British journal of pharmacology
July 1, 1981
A R Green, J E Hall, A R Rees
88 citations
Several drugs that block serotonin (5-HT) receptors were tested for their effects on behaviors in rats induced by increasing serotonin activity. Methysergide, methergoline, methiothepin, and (-)-propranolol inhibited head weaving, forepaw treading, and hind-limb abduction, while cyproheptadine, cinanserin, and mianserin had no effect. At a higher dose, cyproheptadine did inhibit the behaviors. Methiothepin also blocked dopamine-related activity, suggesting its effects involve dopamine antagonism. Depleting serotonin with p-chlorophenylalanine enhanced responses to serotonin agonists. The findings suggest that some drugs fail to block serotonin-induced behaviors because they are weak antagonists, and caution is needed when interpreting serotonin's role in behaviors based on single antagonists.
British journal of pharmacology
November 1, 2008
R Capasso, F Borrelli, M G Cascio et al.
82 citations
Salvinorin A, the active compound in Salvia divinorum, slows intestinal movement by activating kappa-opioid receptors (KORs). In mice with croton oil-induced intestinal inflammation, this effect also involves cannabinoid CB1 receptors, as the CB1 antagonist rimonabant blocked the motility delay. In healthy mice, rimonabant did not affect salvinorin A's action. Binding tests showed salvinorin A has very weak affinity for CB1 and CB2 receptors and does not inhibit endocannabinoid breakdown or uptake. The findings suggest a functional interaction between CB1 receptors and KORs occurs specifically in the inflamed gut, not in the normal gut.
British journal of pharmacology
May 1, 1989
A Adell, G S Sarna, P H Hutson et al.
77 citations
In rats, reserpine depleted brain serotonin (5-HT) by 86% but did not block the behavioral syndrome caused by p-chloroamphetamine (PCA) or 5-MeODMT, except for changes in Straub tail and head weaving. Extracellular serotonin in the frontal cortex was about 1/1000th of brain levels before PCA, and PCA increased dialysate serotonin similarly in reserpine- and vehicle-pretreated rats. The results suggest PCA releases serotonin from the neuronal cytoplasm to produce the syndrome, while normal physiological release comes from vesicular stores.
British journal of pharmacology
April 1, 2014
A Villaseñor, A Ramamoorthy, M Silva Dos Santos et al.
69 citations
Ketamine rapidly lifts depression in about 65% of people with treatment-resistant bipolar disorder, but why some respond and others do not has been unclear. By analyzing plasma from 22 bipolar patients given ketamine or placebo, researchers found that metabolomic patterns—especially those related to mitochondrial fatty acid breakdown—differed between responders and non-responders, but only in patients maintained on lithium, not valproate. In lithium-treated responders, certain lysophospholipids were elevated. These metabolic differences existed before ketamine was given, suggesting that a simple blood test could predict who will benefit from ketamine and help personalize treatment.
British journal of pharmacology
April 1, 2004
Claudio A Villalobos, Paulina Bull, Patricio Sáez et al.
50 citations
Certain phenylethylamines (PEAs), including 2C-I, 2C-B, 2C-D, and 2C-H, block serotonin 5-HT2A receptors but not 5-HT2C receptors, showing subtype selectivity. In experiments with frog oocytes engineered to carry rat receptor clones, these compounds inhibited serotonin-induced currents at the 5-HT2A receptor, requiring a two-minute preincubation for maximum effect. The blocking potency depended on the chemical substituent at the fourth carbon position, with 2C-I being the most potent, followed by 2C-B, 2C-D, and 2C-H. The findings suggest that the psychoactive effects of these compounds may not rely solely on activating 5-HT2A receptors, as previously thought.
British journal of pharmacology
February 1, 1996
M E Benwell, P E Holtom, R J Moran et al.
40 citations
Ibogaine, given to rats 22 hours earlier, reduced the nicotine-triggered increase in dopamine overflow in the nucleus accumbens, a brain region linked to reward, but did not affect nicotine-induced hyperlocomotion. Ibogaine alone caused no changes in dopamine or movement. In the elevated plus-maze test, ibogaine reduced open-arm entries in both saline- and nicotine-treated rats, suggesting anxiety-like effects, and increased total activity in nicotine-treated rats was unaffected by ibogaine. Ibogaine also altered levels of serotonin metabolites in several brain regions, with changes lasting at least 7 days. The authors suggest ibogaine may inhibit nicotine's rewarding effects but caution that its long-lasting anxiogenic effects require further study before it could be recommended for smoking cessation.
British journal of pharmacology
April 1, 1986
L Rényi
39 citations
In rats, the ejaculatory response and other behaviors linked to serotonin (5-HT) were tested after giving a serotonin-releasing drug (5-MeODMT) following treatment with various serotonin reuptake inhibitors (fluoxetine, zimeldine, alaproclate, citalopram). Acute doses of fluoxetine and zimeldine reduced the ejaculatory response when given 48 hours before 5-MeODMT, an effect blocked by a serotonin receptor antagonist. After 7 or 14 days, a single dose of fluoxetine enhanced the response, which returned to normal by day 24. Repeated fluoxetine treatment extended the blockade and delayed sensitization. Alaproclate and citalopram only blocked the response 1 hour after acute dosing. The findings indicate that different serotonin reuptake inhibitors do not uniformly alter serotonin receptor functions.
British journal of pharmacology
March 1, 2023
Antonio Inserra, Giada Giorgini, Sebastien Lacroix et al.
38 citations
Repeated doses of LSD increase social behavior in male mice and alter brain chemistry and gut bacteria. LSD raised social preference and novelty seeking. In the hippocampus, LSD lowered several endocannabinoid-like compounds, including anandamide and related N-acylethanolamines, certain monoacylglycerols, prostaglandins, thromboxane, and kynurenine. The prefrontal cortex showed fewer changes. LSD also reduced the diversity of gut bacteria, prevented a shift in the Firmicutes:Bacteroidetes ratio, and changed the abundance of specific bacterial groups such as Bifidobacterium. These findings suggest that the prosocial effects of LSD involve the hippocampal endocannabinoidome and kynurenine pathway, along with gut microbiome alterations.
British journal of pharmacology
March 1, 2002
Nicholas Macinnes, Sheila L Handley
30 citations
Rats trained to distinguish the imidazoline I2-site ligand 2-BFI from saline showed that several compounds that reversibly inhibit monoamine oxidase A (MAO-A), including the anti-addictive drug ibogaine, produced similar internal cues, substituting for 2-BFI in a dose-dependent manner. In contrast, MAO-B inhibitors and other related compounds failed to substitute. The findings suggest that the subjective effects of I2-site ligands are linked to reversible MAO-A inhibition, likely through increased extracellular monoamine levels, and that ibogaine shares these subjective effects.
British journal of pharmacology
June 1, 2024
Isabel Werle, Laura M M Nascimento, Aymee L A Dos Santos et al.
21 citations
A single oral dose of ayahuasca containing 0.3 mg/kg of DMT increased within-session extinction of contextual freezing behavior in rats without affecting recall; two consecutive daily doses enhanced extinction recall. These effects occurred for both 1- and 21-day-old memories in males and females, independent of changes in anxiety or general exploratory activity. Blocking 5-HT2A receptors in the infralimbic cortex prevented within-session extinction, while blocking 5-HT1A receptors prevented between-session extinction. The findings highlight complementary mechanisms by which ayahuasca facilitates behavioral suppression of aversive memories, suggesting potential benefits for stress-related disorders.
British journal of pharmacology
October 1, 1986
T Archer, W Danysz, G Jonsson et al.
16 citations
In rats, drugs that block alpha-2 adrenoceptors (yohimbine and phentolamine) injected into the spinal cord prevented or reduced the pain-relieving effects of a serotonin-like drug (5-MeODMT) in three different pain tests (hot-plate, tail-flick, and shock titration). A different blocker (prazosin) reduced the pain relief in two of the tests but not the third. Yohimbine alone lowered pain thresholds in a dose-dependent way. The results indicate that alpha-2 adrenoceptors interact with serotonin-induced pain relief at the spinal level.
British journal of pharmacology
December 1, 2024
Yong-Yu Yin, Jiao-Zhao Yan, Qian-Qian Wei et al.
13 citations
Ketamine produces rapid antidepressant-like effects in mice within 60 minutes and increases brain serotonin levels. The sustained effects at 24 hours require an intact serotonin system: depleting serotonin or knocking out the serotonin synthesis enzyme Tph2 eliminated the 24-hour but not the 60-minute effects. Blocking AMPA receptors with NBQX also prevented the rise in serotonin and abolished the sustained antidepressant-like effects. Serotonergic neurotransmission is necessary for ketamine's lasting antidepressant action, and this mechanism involves AMPA receptors.
British journal of pharmacology
January 1, 2022
Kristýna Štefková-mazochová, Hynek Danda, Wim Dehaen et al.
13 citations
Deschloroketamine (DCK), a structural analogue of ketamine sold as a recreational drug, was tested in Wistar rats to examine its pharmacokinetics, acute effects, and addictive potential. DCK rapidly entered the brain, with peak levels at 30 minutes and sustained high levels for 2 hours. It blocks NMDA receptors similarly to ketamine, with the S-enantiomer more potent. DCK stimulated locomotion, induced place preference (a sign of reward), and strongly disrupted prepulse inhibition (PPI). Locomotor stimulation faded faster than PPI disruption. S-DCK had stronger stimulatory effects than R-DCK, but both equally disrupted PPI. DCK's behavioral and addictive profiles resemble ketamine's, with a slightly slower clearance, matching its reported longer duration. These findings clarify risks of illicit DCK use.
British journal of pharmacology
October 28, 2024
Laith Alexander, Dasha Anderson, Luke Baxter et al.
11 citations
Psychedelic drugs are being investigated as a new class of rapid-acting antidepressants, but their mechanisms remain unclear—specifically whether antidepressant and psychedelic effects arise from related or independent processes. This review examines behavioral methods used in animal studies to measure both the psychedelic and antidepressant effects of these drugs. It highlights conceptual and methodological challenges, stresses the importance of using doses comparable to those in human clinical use, and calls for attention to potential sex differences in preclinical research. Understanding these mechanisms could help identify new drug targets and improve treatments.
British journal of pharmacology
August 1, 1986
L Rényi
10 citations
Repeated but not single treatment with the 5-HT agonist 5-MeODMT strongly but reversibly reduced the ejaculatory response and other behavioral responses in rats. Repeated treatment with nonselective, irreversible MAO inhibitors nialamide and pargyline markedly reduced the ejaculatory response but only slightly affected behavioral responses. Repeated treatment with MAO-B inhibitor (-)-deprenyl, MAO-A inhibitor clorgyline, reversible MAO-A inhibitor moclobemide, and low doses of PCA did not affect either response. Combined repeated treatment with clorgyline plus PCA caused an almost complete blockade of all responses. Selective, reversible MAO-A inhibitors amiflamine, alpha-ethyltryptamine, and alpha-methyltryptamine reduced the ejaculatory response after both single and repeated treatments, with behavioral responses blocked only after repeated treatment. The authors conclude that single and repeated treatments with different MAO inhibitors do not produce a common alteration in 5-HT2 receptor functions.
British journal of pharmacology
June 22, 2025
Aurelija Ippolito, Sridhar Vasudevan, Shaun Hurley et al.
9 citations
Serotonergic psychedelic drugs are being studied as treatments for psychiatric disorders like major depression. All such drugs activate the 5-HT2A receptor, but some 5-HT2A receptor agonists are not psychedelic. This investigation tested six psychedelic drugs (psilocin, 5-MeO-DMT, LSD, mescaline, 25B-NBOMe, and DOI) and three non-psychedelic drugs (lisuride, TBG, and IHCH-7079) for their effects on Gq-coupled and β-arrestin2 signaling pathways in cells expressing human 5-HT2A receptors. All psychedelic drugs were unbiased partial agonists at both pathways. The non-psychedelic drugs were not distinguished by signaling bias but showed the lowest signaling efficacy among all drugs tested, a finding confirmed in rat C6 cells. Low 5-HT2A receptor signaling efficacy may explain why some agonists lack psychedelic effects.
British journal of pharmacology
October 2, 2024
Ryan H Gumpper, David E Nichols
9 citations
Classic serotonergic psychedelics come in three main chemical families: phenethylamines, ergolines, and tryptamines. Each family has distinct structural features that determine its psychedelic activity in humans. The 5-HT2A receptor, a G-protein coupled receptor, is the primary target for these compounds. Recent X-ray and cryoEM structures showing various ligands bound to the receptor reveal the atomic-level details of how different psychedelic molecules interact with this receptor. These structural insights help explain known pharmacological observations about how psychedelic drugs work and may guide future drug development.
British journal of pharmacology
May 23, 2025
Trevor Sharp, Aurelija Ippolito
8 citations
Psychedelic drugs like LSD and psilocin, once banned and stigmatized, are now being studied for their long-lasting benefits in mental illnesses such as depression, addictions, and anxiety disorders. Their powerful hallucinatory effects are thought to be mediated by agonist action at 5-HT2A receptors, but the link between the psychedelic experience and therapeutic outcomes remains uncertain. Recent research has identified a new class of 5-HT2A receptor agonists that may retain therapeutic potential without inducing hallucinations, with biased signalling, partial agonism, and increased neuroplasticity offering possible explanations for their effects. This article explores the neuropsychopharmacological properties of both hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists as potential novel psychiatric treatments.
British journal of pharmacology
April 1, 2000
M K Mundey, N A Blaylock, R Mason et al.
6 citations
Ibogaine and 18-methoxycoronaridine, alkaloids with reported anti-addictive properties, modulated electrically-evoked contractions in smooth muscle preparations but did not selectively interact with mu-opioid receptors. In guinea-pig ileum, both drugs concentration-dependently inhibited cholinergic contractions (ibogaine pIC50 5.28, 18-methoxycoronaridine pIC50 5.05), an effect not blocked by naloxone. In rat vas deferens, they enhanced purinergic contractions and caused a 3- to 5-fold rightward shift of DAMGO-induced inhibition. In guinea-pig bladder, both drugs doubled the purinergic component of neurogenic contractions without affecting cholinergic contractions. Ibogaine, but not 18-methoxycoronaridine, enhanced spontaneous contractions of rat portal vein. The pronounced enhancement of purinergic contractions is a novel finding warranting further investigation.
British journal of pharmacology
November 14, 2025
Valéria Tékus, Éva Borbély, Andreas Goebel et al.
5 citations
A systematic review of Phase 1-3 clinical trials from 2014 to 2024 found no breakthrough in pharmacotherapy for chronic primary pain conditions including fibromyalgia, complex regional pain syndrome, and chronic low back pain. The lack of progress may stem from unsuccessful approaches to reveal pathophysiological mechanisms, lack of translational preclinical animal models, and patient population heterogeneity with comorbidities. Most trials focused on repurposing antidepressants, antiepileptics, psychedelics, and immune modulators. Promising candidates targeted cannabinoid, glutamate, GABAergic, neuroinflammatory, and immune mechanisms. Only cannabidiol (CBD) and (es)ketamine were tested for all three conditions despite similar etiological factors.
British journal of pharmacology
July 28, 2025
Omar Qureshi, Jamie Cowley, Ashley Pegg et al.
5 citations
Psychedelic drugs that activate 5-HT2A receptors are known for treating psychiatric disorders, but growing evidence shows they also modulate immune responses by inhibiting pro-inflammatory cytokine release. In vivo studies demonstrate that psychedelics like (R)-DOI reduce inflammation in animal models of asthma and other inflammatory diseases. Clinical studies with psilocybin show effects on circulating cytokine levels, supporting translation from animal models to humans. These findings highlight the promise of targeting inflammation therapeutically. Recent research has identified compounds that maintain therapeutic potential without causing psychedelic effects, termed PIPI drugs (Psychedelic drug Informed but Psychedelic experience Inactive), offering new avenues for treating mental health and inflammation.
British journal of pharmacology
June 1, 2026
Szabolcs Koncz, Dóra Pothorszki, Noémi Papp et al.
2 citations
In rats, the (S)-enantiomer of ketamine (esketamine) produces a fourfold stronger wake-promoting effect and a twofold stronger increase in gamma brainwave power during wakefulness compared to the (R)-enantiomer (arketamine). Only esketamine enhances delta power during NREM sleep after gamma activity normalizes, a pattern called the gamma-delta shift. This shift, previously proposed as a marker of antidepressant activity for racemic ketamine, appears specific to esketamine. The findings help clarify which enantiomer drives the EEG changes and suggest that the gamma-delta shift may serve as a biomarker for antidepressant effects, relevant to treatment-resistant depression.
British journal of pharmacology
May 13, 2025
Brian Lord, Sirak Simavorian, Ian Fraser et al.
2 citations
A selective GluN2A antagonist, JNJ-78911118, blocks GluN1/2A receptors with an IC50 of 44 nM and shows selectivity over other NMDA receptor subtypes. It increases prefrontal cortex monoamine levels in wild-type but not GluN2A knockout mice, blocks hippocampal long-term potentiation, and boosts dendritic complexity, synapse number, and mEPSC frequency in rat cortical neurons. In rats, no Olney's lesions occurred, but acute increases in heart rate and blood pressure were detected. The molecule reproduces effects of known rapidly acting antidepressants on neurotransmitter levels and synaptic plasticity, offering a tool to study GluN2A biology.
British journal of pharmacology
July 1, 2026
Yuanyuan Wang, Yishan Yao, Ruibin Su et al.
1 citation
The psychedelic compound 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT) suppresses innate fear responses in rats by activating 5-HT₂A receptors, which recruit vasoactive intestinal polypeptide (VIP) interneurons in the prelimbic cortex. In behavioral experiments, 4-AcO-DMT reduced predator odor-evoked 22-kHz ultrasonic vocalizations, a fear-related response, through this specific cortical microcircuit mechanism. Chemogenetic activation of VIP interneurons abolished the fear-suppressing effect, confirming their role. The findings advance understanding of how serotonergic psychedelics modulate fear circuits at a neurobiological level, with potential implications for treating fear-related psychiatric disorders like phobias and anxiety.
British journal of pharmacology
November 23, 2025
Tianhua Wang, Rainer K W Schwarting, Markus Wöhr
1 citation
MDMA (ecstasy) stimulates arousal and euphoria by releasing dopamine, noradrenaline, and serotonin in the brain, but which chemical drives these effects has been unclear. In rats genetically modified to lack central serotonin, MDMA failed to increase psychomotor activity (a marker of arousal) and 50-kHz ultrasonic vocalizations (a marker of euphoria). Rats with reduced serotonin showed no euphoric response and only partial arousal. The findings indicate that central serotonin is necessary for MDMA's arousal- and euphoria-inducing effects, suggesting dopamine and noradrenaline are not sufficient to produce these responses.