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.