British Journal of Pharmacology
June 1, 1983
Nabil A. Anis, Stephen C. Berry, N.r. Burton et al.
1,415 citations
Ketamine and phencyclidine selectively block excitation of spinal neurons by N-methyl-aspartate (NMA) while leaving responses to quisqualate and kainate largely unaffected. In cats and rats, ketamine reduced responses to L-aspartate more than those to L-glutamate. On Renshaw cells, both drugs reduced acetylcholine responses less than NMA responses but more than quisqualate or kainate responses. Intravenous ketamine (2.5-20 mg/kg) and phencyclidine (0.2-0.5 mg/kg) also selectively blocked NMA-induced excitation. The findings suggest that reducing synaptic excitation mediated via NMA receptors contributes to the anaesthetic and analgesic properties of these dissociative anaesthetics.
British Journal of Pharmacology
September 1, 1968
N.‐e. Andén, H. Corrodi, Kjell Fuxé et al.
274 citations
Lysergic acid diethylamide (LSD) produces functional effects in rat spinal cord and brain similar to those of the serotonin (5-hydroxytryptamine) precursor 5-hydroxytryptophan, indicating that LSD stimulates central serotonin receptors. Using histochemical and biochemical techniques, LSD reduced the turnover rate of serotonin in the brain and spinal cord after inhibition of tryptophan hydroxylase. The turnover of noradrenaline, but not dopamine, was somewhat accelerated. These effects were dose- and time-dependent and were not observed with the LSD analogues 2-bromo-LSD and methysergide. The retardation of serotonin turnover by LSD may result from negative feedback mechanisms triggered by direct stimulation of central serotonin receptors.
British Journal of Pharmacology
January 1, 2002
Annis O. Mechan, B. Moreno Esteban, Esther O’shea et al.
219 citations
MDMA (ecstasy) causes acute hyperthermia in rats by increasing dopamine release, which acts on D1 receptors, rather than through serotonin release. Blocking serotonin receptors or inhibiting serotonin reuptake did not prevent the rise in body temperature, but blocking D1 dopamine receptors with SCH 23390 did. The tail skin temperature did not increase, suggesting MDMA impairs heat dissipation. These findings indicate that dopamine, not serotonin, is the primary driver of MDMA-induced hyperthermia, which has implications for clinical treatment.
British Journal of Pharmacology
December 1, 1971
A. David Smith
179 citations
In rats treated with a monoamine oxidase inhibitor, the hyperactivity and fever caused by L-tryptophan were blocked by chlorpromazine. Chlorpromazine did not slow the increased production of the brain chemical serotonin from tryptophan. Hyperactivity and fever were also triggered by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), and a monoamine oxidase inhibitor made the hyperactivity stronger. Blocking serotonin synthesis with p-chlorophenylalanine did not stop the hyperactivity from 5-MeODMT. Chlorpromazine likely inhibits these effects by competing with serotonin or 5-MeODMT at receptor sites or through physiological antagonism.
British Journal of Pharmacology
June 1, 1997
M. Isabel Colado, Esther O’shea, R Granados et al.
176 citations
High doses of MDMA (ecstasy) given to pregnant rats on days 14–17 of gestation caused a marked hyperthermic response in the mothers, reduced their body weight, and decreased litter size by about 20%. In the mothers' brains, serotonin (5-HT) and its metabolite 5-HIAA fell by over 65% in the hippocampus and striatum and by 40% in the cortex one week after birth. However, the brains of the newborn pups showed no such decreases. MDMA also increased lipid peroxidation (TBARS) in the cortex of adult rats but not in 7–10 day old neonates.
British Journal of Pharmacology
July 1, 1997
María Isabel Colado, Esther O’shea, R Granados et al.
175 citations
MDMA (ecstasy) and p-chloroamphetamine (PCA) damage serotonin neurons in rat brain by increasing free radical formation, measured as 2,3-dihydroxybenzoic acid from salicylic acid via microdialysis in the hippocampus. A single dose of MDMA (15 mg/kg) raised 2,3-DHBA for at least 6 hours and reduced serotonin and its metabolite by over 50% in hippocampus, cortex, and striatum seven days later. PCA (5 mg/kg) also increased 2,3-DHBA. Fenfluramine (15 mg/kg) did not increase free radicals but still caused long-term serotonin loss. Pretreatment with fenfluramine blocked MDMA's free radical rise, indicating radicals originate in serotonin neurons. The free radical scavenger PBN prevented the acute radical increase and attenuated long-term hippocampal damage by 30%. Thus, MDMA and PCA damage serotonin neurons via free radicals, while fenfluramine acts through a different mechanism.
British Journal of Pharmacology
August 1, 1995
M. Isabel Colado, Jodi L. Williams, A.r. Green
165 citations
In Dark Agouti rats, female animals had 57% higher plasma MDMA concentrations and 48% lower MDA concentrations than males 45 minutes after injection, and showed a stronger hyperthermic response to MDMA. This suggests impaired N-demethylation in females, which model the human poor metabolizer phenotype for debrisoquine 4-hydroxylase. A single 10 mg/kg dose of MDMA caused substantial loss of serotonin and its metabolite in cortex and hippocampus seven days later, along with a 27% decrease in [3H]-paroxetine binding, indicating neurodegeneration. MDA at 5 mg/kg produced about 40% serotonin loss in both sexes. Low debrisoquine hydroxylase activity did not prevent formation of neurotoxic metabolites.
British Journal of Pharmacology
October 1, 1970
R.j. Boakes, Philip Bradley, Ian Briggs et al.
164 citations
Lysergic acid diethylamide (LSD) antagonizes excitation produced by serotonin (5-HT) and glutamate on certain brain stem neurons in decerebrate cats. When applied directly or intravenously, LSD blocked 5-HT-induced excitation and also blocked glutamate excitation on neurons that could be excited by 5-HT. However, LSD did not affect inhibitory actions of 5-HT, glutamate effects on neurons inhibited by 5-HT, or actions of acetylcholine, noradrenaline, homocysteic acid, glycine, or GABA. Methysergide was a weaker antagonist, and 2-bromo-LSD rarely showed antagonism. The authors propose that antagonism to 5-HT and glutamate excitation may underlie LSD's psychotomimetic effects.
British Journal of Pharmacology
May 5, 2009
Daniela Braida, Valeria Capurro, Alessia Zani et al.
145 citations
Salvinorin A, the active ingredient in Salvia divinorum, produced both anxiety-reducing and antidepressant-like effects in rats and mice. These effects were prevented by blocking either kappa-opioid or CB1 cannabinoid receptors. Salvinorin A reduced fatty acid amide hydrolase activity in the amygdala but showed very weak binding to CB1 receptors. The findings suggest that both kappa-opioid and endocannabinoid systems mediate these mood-altering effects, which may help explain subjective experiences reported by recreational users.
British Journal of Pharmacology
March 1, 1993
María Isabel Colado, Tracey K. Murray, A.r. Green
133 citations
Chlormethiazole and dizocilpine prevent neurotoxicity from MDMA (Ecstasy) but not from PCA or fenfluramine in rat brain. MDMA caused about 30% loss of serotonin and its metabolite in cortex and hippocampus; chlormethiazole given before and after MDMA fully protected both regions, while dizocilpine protected only the hippocampus. A single dose of chlormethiazole 20 minutes after MDMA also fully protected the hippocampus but not the cortex and reduced MDMA-induced hyperthermia (about +2.5°C). PCA caused 70% serotonin loss; neither drug prevented this, even when a lower PCA dose caused only 30% loss. Fenfluramine-induced serotonin loss was also not prevented. Both drugs blocked serotonin-related behaviors from all three toxins. The findings suggest different mechanisms underlie neurotoxicity from these amphetamines, and hyperthermia alone does not account for the damage.
British Journal of Pharmacology
December 1, 2001
M. Isabel Colado, Jorge Camarero, Annis O. Mechan et al.
122 citations
MDMA (ecstasy) causes long-term damage to dopamine nerve terminals in the mouse striatum, accompanied by acute hyperthermia. Blocking NMDA receptors or using clomethiazole did not protect against this damage. The free radical trap PBN and the nitric oxide synthase inhibitor 7-NI were protective but also lowered body temperature. Two other NOS inhibitors, S-methyl-L-thiocitrulline and AR-R17477AR, provided significant neuroprotection with little effect on hyperthermia. MDMA increased free radical formation in the striatum, which was prevented by AR-R17477AR, which lacks radical-trapping activity. This suggests MDMA neurotoxicity involves radicals from MDMA or dopamine metabolites combining with nitric oxide to form damaging peroxynitrites.
British Journal of Pharmacology
October 29, 2003
Julie Salzmann, Cynthia Marie‐claire, Stéphanie Le Guen et al.
120 citations
The ras-dependent protein kinase ERK pathway plays a role in the rewarding and locomotor effects of MDMA (ecstasy) in mice. Repeated MDMA treatment at 9 mg/kg (but not 3 or 6 mg/kg) induced conditioned place preference, a measure of reward, and increased locomotor activity; both effects were blocked by an inhibitor of ERK activation. MDMA also increased transcription of the immediate early gene c-fos in the caudate putamen, nucleus accumbens, and hippocampus, and of egr-1 and egr-3 in the caudate putamen. The ERK inhibitor suppressed these gene expression changes only in the caudate putamen, indicating that other signaling pathways regulate immediate early gene transcription elsewhere.
British Journal of Pharmacology
March 13, 2015
Anna Rickli, Simone Kopf, Marius C. Hoener et al.
115 citations
Benzofurans, a class of newly used psychoactive substances, inhibit norepinephrine and serotonin uptake more than dopamine uptake, similar to MDMA and unlike methamphetamine. They also release monoamines and interact with trace amine-associated receptor 1, like classic amphetamines. Most benzofurans are partial 5-HT2A receptor agonists, similar to MDMA, but also activate 5-HT2B receptors, which is associated with heart valve fibrosis, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY potently interacts with 5-HT2 receptors and binds to TA1 receptors, indicating predominant hallucinogenic properties and a risk for vasoconstriction.
British Journal of Pharmacology
November 25, 2021
Éva Borbély, Mária Simon, Eberhard Fuchs et al.
103 citations
Major depressive disorder is a leading cause of disability worldwide, and conventional therapies fail many patients, especially those with treatment-resistant depression (TRD). This review examines novel drug targets and candidates in Phase I–III clinical trials. The most promising approaches include blocking glutamatergic neurotransmission with NMDA and mGlu5 receptor antagonists, modulating the opioidergic system with κ receptor antagonists, and using hallucinogenic tryptamine derivatives. The only registered drug for TRD is the NMDA receptor antagonist S-ketamine, but add-on therapies with second-generation antipsychotics, nutritive, anti-inflammatory, and neuroprotective agents also appear effective. Ongoing large-scale omics and neuroimaging studies may reveal new molecular mechanisms and therapeutic strategies.
British Journal of Pharmacology
September 1, 2001
Violeta Sánchez Sánchez, Jorge Camarero, B. Moreno Esteban et al.
103 citations
Fluoxetine provides long-lasting protection against MDMA-induced damage to serotonin nerve endings in rat brain, while fluvoxamine only protects when given at the same time. MDMA caused loss of serotonin and its metabolite in cortex, hippocampus, and striatum, and reduced paroxetine binding one week later. Fluoxetine given with MDMA or up to four days before offered complete protection, and significant protection when given seven days before. Fluvoxamine required concurrent administration. Fluoxetine's protection appears due to its and its active metabolite's inhibition of the serotonin transporter, not by altering MDMA accumulation or metabolism.
British Journal of Pharmacology
March 3, 2010
James R. Docherty, Ar Green
88 citations
Hyperthermia is a well-known acute adverse effect of MDMA (ecstasy) use, but the drug's influence on body temperature is complex, involving actions on serotonin, dopamine, and noradrenaline systems. In laboratory animals, MDMA can cause either hyperthermia or hypothermia depending on ambient temperature, through central thermoregulation and peripheral changes in blood flow and heat generation. Serotonin receptors modulate the hyperthermic response, while dopamine and noradrenaline systems also contribute—noradrenaline activates receptors that constrict skin blood vessels and increase heat production in brown fat. Hyperthermia in recreational users can be fatal, and no single drug is likely to reverse it; careful body cooling remains the main treatment. Educating users about ambient temperature control is key to prevention.
British Journal of Pharmacology
February 1, 1999
María Isabel Colado, Esther O’shea, R Granados et al.
82 citations
Dopamine does not appear to cause the damage to serotonin nerve endings that occurs in the brain of Dark Agouti rats after MDMA (ecstasy) administration. The drug haloperidol prevented both the acute rise in body temperature and the long-term loss of serotonin when given around the time of MDMA, but this protection was minimal when body temperature was kept high. MDMA increased dopamine levels in the brain by 800%, but boosting dopamine further with L-DOPA did not worsen the nerve damage, nor did it make a low, non-toxic dose of MDMA become toxic. The findings suggest that earlier studies linking dopamine to MDMA's neurotoxicity may have been confounded by effects on body temperature.
British Journal of Pharmacology
March 8, 2012
C.m. Hysek, Yasmin Schmid, Anna Rickli et al.
81 citations
The α₁- and β-adrenoceptor antagonist carvedilol reduced MDMA-induced increases in blood pressure, heart rate, and body temperature in healthy subjects, but did not affect the subjective or psychotropic effects of MDMA, such as drug liking, high, or stimulation. Carvedilol also did not alter plasma exposure to MDMA. These findings suggest that α₁- and β-adrenoceptors contribute to the cardiostimulant and thermogenic effects of MDMA in humans but not to its psychological effects, indicating carvedilol could be useful for treating cardiovascular and hyperthermic complications associated with ecstasy use.
British Journal of Pharmacology
June 1, 1998
María Isabel Colado, R Granados, Esther O’shea et al.
80 citations
In rats, the drug MDMA ('ecstasy') caused a rapid rise in body temperature (hyperthermia) and, seven days later, damage to serotonin nerve endings in the brain. A low-affinity NMDA receptor blocker, AR-R15896AR, did not prevent the hyperthermia or the long-term loss of serotonin markers in the cortex, striatum, and hippocampus. In contrast, the neuroprotective agent clomethiazole abolished the hyperthermic response and markedly reduced serotonin loss—by about 75% at normal room temperature.
British Journal of Pharmacology
February 1, 2002
Mary L. Forsling, John K. Fallon, Darshna Shah et al.
77 citations
MDMA and its metabolites can stimulate release of the hormones vasopressin and oxytocin from rat hypothalamic tissue in the laboratory. The metabolite HMMA (4-hydroxy-3-methoxymethamphetamine) was the most potent, increasing basal vasopressin release more than twofold and oxytocin release by about 60% at a concentration of 10 nM. MDMA itself produced smaller increases. The effect on vasopressin release was consistently greater than on oxytocin. These findings suggest that MDMA-induced hyponatraemia (low blood sodium) may result from excessive vasopressin secretion triggered by the drug or its breakdown products.
British Journal of Pharmacology
March 24, 2014
Andrew R. Green, Madeleine V. King, S.e. Shortall et al.
70 citations
Mephedrone, a substituted β-keto amphetamine banned in the UK in 2010, continues to be used recreationally. Users compare its effects to MDMA (ecstasy), but preclinical data reveal key differences. Both drugs enhance locomotor activity and change rectal temperature in rodents, but mephedrone's effects are shorter due to its rapid metabolism and short plasma half-life. Unlike MDMA, mephedrone has no pharmacologically active metabolites and little evidence of inducing neurotoxic decreases in monoamine concentrations. Both drugs induce dopamine and serotonin release, but mephedrone's effect on serotonin release is more marked. Mephedrone shows high abuse liability, supporting self-administration at higher rates than MDMA, and its pharmacological profile differs from other cathinones as well.
British Journal of Pharmacology
July 4, 2005
A Richard Green, Esther O’shea, Kathryn S. Saadat et al.
70 citations
In rats, MDMA (ecstasy) causes hyperthermia at normal or warm room temperatures but hypothermia in cool conditions. At 15°C, MDMA rapidly lowered rectal temperature; this effect was blocked by a dopamine D2 receptor antagonist but not a D1 antagonist. A neurotoxic MDMA regimen reduced serotonin in the brain by about 30% after a week. This serotonin lesion did not affect tail temperature increases when rats moved from 20°C to 30°C, but led to lower tail temperatures when returned to 24°C. Acute MDMA in lesioned rats at 30°C caused a sustained drop in tail temperature. The findings suggest that thermoregulatory problems in MDMA-lesioned rats stem partly from impaired heat loss through the tail, a key heat-loss organ.
British Journal of Pharmacology
January 1, 2005
Isabel Escobedo, Esther O’shea, Laura Orío et al.
68 citations
MDMA itself does not cause the immediate release of dopamine or serotonin in the mouse brain; instead, peripheral injection of MDMA reduced striatal dopamine and modestly reduced serotonin one hour after the last dose, but direct injection into the striatum did not produce these acute effects. The metabolite HHMA also did not contribute to acute dopamine depletion, as its effects differed from MDMA after peripheral injection. Long-term dopamine loss seven days later was not due to MDMA itself, since only very high intrastriatal doses caused such loss, and HHMA did not alter striatal dopamine after peripheral injection. HHMA crossed the blood–brain barrier but was not detected in brain after peripheral MDMA, suggesting it is metabolized to other active compounds.
British Journal of Pharmacology
January 1, 1970
68 citations
The release of acetylcholine, 5-hydroxytryptamine, noradrenaline, and D-lysergic acid diethylamide from micropipettes during iontophoresis is directly proportional to the electrical charge passed. Transport numbers are about twice as high for large micropipettes compared to small ones, and D-lysergic acid diethylamide has a very low transport number. Spontaneous leakage of these compounds is small and stable over time. In vitro measurements of acetylcholine release match in vivo findings. Brain-stem concentrations of D-lysergic acid diethylamide after intravenous injection were measured in intact and decerebrate cats.
British Journal of Pharmacology
August 1, 1979
G. Curzon, J.c.r. Fernando, Andrew J. Lees
66 citations
Backward walking and circling in rats require simultaneous release of both dopamine and serotonin. A high dose of amphetamine (which releases dopamine) or drugs that release serotonin (p-chloroamphetamine or fenfluramine) each produced these behaviors. Combining smaller doses of amphetamine with either serotonin-releasing drug also triggered backward walking and circling. However, typical dopamine-driven behaviors (rearing, licking, gnawing) from amphetamine were greatly reduced by the serotonin drugs, while typical serotonin-driven behaviors (wet dog shake, hind limb abduction) were unaffected by amphetamine. Fragmentary backward walking and circling from levallorphan were reduced by low-dose amphetamine. The findings strengthen evidence that these movements depend on both dopamine and serotonin release, with possible relevance to hallucinogenic activity, amphetamine psychosis, schizophrenia, and abnormal movements from L-DOPA treatment.