European journal of pharmacology
July 15, 2025
Isis Koutrouli, Kristýna Mazochová, Rachel R Horsley
4 citations
A selective review of preclinical rodent studies suggests that (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a metabolite of ketamine, reduces behavioral despair, anhedonia, anxiety, and social avoidance in both stressed and non-stressed animals. Antidepressant effects appear rapidly (within 30 minutes) and last up to 21 days at doses between 5 and 125 mg/kg. However, some studies failed to find significant effects at doses below 40 mg/kg, particularly in models with pre-induced depression. No major adverse effects were reported, though side-effect data were limited. The authors conclude that (2R,6R)-HNK shows promise as a next-generation antidepressant but requires further research on long-term safety and mechanisms.
European journal of pharmacology
July 5, 2025
Jolien K E Veraart, Sanne Y Smith-Apeldoorn, Jeanine Kamphuis et al.
2 citations
Oral esketamine shows low and variable bioavailability, complicating its use as an antidepressant. In 17 patients with treatment-resistant depression given oral esketamine twice weekly for six weeks with a titration approach, esketamine and noresketamine serum levels were measured 30 and 60 minutes after administration. No association was found between changes in depressive symptoms and any pharmacokinetic outcomes, including serum levels of esketamine, noresketamine, their sum, or ratios. High inter-individual variability in pharmacokinetics was observed. The small sample and flexible-dose regimen limit conclusions. Clinical response may not correspond to esketamine pharmacokinetics, suggesting individually-based titration according to clinical effects is optimal.
European journal of pharmacology
January 15, 2025
Pierre Pouget, Pierre Daye, Martin Paré
2 citations
Ketamine, which alters synaptic transmission via NMDARs, affects cognitive functions, but its impact on motor control in the brainstem is selective. In primates, ketamine injection substantially decreased the deceleration of horizontal saccades, which rely on glycine-NMDAR-gated currents, while vertical saccade deceleration, controlled by GABA currents, remained largely unaffected. This indicates that despite general circulation of the drug, the motor brainstem generator circuit differentially maintains saccade kinematics. The results provide distinct markers for estimating NMDAR-gated specificity in the prefrontal cortex versus GABA circuit specificity.
European journal of pharmacology
June 5, 2024
Li-Han Sun, Lung Yu, Ya-Hsuan Chan et al.
2 citations
A brief recall of methamphetamine-associated memory combined with ketamine treatment facilitated the extinction of that memory and made it resistant to stress-triggered reinstatement in animals. The combination increased glutamate metabotropic receptor 5 (mGluR5) in GABA neurons of the medial prefrontal cortex (mPFC). Chemogenetic experiments showed that activating mPFC GABA neurons preserved extinction and prevented stress-primed reinstatement, whereas inhibiting them restored vulnerability to reinstatement. The findings suggest that exciting mPFC GABA neurons plays a key role in the effects of brief recall plus ketamine on curbing stress-provoked drug seeking.
European journal of pharmacology
September 5, 2025
Timo Jendrik Faustmann, Stephan Theiss, Philipp Görtz et al.
1 citation
Phencyclidine (PCP), a drug that blocks NMDA receptors, suppresses spontaneous electrical activity in networks of mouse brain cells grown on microelectrode arrays, reducing spike and burst rates. Pre-treating the networks with antipsychotic drugs—clozapine, aripiprazole, or haloperidol—shifted the PCP dose-response curve to the right, indicating protection. Clozapine and aripiprazole provided 20- to 30-fold greater protective potency than haloperidol's 6-fold shift. The findings suggest this in vitro setup can model schizophrenia-related network disruption and test potential treatments.
European journal of pharmacology
July 10, 2026
Amanda Gollo Bertollo, Vinicius Alexandre Wippel, Maiqueli Eduarda Dama Mingoti et al.
Psychedelic compounds show promise as rapid-acting antidepressants, especially for treatment-resistant depression. Their effects are primarily mediated through 5-HT2A receptor activation, which triggers intracellular signaling cascades involving Gq/11 and β-arrestin pathways, leading to neuroplasticity, synaptogenesis, and remodeling of neural circuits like the default mode network. These compounds also modulate glutamatergic transmission and have anti-inflammatory properties. Key transcription factors and epigenetic modifications contribute to enduring changes in gene expression. While 5-HT2A receptors play a central role, other receptors and neurotransmitter systems are also involved. The review identifies knowledge gaps regarding interactions between these mechanisms and suggests future research directions.
European journal of pharmacology
July 19, 2026
Yongning Lv, Zihe Yang, Linjie Li et al.
Intranasal ketamine given twice weekly for two weeks to rats exposed to chronic stress improved depressive-like behaviors, restored hypothalamic neuronal structure, increased synaptic density, and enhanced mitochondrial ultrastructure. RNA sequencing and molecular validation identified increased expression of Ndufa10, a gene encoding a mitochondrial complex I subunit, and its protein NDUFA10 in the hypothalamus. Blocking mitochondrial complex I with rotenone reduced these behavioral and molecular effects, suggesting that mitochondrial complex I activity contributes to ketamine's antidepressant-like actions. α-Synuclein protein changed in parallel without corresponding mRNA changes, indicating a post-transcriptional alteration.
European journal of pharmacology
April 5, 2024
Stanislav Rozov, Roosa Saarreharju, Stanislav Khirug et al.
Inhaling 50% nitrous oxide for one hour and a single low dose of ketamine both alter the activity of genes that regulate mitogen-activated protein kinases in the medial prefrontal cortex of adult mice, particularly in pyramidal cells. Nitrous oxide produced much larger and more widespread changes in gene expression than ketamine. Ketamine increased the firing rate of putative pyramidal neurons and boosted gamma brain wave activity, whereas nitrous oxide did not. The findings suggest that the two drugs share a common molecular target but cause different immediate electrical changes in the brain.
European journal of pharmacology
August 15, 2019
Jason Wallach, Tristan Colestock, Julià Agramunt et al.
Fluorolintane, a 1,2-diarylethylamine sold as a 'research chemical' for dissociative effects, was studied pharmacologically for the first time alongside five related isomers. In vitro binding showed fluorolintane has high affinity for NMDA receptors (Ki = 87.92 nM) and even higher affinities for dopamine transporters (DAT) in most cases. Functional experiments in rat hippocampal slices demonstrated that fluorolintane inhibits NMDA receptor-induced field excitatory postsynaptic potentials and blocks long-term potentiation, consistent with NMDA receptor antagonism. In rats, fluorolintane disrupted prepulse inhibition (a measure of sensorimotor gating) with a median effective dose of 13.3 mg/kg, supporting anecdotal reports of dissociative effects in humans.
European journal of pharmacology
April 5, 2017
James Oluwagbamigbe Fajemiroye, Polepally Reddy Prabhakar, Luiz Carlos da Cunha et al.
A derivative of the hallucinogen salvinorin A, called 22-azidosalvinorin A (SA2), shows antidepressant-like effects in mice. Oral treatment with SA2 at doses of 5, 10, and 20 mg/kg reduced immobility in the forced swimming test and tail suspension test without affecting general locomotion, indicating an antidepressant-like property. This effect was not blocked by serotonin depletion or a 5-HT1A receptor antagonist, but was blocked by depleting catecholamines or blocking α1-adrenoceptors. SA2 mildly inhibited monoamine oxidase and showed affinity for α1A, α1B, α1D, and κ-opioid receptor subtypes, suggesting its antidepressant-like action is mediated through monoamine systems.
European journal of pharmacology
November 15, 2013
Aashish S Morani, Amy Ewald, Katherine M Prevatt-Smith et al.
Activating the κ opioid receptor with the salvinorin A analogue 2-methoxy-methyl salvinorin B (MOM Sal B) at 0.3 mg/kg reduced cocaine-seeking behavior in rats, but also reduced sucrose reinforcement. No sedation was observed—locomotion in cocaine-induced hyperactivity and open field tests was unchanged—yet the forced swim test showed increased immobility and decreased swimming times, indicating pro-depressive effects. The compound thus modulates cocaine-seeking non-selectively without sedation, but depressive side effects may limit its therapeutic use.
European journal of pharmacology
July 11, 2005
Kinzo Matsumoto, Ryo Morishige, Yukihisa Murakami et al.
Isorhynchophylline, a compound from Uncaria plants used in traditional Chinese medicine, preferentially blocks 5-HT2A receptors in the brain, likely through competitive antagonism. In mice, it dose-dependently reduced 5-HT2A-mediated head-twitch responses without affecting 5-HT1A or 5-HT2C behaviors. A related alkaloid, isocorynoxeine, had similar effects, while stereoisomers did not, indicating the oxindole moiety's configuration is essential for this activity.
European journal of pharmacology
June 29, 2001
M Narita, K Yoshizawa, M Nomura et al.
Ketamine, an NMDA receptor antagonist used as an anesthetic, can produce psychotomimetic effects like nightmares and hallucinations with chronic use. In Fischer 344 rats trained to discriminate ketamine (5 mg/kg) from saline, non-competitive NMDA receptor antagonists that block NR2A- and NR2B-containing receptors (phencyclidine, dizocilpine) and an NR2A-preferring antagonist (dextromethorphan) fully substituted for the ketamine cue in a dose-dependent manner. The NR2B-selective antagonist ifenprodil, the competitive NMDA antagonist CPP, and the sigma receptor ligand DTG did not generalize. The findings suggest that antagonism of NR1/NR2A-containing NMDA receptors may be critical for producing ketamine's discriminative stimulus effects.
European journal of pharmacology
April 13, 2001
T Habara, T Hamamura, M Miki et al.
The selective 5-HT2A receptor antagonist M100907 attenuates phencyclidine (PCP)-induced Fos expression in specific rat brain regions. PCP (5 mg/kg) induced Fos expression in the cingulate cortex area 3, agranular insular cortex, piriform cortex, nucleus accumbens, anterior paraventricular thalamic nucleus, and ventral lateral septal nucleus. Pretreatment with M100907 (0.5 mg/kg) reduced Fos expression in the nucleus accumbens core and shell, agranular insular cortex, and piriform cortex, but not in other regions. M100907 alone did not induce Fos expression in any region, including the dorsolateral caudate/putamen. These results indicate that 5-HT2A receptor antagonism attenuates Fos expression in a regionally specific manner in the PCP model of psychosis.
European journal of pharmacology
October 1, 1984
M D Hynes, D L Hymson
Nitrous oxide, an analgesic and anesthetic gas, produces subjective effects in rats that resemble those of psychotomimetic drugs rather than morphine. Rats trained to discriminate ethylketocyclazocine, a psychotomimetic opioid, generalized the cue to nitrous oxide in a concentration-dependent manner, while rats trained to discriminate morphine did not generalize even at 80 percent nitrous oxide. The narcotic antagonist naltrexone did not block this generalization. These findings align with human studies and suggest that nitrous oxide, despite sharing some analgesic properties with morphine, has distinct subjective effects similar to psychotomimetic substances.