmoud M. Khattab et al.
In rats, a single low dose of ketamine more effectively than repeated low doses counteracts cognitive impairment and depressive-like behavior caused by the chemotherapy drug doxorubicin. The single dose better reduced brain inflammation and normalized levels of glutamate transporter GLT-1, serotonin transporter SERT, dopamine transporter DAT, and brain-derived neurotrophic factor (BDNF)/TrkB signaling. Repeated dosing showed weaker or no benefits on these molecular markers.
Neuropharmacology
May 1, 2026
Jairo S Acosta-Vargas, Natalia De Las Heras-Martínez, Alberto Marcos et al.
Adolescent rats exposed to vaporized THC, alone or with CBD, showed no significant changes in behavioral traits or alcohol self-administration compared to controls. However, females exhibited a more vulnerable pattern of alcohol consumption and seeking. In THC-exposed males, a negative correlation appeared between sucrose preference and compulsive alcohol seeking; in females, THC disrupted the link between novelty preference and alcohol intake and was associated with a negative correlation between goal-tracking and compulsive seeking. Naltrexone reduced alcohol intake most effectively in THC-exposed rats versus those given a high-CBD/low-THC mixture. Adolescent cannabinoid exposure has limited effects on overall alcohol risk but may alter psychological underpinnings of alcohol-related behaviors and increase naltrexone potency, with sex differences highlighting the need for personalized interventions.
Neuropharmacology
February 9, 2026
Mikael Palner, Elisabeth Kolesnik, Christina Baun et al.
The study tested whether the psychedelic compound N,N-dimethyltryptamine (DMT) exists naturally in the mammalian brain and acts as a co-transmitter with serotonin. In rats, blocking monoamine oxidase with pargyline did not allow detection of endogenous DMT, while blocking acidic metabolite transport with probenecid slightly elevated the DMT metabolite 3-indoleacetic acid, likely from tryptamine. Exogenous DMT was rapidly taken up and cleared from the brain, with peak concentrations at 45 minutes and near-complete washout by 210 minutes. Blocking serotonin reuptake or vesicular monoamine transporters did not alter DMT levels. The results do not support the hypothesis that DMT is an endogenous co-transmitter with serotonin.
Neuropharmacology
January 1, 2026
Luisa Prochazkova, Laura C Carvalho, Natasza Marrouch et al.
Microdosing psychedelics is associated with self-reported positive changes in health behaviors, particularly in sleep, contemplative practices, physical activity, and work-life balance. A survey of 365 people with microdosing experience found that the intention to change was the strongest predictor of behavioral change, while dose, protocol, and psychiatric status were not significant predictors. Thematic analysis of qualitative responses suggested potential psychological mechanisms including improved mental health, cognitive clarity, self-awareness, self-determination, and relatedness. The findings provide an initial exploration into how microdosing might support health behavior change, but controlled studies are needed to confirm these associations.
Neuropharmacology
December 15, 2024
Okko Alitalo, Samuel Kohtala, Marko Rosenholm et al.
A brief exposure to nitrous oxide (N2O) causes a drop in body temperature, reduced movement, enhanced slow-wave brain activity, decreased brain glucose use, and increased phosphorylation of TrkB, GSK3β, and p70S6K in the medial prefrontal cortex of adult male mice. Preventing the hypothermic response in a chronic stress model of depression weakened the antidepressant-like behavioral effects of N2O in the saccharin preference test. These findings indicate that N2O treatment modulates TrkB signaling and related neurotrophic pathways in a temperature-dependent manner, linking altered thermoregulation and energy expenditure to antidepressant-like behavioral responses.
Neuropharmacology
May 1, 2023
Xiayun Wan, Akifumi Eguchi, Lijia Chang et al.
A single injection of arketamine (10 mg/kg) reduced anhedonia-like behavior and reversed the loss of femoral neck cortical and total bone mineral density in mice susceptible to chronic social defeat stress. The abundance of certain gut microbiota and plasma metabolites differed between arketamine-treated and saline-treated susceptible mice, and these microbial and metabolite abundances correlated with bone mineral density. The findings suggest arketamine may improve both depressive symptoms and bone density through a gut-microbiota-bone-brain axis, indicating potential as a therapy for depressed patients with low bone mineral density.
Neuropharmacology
February 1, 2023
Yu-Jung Cheng, Chieh-Hsin Lin, Hsien-Yuan Lane
A review compares the antidepressant mechanisms of sarcosine, benzoate, ketamine, esketamine, and arketamine. These compounds modulate N-methyl-d-aspartate glutamate receptors (NMDARs) and reduce brain inflammation by inhibiting microglial activity. Though they act differently as antagonists or coagonists of NMDARs, all have shown efficacy in animal models or human trials. The review concludes that these drugs act as both NMDAR modulators and anti-inflammatory agents, making them potentially effective for treating depression.
Neuropharmacology
February 1, 2023
Shigeyuki Chaki, Mai Watanabe
The limited efficacy of current antidepressants has driven research into the glutamatergic system as a drug target for depression, validated by ketamine's antidepressant effects and leading to the approval of esketamine (Spravato®). However, ketamine and esketamine have adverse effects that limit routine use. Understanding ketamine's mechanisms has spurred drug discovery for agents with similar efficacy but fewer side effects. Efforts include identifying active circulating substances after ketamine administration and agents targeting its mechanisms. Clinical trials are ongoing, and in 2022, AUVELITY™ (dextromethorphan with bupropion) was FDA-approved. Future development aims for safer, rapidly acting antidepressants as potent as ketamine.
Neuropharmacology
August 1, 2022
Mireia Tarrés-Gatius, Ximena López-Hill, Lluis Miquel-Rio et al.
Non-competitive NMDA receptor antagonists like PCP and MK-801 produce schizophrenia-like effects, but the specific receptor subunits and brain regions involved are unclear. Using GluN2C knockout mice, the authors found that deleting the GluN2C subunit reduced stereotyped behaviors such as circling, rearing, and ataxia signs induced by PCP and MK-801, indicating better motor coordination. However, other motor effects and sensorimotor gating deficits (pre-pulse inhibition) remained unchanged. PCP and MK-801 activated c-fos in thalamo-cortical networks but reduced it in the cerebellum, with differences between genotypes matching motor coordination changes. Resting-state fMRI showed enhanced cortico-thalamic-cerebellar connectivity in knockout mice that was less disrupted by MK-801. Thus, GluN2C-containing NMDA receptors in cerebellar circuits mediate some motor incoordination effects but not sensorimotor gating deficits.
Neuropharmacology
October 1, 2019
Samuel Kohtala, Wiebke Theilmann, Marko Rosenholm et al.
Ketamine's acute effects on TrkB-GSK3β signaling in the mouse cortex are not limited to subanesthetic (antidepressant) doses; sedative or anesthetic doses produce more prominent increases in slow EEG oscillations and phosphorylation of TrkBY816 and GSK3βS9. A sedative dose of 6,6-d2-ketamine (100 mg/kg) recapitulated these effects, while cis-HNK (20 mg/kg) produced negligible acute effects on this signaling or slow oscillations. The findings indicate that the molecular mechanisms associated with ketamine's antidepressant actions are not exclusively triggered by low doses and that cis-HNK is not responsible for these acute signaling changes.
Neuropharmacology
June 1, 2019
Jacques D Nguyen, Yanabel Grant, Kevin M Creehan et al.
Combined Δ9-tetrahydrocannabinol (THC) and oxycodone produced additive pain-relieving effects while reducing opioid self-administration in rats. Male rats trained to self-administer oxycodone intravenously obtained fewer infusions after inhaling vaporized THC or receiving injected THC (0-10 mg/kg, i.p.) compared to vehicle. Follow-up tests showed dose-dependent reductions across different oxycodone doses, with an intact loading dose arguing against general behavioral suppression. In separate groups of male and female Wistar rats, tail withdrawal latency increased more after inhaled THC (50 mg/mL) plus oxycodone (100 mg/mL) than either alone; similar additive antinociception occurred with injected THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). These additive effects suggest THC could enhance opioid therapeutic efficacy and reduce abuse.
Neuropharmacology
November 1, 2018
Robin L Carhart-Harris
The entropic brain hypothesis proposes that the entropy of spontaneous brain activity, within certain limits, indexes the informational richness of conscious states. Four years after its original publication, evidence from separate studies increasingly supports the principle that brain entropy is elevated in the psychedelic state, and evidence for greater brain criticality under psychedelics is also highlighted. Heightened brain criticality may make the brain more sensitive to intrinsic and extrinsic perturbations, translating as a heightened susceptibility to 'set' and 'setting'. This updated hypothesis offers more concrete information on specific measures of brain entropy and suggests new studies to scrutinize its utility for conditions such as depression and disorders of consciousness.
Neuropharmacology
October 1, 2018
Andrea Ossato, Sabrine Bilel, Adolfo Gregori et al.
Methoxetamine (MXE), a dissociative drug similar to ketamine and phencyclidine, alters neurological and sensorimotor functions in mice in a dose-dependent manner. Acute systemic administration of MXE, ketamine, and phencyclidine (0.01–30 mg/kg i.p.) differentially affected visual, acoustic, and tactile responses, thermal and mechanical pain, motor activity, and acoustic startle reactivity. MXE and ketamine (1 and 30 mg/kg i.p.) and phencyclidine (1 and 10 mg/kg i.p.) also significantly affected cardiorespiratory parameters and systolic and diastolic blood pressure. The findings suggest MXE produces effects comparable to its parent compounds, with specificity depending on dose and parameter examined.
Neuropharmacology
July 15, 2018
Maria Amat-Foraster, Anders A Jensen, Niels Plath et al.
Sub-anesthetic doses of ketamine (1, 2, and 5 mg/kg intravenously) decreased the firing rate of neurons in the reticular thalamic nucleus, mediodorsal and centromedial thalamic nuclei, and layer VI of the medial prefrontal cortex in anesthetized male Wistar rats. Ketamine also reduced low-frequency oscillations across these areas while increasing gamma oscillations in the medial prefrontal cortex and mediodorsal/centromedial thalamic nuclei. Lower doses (0.25 and 0.5 mg/kg) had no effect. Unlike phencyclidine, ketamine's inhibition of reticular thalamic nucleus neurons did not disinhibit excitatory neurons in other areas, likely due to concurrent NMDA receptor blockade there. The early transient inhibition may relate to psychotomimetic effects, while prolonged gamma increases may underlie antidepressant action.
Neuropharmacology
January 31, 2018
Sean B. Dolan, Zhenglan Chen, Renqi Huang et al.
Three synthetic cathinone analogs of MDMA—methylone, butylone, and pentylone—act as substrates at the serotonin transporter, producing inward currents there while having little effect at the dopamine transporter. In rats, all three compounds fully substituted for the discriminative stimulus effects of methamphetamine. Methylone and butylone fully substituted for MDMA and partially for DOM, whereas pentylone only partially substituted for MDMA and failed to substitute for DOM. The dopamine D1 receptor antagonist SCH23390 fully blocked methamphetamine-like effects but had minimal effect on MDMA-like effects. All compounds were robustly self-administered, with pentylone producing the greatest self-administration. These findings suggest that Ecstasy formulations adulterated with synthetic cathinones may drive more compulsive use than MDMA alone.
Neuropharmacology
November 1, 2014
Bronwyn Kivell, Zeljko Uzelac, Santhanalakshmi Sundaramurthy et al.
Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, increases dopamine transporter (DAT) activity in cells and rat striatum, which reduces dopamine signaling. This effect is mediated by KOR activation and the ERK1/2 pathway, and involves physical interaction between KOR and DAT proteins. SalA also decreases serotonin transporter activity but does not affect norepinephrine transporter activity. The enhanced dopamine transport, combined with reduced dopamine release, may contribute to the dysphoric and pro-depressant effects of SalA and other KOR agonists.
Neuropharmacology
June 1, 2014
Mei-Yi Lee, Chun-Cheng Chiang, Hong-Yi Chiu et al.
N-acetylcysteine (NAC) attenuates hallucinogenic effects caused by activation of the serotonin 5-HT2A receptor, as shown in mice. NAC reduced head twitch responses, expression of c-Fos and Egr-2 in brain regions, and excitatory field potentials in cortical slices induced by the hallucinogenic drug DOI. These effects were reversed by blocking the cystine-glutamate antiporter or the mGluR2 receptor, indicating NAC works by increasing activity of the antiporter followed by activation of mGluR2 receptors. NAC may be a potential therapeutic for hallucinations and psychosis.
Neuropharmacology
January 20, 2011
The behavioral effects of indoleamine hallucinogens involve multiple receptors, not just a single target.
Neuropharmacology
January 1, 1996
K A Grant, G Colombo, J Grant et al.
In rats trained to recognize the drug dizocilpine, various NMDA receptor antagonists were tested for their ability to produce similar effects. The dissociative anesthetics dizocilpine, phencyclidine, and ketamine fully substituted for dizocilpine without slowing response rates. Dexoxadrol also fully substituted but reduced response rates by 35%. Memantine, a low-affinity antagonist, fully substituted but only at doses that reduced response rates by 68%. Other low-affinity antagonists showed partial or no substitution, often at rate-reducing doses. The findings indicate that low-affinity NMDA antagonists produce discriminative stimulus effects distinct from those of dissociative anesthetics, with only the more potent low-affinity drugs showing substantial substitution, and then only at doses that impair behavior.
Neuropharmacology
September 1, 1990
A A Reid, M V Mattson, B R De Costa et al.
Phencyclidine (PCP) and its analog TCP bind non-selectively to two high-affinity binding sites in guinea pig brain: one coupled to the NMDA glutamate receptor (site 1) and the other associated with the dopamine reuptake carrier (site 2). The compound (+)MK801 is highly selective for site 1 and produces minimal psychotomimetic effects in humans at doses that reduce seizures, whereas PCP produces psychotomimetic effects. This suggests that (+)MK801 can serve as a marker for site 1 and that PCP's psychotomimetic effects may be mediated by site 2.
Neuropharmacology
August 1, 1984
N Khazan, G A Young, E E El-Fakany et al.
The prototype sigma agonist SKF-10,047 has opioid properties in its (-) isomer and psychotogenic properties in both its (+) and (-) isomers, similar to PCP. (-)-SKF-10,047 blocked EEG and behavioral effects of morphine in naive rats, precipitated withdrawal in morphine-dependent rats, produced physical dependence shown by naloxone-induced withdrawal, and displaced [3H]dihydromorphine from brain homogenates. (+)-SKF-10,047 did not produce dependence or displace [3H]dihydromorphine. This dissociation suggests sigma receptors are linked to psychogenic effects, not opioid effects, which are likely mediated by mu or kappa receptors.