Pharmacology, biochemistry, and behavior
September 1, 2023
Yixue Qin, Haoxuan Li, Yuqi Zhang et al.
6 citations
Adding retigabine, a KCNQ channel opener, to a low dose of ketamine that alone had no antidepressant effect produced a strong antidepressant effect in both male and female C57BL/6J mice in the forced swim test. Retigabine also prolonged the duration of ketamine's antidepressant effect. The findings suggest that adjunctive retigabine could enhance ketamine's antidepressant properties, potentially allowing lower ketamine doses and reducing its risk of dependence.
Pharmacology, biochemistry, and behavior
February 1, 2025
Erin A Clark, Lien Wang, Taleen Hanania et al.
5 citations
Activating the 5-HT1B receptor with the drug CP-94253 produces rapid and sustained antidepressant-like effects in rodents, similar to ketamine. In mice, CP-94253 reduced immobility in the forced swim test and showed a strong antidepressant signature in a behavioral screening platform. Effects lasted at least 24 hours after a single dose in both naive rats and those receiving chronic interferon alpha treatment. The drug also enhanced hippocampal long-term potentiation measured 24 hours later. In mice subjected to chronic social defeat stress, antidepressant-like effects appeared within 1 hour in the tail suspension test and within 24 hours in the sucrose preference test.
Pharmacology, biochemistry, and behavior
December 1, 2024
Lucie Olejníková-Ladislavová, Michaela Fujáková-Lipski, Klára Šíchová et al.
5 citations
Mescaline, a classical psychedelic, primarily acts on serotonin 5-HT2A/C receptors but also binds to 5-HT1A and 5-HT2B receptors. In adult male rats, the highest dose (100 mg/kg) caused hyperlocomotion, which was reversed by almost all antagonists tested. Sensorimotor gating deficits, measured as prepulse inhibition of acoustic startle, were selectively normalized by a 5-HT2A antagonist, while a 5-HT2C antagonist partially reversed deficits from lower doses. These findings indicate that mescaline's behavioral effects are mainly mediated by the 5-HT2A receptor subtype, with a lesser role for 5-HT2C receptors, and limited involvement of other subtypes.
Pharmacology, biochemistry, and behavior
December 1, 2024
Camilla W Pretzel, João V Borba, Cássio M Resmim et al.
5 citations
Acute exposure to subanesthetic doses of ketamine (20 and 40 mg/L) increased total distance traveled in adult zebrafish, indicating hyperlocomotion. All tested concentrations (2, 20, and 40 mg/L) elicited circling behavior, a stereotyped-like response that diminished over time. Ketamine also reduced thigmotaxis and homebase activity while increasing the average length of trips, suggesting anxiolytic-like effects on spatio-temporal exploratory dynamics. These findings support ketamine's modulatory influence on behavior and highlight homebase-related measurements as useful for assessing behavioral changes in zebrafish models.
Pharmacology, biochemistry, and behavior
December 1, 2024
Guilin Liu, Li Ma, Akemi Sakamoto et al.
4 citations
A single dose of arketamine, the (R)-enantiomer of ketamine, reduced depression-like behavior and inflammation in mice given lipopolysaccharide (LPS), a bacterial toxin that triggers an immune response. Arketamine also prevented these effects when given six days before LPS. LPS lowered the proportion of γδ T cells in the spleen, and arketamine reversed this change and reduced spleen enlargement and interleukin-6 levels. Blocking γδ T cells with an antibody eliminated arketamine's benefits, suggesting these immune cells are essential for its effects. The findings indicate splenic γδ T cells may be a new target for treating inflammation-related depression.
Pharmacology, biochemistry, and behavior
October 28, 2023
Antonio D R Agüera, Clara Cándido, Rocío Donaire et al.
4 citations
Ketamine, an NMDA receptor antagonist with known antidepressant and memory effects, was tested in rats undergoing a reward-downshift task that induces frustration and aversive memory. Male rats given 32% sucrose then unexpectedly shifted to 4% sucrose showed greater suppression of intake when injected with ketamine (10 mg/kg) either before or after the first downshift session, compared to saline-injected controls. This suppression lasted beyond the injection days. In separate experiments, the same ketamine dose produced conditioned taste aversion to 4% sucrose even without reward downshift. The findings suggest ketamine creates an aversive state that adds to frustration from reward loss and can itself support conditioned taste aversion.
Pharmacology, biochemistry, and behavior
February 1, 2022
Jin Mook Kim, Boreum Han, Hyun Kyu Min et al.
4 citations
Deschloroketamine (10 mg/kg) and diphenidine (10-60 mg/kg) produced increased locomotor activation and stereotypy similar to ketamine (10 mg/kg) in mice. Both substances increased preference for the drug-paired compartment in conditioned place preference testing, indicating rewarding effects. In self-administration tests, deschloroketamine (1 mg/kg/infusion) increased active lever presses and infusions, suggesting reinforcing effects, whereas diphenidine (1, 2 mg/kg/infusion) did not alter these measures. Both compounds increased dopamine levels in PC-12 cells. The data suggest deschloroketamine may have both rewarding and reinforcing effects, while diphenidine only induced rewarding effects.
Pharmacology, biochemistry, and behavior
June 1, 1990
G R Cuadra, V A Molina
4 citations
Rats classified as killers, nonkillers, or grouped received a brain injection of a chemical that destroys serotonin fibers or a placebo. After 7-10 days, all rats showed typical behaviors (forepaw treading, hindlimb abduction) when given a serotonin-like drug. Nonkiller and grouped rats with the lesion showed heightened behavioral responses, indicating supersensitivity. Killer rats with the same lesion showed a smaller increase in these behaviors. Serotonin uptake measurements confirmed that the lesion reduced serotonin uptake equally in all lesioned rats. The findings suggest that killer rats have a reduced ability to adapt their serotonin systems after damage.
Pharmacology, biochemistry, and behavior
January 1, 1982
T P Blackburn, B Cox, C G Heapy et al.
4 citations
In rats with a unilateral lesion of the dorsal raphe nucleus (DRN), the compound 5-MeODMT caused turning toward the opposite side. This behavior was blocked by several serotonin antagonists, including methysergide, cyproheptadine, cinanserin, and the peripheral antagonist xylamidine. Among other neurotransmitter antagonists tested, only haloperidol was effective; hyoscine, picrotoxin, naloxone, and strychnine were not. Pretreatment with alpha-methyl-p-tyrosine also reduced the turning. These results suggest involvement of a central dopaminergic system. Additional lesions of the medial forebrain bundle with 6-OHDA changed the turning direction to the same side, supporting this interpretation.
Pharmacology, biochemistry, and behavior
December 1, 2024
Lifen Liu, Rui Li, Lanxia Wu et al.
3 citations
In rats exposed to a combined stress model (single prolonged stress plus plantar shock), those treated with (2R,6R)-hydroxyketamine (HNK) showed reduced depression- and anxiety-like behaviors, including increased exploratory activity. The compound reversed stress-induced disruptions in the PI3K/AKT signaling pathway in the hippocampus and prefrontal cortex, but not in the amygdala. Traumatic stress itself altered PI3K/AKT signaling in all three brain regions. These results suggest that (2R,6R)-HNK may alleviate negative emotional symptoms after trauma by modulating PI3K/AKT signaling, particularly in the hippocampus.
Pharmacology, biochemistry, and behavior
March 1, 2025
Yiwei Shen, Wei Ran, Dawei Liu et al.
2 citations
Electroconvulsive therapy (ECT) effectively treats depression but impairs learning and memory. Ketamine may reduce these cognitive side effects. Using a rat model of depression, researchers tested whether esketamine (a ketamine derivative) protects memory after electroconvulsive shock (ECS), the animal analogue of ECT. A low dose of esketamine increased the expression of metabotropic glutamate receptor 5 (mGluR5) and NMDA receptor 1 in the hippocampus, reduced ECS-induced memory impairment, and improved depressive-like behavior. Blocking mGluR5 with the antagonist MTEP reversed these effects. The findings suggest esketamine protects spatial learning and memory after ECS by upregulating mGluR5 and enhancing NMDA receptor activation.
Pharmacology, biochemistry, and behavior
February 1, 2024
Paul J Fletcher, Zhaoxia Li, Xiao Dong Ji et al.
2 citations
Psychedelic drugs that activate the 5-HT2A receptor, such as psilocybin, show promise for treating alcohol-use disorders. This study tested whether psilocybin or the 5-HT2A agonist TCB-2 could reverse the sensitized locomotor activity caused by repeated ethanol exposure in male DBA/2J mice. Mice received repeated ethanol injections to induce sensitization, then five daily doses of psilocybin (0, 0.3, or 1 mg/kg) or TCB-2 (0, 1, or 3 mg/kg). A subsequent ethanol challenge showed that sensitized mice still had enhanced activity, and neither psilocybin nor TCB-2 reduced this sensitized response. The results suggest that these drugs' short-term effects on ethanol intake may not involve reversing long-term behavioral or neural adaptations from repeated ethanol exposure.
Pharmacology, biochemistry, and behavior
February 1, 2026
Daniel A Palacios-Lagunas, Juan C Hernández-mondragón, Kjell Fuxe et al.
1 citation
MDMA, known for promoting prosocial feelings in humans, unexpectedly reduced social behavior in male rats regardless of whether they lived alone or in groups. In female rats, the same reduction occurred only in those housed individually; group-housed females showed no change. The data also hinted that individual rats varied in their response to MDMA, suggesting personal differences matter. More research is needed to understand how such variation influences MDMA's effects.
Pharmacology, biochemistry, and behavior
July 1, 2025
Negar G Ardabili, Shira Tan, Anthony L Riley
1 citation
Pre-exposure to the synthetic cathinone eutylone did not reduce the aversive effects of cocaine or MDMA in male rats, despite sharing some pharmacological activity. Rats given eutylone before taste avoidance conditioning still developed strong avoidance to cocaine and MDMA. However, pre-exposure to eutylone did attenuate the aversive effects of eutylone itself, indicating the drug was active in the preparation. The failure to alter cocaine or MDMA avoidance suggests eutylone's hybrid pharmacology may produce a distinct interoceptive state unlike that of either drug.
Pharmacology, biochemistry, and behavior
December 1, 2024
Ellen Scotton, Paola Rampelotto Ziani, Renata Luiza Boff Wilges et al.
1 citation
Anhedonia, a core symptom of major depressive disorder, was studied in male Wistar rats exposed to chronic variable stress. Rats classified as anhedonic-like showed reduced sucrose preference, which was reversed by a single dose of (R)-ketamine. High-throughput proteomics of the prefrontal cortex revealed that anhedonia was linked to downregulation of Neuronal Pentraxin Receptor and Galectin-1, suggesting disruption in inflammatory response, neurotransmitter activity, and glutamatergic synapses. (R)-ketamine response was associated with novel protein targets involved in oxidative stress, energy metabolism, synaptogenesis, dendritic arborization, neuroinflammation, gene expression, and telomere length. These pathways overlap with known depression pathophysiology and may offer therapeutic targets for anhedonia.
Pharmacology, biochemistry, and behavior
August 1, 2026
Mengyang He, Zhifei Shi, Ruijie Zhan et al.
Depression involves multiple dysfunctions across brain systems, including emotional-cognitive circuits, stress hormone regulation, neurotransmitter systems, and neuroplasticity. This review argues that the BDNF/CREB signaling pathway acts as a central hub connecting these systems. It explains how genetic variations, stress-related epigenetic changes, and microRNA regulation affect this pathway, which in turn influences brain plasticity, stress toxicity, and neurotransmitter balance. The review also describes how antidepressants like ketamine, rTMS, and SSRIs work by activating this pathway, supporting its potential as a biomarker and treatment target. Limitations and future directions integrating multiomics and neuroimaging are discussed, reconceptualizing depression as a network disorder centered on BDNF/CREB signaling.
Pharmacology, biochemistry, and behavior
June 30, 2026
Lucie Ladislavová, Viera Kútná, Kristýna Mazochová et al.
Chronic microdosing of psilocin (0.05 or 0.075 mg/kg) in adult male Wistar rats over five weeks did not alter locomotor activity, depressive-like behavior, sociability, or novelty seeking, and did not increase cell proliferation in the dentate gyrus of the hippocampus. A small anxiogenic effect was detected in the Elevated Plus Maze. The findings suggest that, under this dosing schedule, psilocin microdosing produces limited behavioral effects and does not enhance hippocampal progenitor proliferation.
Pharmacology, biochemistry, and behavior
May 29, 2026
Madeline T Van Fossen, Alexia G Dalton, Adam J Prus
Dextromethorphan, an FDA-approved drug for major depressive disorder when combined with bupropion, acutely reduces compulsive-like drinking in a rat model of obsessive-compulsive disorder. The drug acts as an inhibitor of serotonin transporters and an antagonist of sigma-1 and NMDA receptors. In the study, rats were trained in a schedule-induced polydipsia procedure, which models compulsive behavior, and were divided into low and high drinkers. Dextromethorphan dose-dependently decreased water consumption in both groups, while the NMDA receptor antagonist ketamine selectively reduced drinking only in high drinkers. However, none of the tested antagonists reversed dextromethorphan's effects, suggesting further investigation into its potential as an OCD treatment.
Pharmacology, biochemistry, and behavior
March 1, 2026
Negar G Ardabili, Shira Tan, María Elisa Márquez De Prado Arrarás et al.
A history of exposure to the synthetic cathinone eutylone alters the rewarding but not the aversive effects of cocaine and MDMA in female rats. Adult female Sprague-Dawley rats were given prior eutylone or saline, then underwent conditioning where saccharin taste and a distinct compartment were paired with cocaine, MDMA, or eutylone. All three drugs produced taste avoidance. Prior eutylone reduced the taste avoidance caused by eutylone itself but did not affect avoidance caused by cocaine or MDMA. Eutylone history had no effect on place preferences for MDMA or eutylone but increased place preferences for cocaine. The dissociable effects on reward versus aversion suggest that the subjective effects of eutylone differ from those of MDMA and cocaine, and that the neural bases for these drug effects are separable.
Pharmacology, biochemistry, and behavior
November 1, 2025
Shadan Rahmani, Rachel Crupi, Anthony L Riley et al.
A resurgence of interest in psychedelic drugs for therapeutic use is underway, with anecdotal and evidence-based reports suggesting they may treat depression, anxiety, PTSD, and substance abuse. However, available data are limited and their use remains controversial. This paper reports on talks by eighteen experts at a symposium covering safety and effectiveness of psychedelic-assisted therapies, brain systems involved, ethical issues, access pathways, regulation, and patenting. The symposium revealed the potential of psychedelics for treating psychiatric disorders and the scientific, legal, and policy challenges to realizing that potential.
Pharmacology, biochemistry, and behavior
February 1, 2025
Talita Rodrigues, Getulio Nicola Bressan, Patrícia Zorzi Juliani et al.
In a mouse model of schizophrenia-like symptoms induced by ketamine, the drug pioglitazone (an activator of PPAR-γ receptors) reversed some of the cognitive and behavioral changes. Ketamine reduced exploration in a novel object recognition test and decreased GAD67 immunoreactivity in the hippocampus. Pioglitazone, given for the last 7 days of a 14-day ketamine regimen, restored performance on the recognition test and normalized hippocampal GAD67 levels. The results suggest that pioglitazone may improve cognitive symptoms associated with schizophrenia, possibly through modulation of GABA-related signaling in the hippocampus.