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
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
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
P. B. Bradley, J. M. Candy
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.
British Journal of Pharmacology
August 1, 2002
Daniela Braida, Mariaelvina Sala
64 citations
Rats can learn to self-administer MDMA directly into the brain's ventricles, and the amount they take depends on the dose and on cannabinoid signaling. At most doses, rats pressed a lever more often to receive MDMA, except at the highest dose tested. Adding a synthetic cannabinoid (CP 55,940) to MDMA reduced lever pressing for the drug. Blocking the CB1 cannabinoid receptor with SR 141716A increased MDMA self-administration. These results indicate that the brain's own endocannabinoid system normally restrains MDMA-seeking behavior.
British Journal of Pharmacology
February 20, 2006
Sotiria Bexis, James R. Docherty
62 citations
In conscious rats, the amphetamine derivatives MDMA, MDA, and MDEA (each at 20 mg/kg) affected blood pressure, heart rate, body temperature, and movement. MDA caused the largest and most prolonged rise in blood pressure, accompanied by a slowed heart rate, while MDEA produced a brief, non-significant drop in diastolic pressure. All three initially lowered core body temperature, but MDA later caused a rise in temperature, with recovery speed fastest for MDA, then MDMA, then MDEA. Blocking α2A-adrenoceptors with BRL 44408 prolonged MDMA's hypothermic effect and triggered increased movement only with MDMA. In isolated rat aorta and vas deferens, the drugs' potency for contraction matched MDA > MDMA > MDEA, with MDEA acting as an antagonist.
British Journal of Pharmacology
January 1, 1994
María Isabel Colado, A.r. Green
62 citations
In rats, the drug MDMA ('Ecstasy') caused a 50% loss of serotonin (5-HT) and its metabolite 5-HIAA in the cortex and hippocampus four days later, indicating long-term neurotoxicity. The compounds gamma-butyrolactone and pentobarbitone protected against this loss, while ondansetron did not. MDMA did not significantly affect striatal dopamine levels but slightly reduced DOPAC. Four hours after MDMA, serotonin was depleted by over 80%, and none of the protective drugs altered this initial loss, suggesting protection does not work by blocking serotonin release. Protective compounds may instead inhibit dopamine release in the striatum, as MDMA's neurotoxicity depends on dopamine neurons.
British Journal of Pharmacology
December 30, 2010
Susan Schenk, David Gittings, Joyce Colussi‐mas
61 citations
In rats trained to self-administer MDMA (ecstasy), a light cue previously paired with the drug triggered drug-seeking behavior. This effect was amplified by priming injections of drugs that activate dopamine D2-like receptors (quinpirole, amphetamine, GBR 12909) but not by a D1-like receptor agonist (SKF 81297), the non-selective dopamine agonist apomorphine, or serotonin (5-HT) receptor agonists. A serotonin uptake inhibitor reduced cue-induced drug-seeking but did not block the potentiation caused by a dopamine uptake inhibitor. Blocking either D1 or D2 receptors attenuated the MDMA-enhanced drug-seeking. The findings suggest that after repeated MDMA use, dopamine pathways become more influential in driving relapse to drug-seeking, partly because MDMA reduces brain serotonin levels.
British Journal of Pharmacology
June 1, 2012
Natacha Vanattou‐saïfoudine, Ruth Mcnamara, Andrew Harkin
60 citations
Consuming caffeine with recreational psychostimulant drugs like MDMA (ecstasy) can cause severe acute adverse reactions and long-term harm. Caffeine increases toxicity by disrupting body temperature regulation, causing heart damage, and lowering the seizure threshold. In rats, co-administering caffeine with MDMA dramatically raises core body temperature, heart rate, and death rates, and worsens long-term damage to serotonin neurons. The interaction involves MDMA boosting dopamine release while caffeine blocks adenosine receptors and inhibits PDE. Similar mechanisms apply to interactions with cocaine, d-amphetamine, and ephedrine. Understanding these mechanisms helps guide interventions for managing severe reactions and drug-related toxicity from combined caffeine and psychostimulant use.
British Journal of Pharmacology
June 12, 2006
Esther O’shea, Laura Orío, Isabel Escobedo et al.
57 citations
MDMA (ecstasy) causes long-term damage to serotonin neurons in the rat brain, but measuring serotonin levels alone may overestimate the extent of that damage. In male DA rats given a single dose of MDMA, serotonin content and a marker of serotonin nerve terminals were reduced in the cortex and hippocampus for up to 32 weeks. The activity of the enzyme that makes serotonin was also reduced for 8 weeks but recovered by 32 weeks. Housing rats in a cold environment prevented the loss of nerve-terminal markers but not the drop in serotonin levels, suggesting that the serotonin loss partly reflects enzyme inhibition rather than only neuron death. The damaged neurons did not increase serotonin production to compensate.
British Journal of Pharmacology
November 1, 1999
Aisling Lavelle, Valerie Honner, James R. Docherty
55 citations
MDMA (ecstasy) acts as an agonist at alpha-2 adrenoceptors in the rat peripheral nervous system, inhibiting noradrenaline release and nerve-stimulated contractions. In atrial slices, MDMA (10 µM) reduced tritium release evoked by electrical stimulation, an effect blocked by the alpha-2 antagonist yohimbine. In the epididymal vas deferens, MDMA inhibited contractions with a pD2 of 5.88, antagonized by yohimbine but not by a serotonin receptor antagonist. In the prostatic vas deferens, yohimbine converted MDMA's inhibition into potentiation of contractions. Radioligand binding showed MDMA had similar affinities for alpha-2B, alpha-2C, and alpha-2D adrenoceptor subtypes, with pKi values around 5.1–5.3.
British Journal of Pharmacology
March 1, 1974
Philip Bradley, Ian Briggs
54 citations
Three psychotomimetic tryptamines—DMT, bufotenine, and 5-MeODMT—specifically blocked serotonin-induced excitations of single neurons in the brain stem of anesthetized rats and decerebrate cats, similar to LSD. The non-psychotomimetic 5-MeOT had no such antagonistic effect. Unlike LSD, the psychotomimetic tryptamines rarely blocked glutamate effects, suggesting separate but spatially close serotonin and glutamate receptors. These tryptamines could mimic serotonin's actions on neurons, but the psychotomimetic ones were less potent than 5-MeOT. The serotonin-mimicking effects were not due to serotonin release, as they persisted after depletion of serotonin by p-chlorophenylalanine or reserpine, indicating direct action on serotonin receptors. The findings support the hypothesis that LSD-like psychotomimetics act by antagonizing serotonin in the lower brain stem, not by stimulating serotonin receptors.
British Journal of Pharmacology
June 1, 2004
Jon E. Sprague, Robert E. Brutcher, Edward Mills et al.
53 citations
In male rats, the drug MDMA (Ecstasy) caused a rapid and large increase in body temperature, which was significantly reduced by blocking two types of receptors: α₁-adrenoreceptors and β₃-adrenoreceptors. MDMA also raised levels of creatine kinase (a marker of muscle breakdown, peaking at 4 hours) and increased blood urea nitrogen and serum creatinine (markers of kidney function) at 4 hours. These effects were prevented by giving a combination of the α₁ antagonist prazosin and the β₃ antagonist SR59230A. The findings indicate that both receptor types are critically involved in MDMA-induced hyperthermia and the resulting muscle damage.
British Journal of Pharmacology
October 8, 2012
S.e. Shortall, Andrew R. Green, Km Swift et al.
51 citations
Mephedrone, a synthetic cathinone, produces different effects on body temperature and brain chemistry than MDMA (ecstasy) in rats. MDMA caused sustained decreases in rectal and tail temperature, while mephedrone caused only a transient drop in rectal temperature and a prolonged decrease in tail temperature. In contrast, cathinone and methcathinone raised rectal temperature. MDMA reduced serotonin and certain metabolites in several brain regions, whereas cathinone and methcathinone increased the dopamine metabolite homovanillic acid and serotonin metabolite 5-HIAA in the striatum. Mephedrone increased plasma noradrenaline, which was blocked by certain receptor antagonists. The adverse effects of cathinones in humans cannot be extrapolated from MDMA data.
British Journal of Pharmacology
November 15, 2013
Ana Belén López-rodríguez, Alvaro Llorente‐berzal, Luis Miguel García‐segura et al.
50 citations
In adolescent rats, chronic treatment with THC (the main psychoactive component of cannabis) and/or MDMA (ecstasy) caused long-lasting, sex-dependent changes in brain inflammation and serotonin markers. In males, both drugs increased reactive microglia (a sign of neuroinflammation). In females, each drug alone decreased reactive microglia, but the combination brought levels back to normal. MDMA reduced serotonin-transporter fibers in both sexes; THC counteracted this in males but not females. THC also reduced CB1 cannabinoid receptors in females, an effect worsened by adding MDMA. These results show that adolescent exposure to these drugs produces persistent, sex-specific neurochemical and glial alterations.
British Journal of Pharmacology
March 9, 2012
A. C. Parrott
50 citations
A commentary argues that MDMA (ecstasy) is clearly damaging to humans, contradicting the claim that animal data cannot predict its adverse effects and that MDMA does not produce serotonin neurotoxicity in the human brain. Neuroimaging studies worldwide consistently show reduced levels of the serotonin transporter (SERT) across higher brain regions in abstinent recreational users, even after controlling for confounds. These SERT reductions correlate with impairments in memory and higher cognition. The author contends that extensive empirical data demonstrate both structural and functional deficits from MDMA use in humans.
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
June 1, 2001
John Mcdaid, James R. Docherty
46 citations
MDMA (ecstasy) raises diastolic blood pressure in rats through multiple adrenoceptor mechanisms. In pithed rats, MDMA's pressor effects were blocked by α₁-adrenoceptor antagonist prazosin, α₂-antagonists yohimbine and methoxyidazoxan, and the non-selective 5-HT antagonist methiothepin, but not by the 5-HT₂ antagonist ritanserin. In anesthetized rats, MDMA produced a triphasic blood pressure response: an initial pressor phase involving α₂- and possibly α₁-adrenoceptors and 5-HT₂ receptors; a pressor component at 1 minute mediated largely by α₁-adrenoceptors; and a sustained depressor phase involving α₂-adrenoceptors and noradrenaline reuptake. The depressor response was most reduced by combining methoxyidazoxan and cocaine.
British Journal of Pharmacology
April 1, 1979
Martin Graf, A. Pletscher
45 citations
In rabbit blood platelets, tryptamine, serotonin (5-HT), and related compounds like quipazine and mescaline caused a shape change, which was blocked by low concentrations of methysergide. The most potent blockers of the serotonin-induced shape change were ergoline derivatives and neuroleptic drugs, showing high stereoselectivity. LSD, psilocine, and some dimethylated tryptamines acted as mixed agonist-antagonists. Compounds that were agonists or mixed agonist-antagonists on platelets also act as serotonin agonists in the central nervous system. However, platelet serotonin receptors responded differently to antagonists than those in brain areas with dense serotonin innervation, but similarly to receptors in spinal cord, cerebral cortex, and reticular formation. Platelets may serve as cautious models for some, but not all, central serotonin receptors.
British Journal of Pharmacology
July 18, 2005
Sotiria Bexis, James R. Docherty
43 citations
MDMA produces complex effects on body temperature, including both hypothermia and hyperthermia, depending on ambient temperature and species. This study in mice found that MDMA acts as an α₂-adrenoceptor agonist. The α₂-adrenoceptor agonist clonidine caused hypothermia in wild-type mice but not in mice lacking the α₂A-adrenoceptor. MDMA alone caused significant hyperthermia in wild-type mice, but a biphasic response (hypothermia followed by hyperthermia) in knockout mice. Blocking the α₂A-adrenoceptor in wild-type mice before MDMA resulted in initial hypothermia. Thus, MDMA's α₂A-adrenoceptor agonist actions surprisingly shift the body temperature response from biphasic to monophasic hyperthermia.
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
February 1, 1969
Michael F. Sugrue
40 citations
Three psychoactive drugs—LSD-25, psilocybin, and JB-329—reduced noradrenaline levels in the rat hypothalamus. They also affected how quickly rats learned a conditioned avoidance response: LSD-25 and psilocybin slowed learning, while JB-329 sped it up. For LSD-25 and psilocybin, doses that altered learning were lower than those needed to lower hypothalamic noradrenaline, and the peak effect on learning occurred about 1.5 hours after injection, compared to 3 hours for noradrenaline content. The dose causing gross behavioral excitation matched the dose that depleted noradrenaline. Pretreatment with reserpine or α-MT did not change the intensity of excitation from LSD-25 or psilocybin but shortened its duration; JB-329's excitation was abolished by reserpine and reduced by α-MT.
British Journal of Pharmacology
May 24, 2010
Natacha Vanattou‐saïfoudine, Ruth Mcnamara, Andrew Harkin
39 citations
Caffeine worsens the rise in body temperature caused by MDMA ('Ecstasy') in rats. The interaction depends on the combined release of the neurotransmitters serotonin and catecholamines (like dopamine). Blocking dopamine D1, serotonin 5-HT2, or alpha-1 adrenergic receptors prevented both MDMA-induced hyperthermia and its exacerbation by caffeine. Caffeine's effect was mimicked by combining a PDE-4 inhibitor with an adenosine A2A receptor antagonist, but not with an A1 receptor antagonist. The findings suggest that caffeine exacerbates MDMA hyperthermia through a mechanism involving both adenosine A2A receptor antagonism and phosphodiesterase inhibition.
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.