3,4-Methylenedioxymethamphetamine (MDMA) as a unique model of serotonin receptor function and serotonin-dopamine interactions.
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(+)-3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy"; "X"; "E") is a popular recreational amphetamine analog that produces a unique set of effects in humans and animals. MDMA use is often associated with dance parties called "raves", but its use has increased in all segments of society and around the world. Like amphetamine, MDMA elicits hyperactivity when administered to rodents. Unlike amphetamine, which has effects mediated by the release of dopamine (DA) from nerve terminals, MDMA-induced hyperactivity is thought to be dependent upon the release of 5-hydroxtryptamine (5-HT). However, MDMA elicits large increases in synaptic concentrations of both DA and 5-HT, and the interaction between these neurotransmitters may account for the unique characteristics of the drug. Comparisons between MDMA, the selective DA releaser amphetamine, and the selective 5-HT releaser fenfluramine are used in the present discussion to highlight the ability of MDMA to model the locomotor activation induced by the interaction of DA and 5-HT. Furthermore, this review summarizes evidence to suggest that the influence of 5-HT receptors on behavioral function is dependent upon the specific neurochemical environment evoked by a given drug, specifically discussed here with regard to the interaction between 5-HT and DA systems. (+info)
Cannabinoids and the gastrointestinal tract.
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The enteric nervous system of several species, including the mouse, rat, guinea pig and humans, contains cannabinoid CB1 receptors that depress gastrointestinal motility, mainly by inhibiting ongoing contractile transmitter release. Signs of this depressant effect are, in the whole organism, delayed gastric emptying and inhibition of the transit of non-absorbable markers through the small intestine and, in isolated strips of ileal tissue, inhibition of evoked acetylcholine release, peristalsis, and cholinergic and non-adrenergic non-cholinergic (NANC) contractions of longitudinal or circular smooth muscle. These are contractions evoked electrically or by agents that are thought to stimulate contractile transmitter release either in tissue taken from morphine pretreated animals (naloxone) or in unpretreated tissue (gamma-aminobutyric acid and 5-hydroxytryptamine). The inhibitory effects of cannabinoid receptor agonists on gastric emptying and intestinal transit are mediated to some extent by CB1 receptors in the brain as well as by enteric CB1 receptors. Gastric acid secretion is also inhibited in response to CB1 receptor activation, although the detailed underlying mechanism has yet to be elucidated. Cannabinoid receptor agonists delay gastric emptying in humans as well as in rodents and probably also inhibit human gastric acid secretion. Cannabinoid pretreatment induces tolerance to the inhibitory effects of cannabinoid receptor agonists on gastrointestinal motility. Findings that the CB1 selective antagonist/inverse agonist SR141716A produces in vivo and in vitro signs of increased motility of rodent small intestine probably reflect the presence in the enteric nervous system of a population of CB1 receptors that are precoupled to their effector mechanisms. SR141716A has been reported not to behave in this manner in the myenteric plexus-longitudinal muscle preparation (MPLM) of human ileum unless this has first been rendered cannabinoid tolerant. Nor has it been found to induce "withdrawal" contractions in cannabinoid tolerant guinea pig ileal MPLM. Further research is required to investigate the role both of endogenous cannabinoid receptor agonists and of non-CB1 cannabinoid receptors in the gastrointestinal tract. The extent to which the effects on gastrointestinal function of cannabinoid receptor agonists or antagonists/inverse agonists can be exploited therapeutically has yet to be investigated as has the extent to which these drugs can provoke unwanted effects in the gastrointestinal tract when used for other therapeutic purposes. (+info)
A 23 year old man presented with a clinical history and ECG compatible with acute myocardial infarction, having taken a single tablet of ecstasy (3,4-methylenedioxymetamphetamine) 18 hours previously. He was treated with aspirin and thrombolytic therapy; however, cardiac catheterisation showed angiographically normal coronary arteries and left ventricular function. Sympathomimetic drugs are freely available and widely abused in Britain, but there is little evidence of the mechanisms or management of cardiac complications. In such cases the use of standard treatment for acute myocardial infarction is recommended with agents such as glyceryl trinitrate and phentolamine to reduce coronary artery spasm. Early coronary angiography may help to determine the relative contribution of spasm, thrombus, and underlying atherosclerotic disease. (+info)
Profiles of urine samples taken from Ecstasy users at Rave parties: analysis by immunoassays, HPLC, and GC-MS.
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The abuse of the designer amphetamines such as 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) is increasing throughout the world. They have become popular drugs, especially at all-night techno dance parties (Raves), and their detection is becoming an important issue. Presently, there are no MDMA- or MDA-specific immunoassays on the market, and detection of the designer amphetamines is dependent upon the use of commercially available amphetamine assays. The success of this approach has been difficult to assess because of the general unavailability of significant numbers of samples from known drug users. The objectives of the present study are to characterize the drug content of urine samples from admitted Ecstasy users by chromatographic methods and to assess the ability of the available amphetamine/methamphetamine immunoassays to detect methylenedioxyamphetamines. We found that, when analyzed by high-performance liquid chromatography with diode-array detection (HPLC-DAD), 64% of 70 urine samples (by gas chromatography-mass spectrometry [GC-MS]: 88% of 64 urine samples) obtained from Rave attendees contained MDMA and/or 3,4-methylenedioxyamphetamine (MDA) alone or in combination with amphetamine, methamphetamine, or other designer amphetamines such as 3,4-methylenedioxyethylamphetamine (MDEA). This suggests that the majority of the Ravers are multidrug users. At the manufacturer's suggested cutoffs, the Abbott TDx Amphetamine/Methamphetamine II and the new Roche HS Amphetamine/MDMA assays demonstrated greater detection sensitivity for MDMA than the other amphetamine immunoassays tested (Abuscreen OnLine Hitachi AMPS, Abuscreen OnLine Integra AMPS, Abuscreen OnLine Integra AMPSX, CEDIA AMPS, and EMIT II AMPS). There is 100% agreement between each of the two immunoassays with the reference chromatographic methods, HPLC-DAD and GC-MS, for the detection of methylenedioxyamphetamines. (+info)
Opioid and cannabinoid modulation of precipitated withdrawal in delta(9)-tetrahydrocannabinol and morphine-dependent mice.
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The goal of the present study was to elucidate the relationship between cannabinoid and opioid systems in drug dependence. The CB(1) cannabinoid receptor antagonist SR 141716A precipitated both paw tremors and head shakes in four different mouse strains that were treated repeatedly with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). SR 141716A-precipitated Delta(9)-THC withdrawal was ameliorated in mu-opioid receptor knockout mice compared with the wild-type control animals and failed to occur in mice devoid of CB(1) cannabinoid receptors. An acute injection of morphine in Delta(9)-THC-dependent mice undergoing SR 1417161A-precipitated withdrawal dose dependently decreased both paw tremors, antagonist dose 50 (AD(50)) (95% CL) = 0.035 (0.03--0.04), and head shakes, AD(50) (95% CL) = 0.07 (0.04--0.12). In morphine-dependent mice, the opioid antagonist naloxone precipitated head shakes, paw tremors, diarrhea, and jumping. As previously reported, naloxone-precipitated morphine withdrawal failed to occur in mu-opioid knockout mice and was significantly decreased in CB(1) cannabinoid receptor knockout mice. Acute treatment of Delta(9)-THC in morphine-dependent mice undergoing naloxone-precipitated withdrawal blocked paw tremors, AD(50) (95% CL) = 0.5 (0.3--1.0), and head shakes AD(50) (95% CL) = 0.6 (0.57--0.74) in dose-dependent manners, but failed to diminish the occurrence of diarrhea or jumping. Finally, naloxone and SR 141716A failed to elicit any overt effects in Delta(9)-THC-dependent and morphine-dependent mice, respectively. These findings taken together indicate that the mu-opioid receptor plays a modulatory role in cannabinoid dependence, thus implicating a reciprocal relationship between the cannabinoid and opioid systems in dependence. (+info)
Identification and quantitation of 11-nor-delta9-tetrahydrocannabivarin-9-carboxylic acid, a major metabolite of delta9-tetrahydrocannabivarin.
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After incubation of delta9-tetrahydrocannabivarin with human hepatocytes, a major metabolic product was detected by gas chromatography-mass spectrometry that showed identical retention time and mass spectrum to the synthetic 11-nor-delta9-tetrahydrocannabivarin-9-carboxylic acid (11-nor-delta9-THCV-9-COOH). Analysis of human urine specimens from marijuana users and plasma samples from Marinol users showed that 11-nor-delta9-THCV-9-COOH was only present in urine specimens of marijuana users. These results supported the conclusion that identification of 11-nor-delta9-THCV-9-COOH in a donor's urine specimen indicates the use or ingestion of cannabis-related product(s) and would not explain the sole use of Marinol. (+info)
Effect of LSD on prepulse inhibition and spontaneous behavior in the rat. A pharmacological analysis and comparison between two rat strains.
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The goal of the present study was to better delineate the mechanisms of action of the prototypical hallucinogen LSD. LSD (0.03, 0.1 and 0.3 mg/kg, s.c.) produced locomotor hyperactivity, disruption of PPI and a number of behaviors indicative of 5-HT activation such as wet-dog shakes, back muscle contractions and forepaw treading. These various behavioral effects of LSD were studied in both Sprague-Dawley and Wistar rats, although with the exception of back muscle contractions which were more prominent in Sprague-Dawley rats, no major strain differences were detected. The PPI disruption induced by LSD (0.1 mg/kg) in Sprague-Dawley rats was completely reversed by pretreatment with the selective 5-HT(2A) antagonist MDL 100907 (0.5 and 1 mg/kg, s.c.). In contrast, pretreatment with antagonists at 5-HT(2C), (SB 242084 (0.5 mg/kg, i.p.)); 5-HT(2B/2C) (SDZ SER 082 (1 mg/kg, s.c.)); 5-HT(1A), ((+)-WAY 100135 (1 and 20 mg/kg, s.c.)) and 5-HT(6) receptors, (RO 04-6790 (30 mg/kg, i.p.)), all failed to influence LSD-induced disruption of PPI. The dopamine DA(2like) receptor antagonist, haloperidol (0.1 and 0.2 mg/kg, s.c.), was without effect against an LSD-induced disruption of PPI. Finally, selective blockade of 5-HT(2A) but not 5-HT(2C) receptors completely abolished the locomotor hyperactivity induced by LSD. These findings provide empirical evidence to support the view that the hallucinogenic effects of LSD are mediated by a direct agonist effect at 5-HT(2A) receptors. (+info)
Simultaneous determination of delta9-tetrahydrocannabinol and 11-nor-9-carboxy-delta9-tetrahydrocannabinol in human plasma by solid-phase extraction and gas chromatography-negative ion chemical ionization-mass spectrometry.
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Delta9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-delta9-tetrahydrocannabinol (THCA) in human plasma can be simultaneously detected using solid-phase extraction with gas chromatography and negative ion chemical ionization mass spectrometry. THC-d3 and THCA-d3 are added as internal standards; protein is precipitated with acetonitrile and the resulting supernatants diluted with 0.1 M sodium acetate (pH 7.0) prior to application to the solid-phase extraction columns. THC and THCA were eluted separately and then pooled, dried under air, and derivatized with trifluoroacetic anhydride and hexafluoroisopropanol. The derivatized THC-d0 gives abundant molecular anions (m/z 410), and the derivatized THCA-d0 gives abundant fragment ions (m/z 422) formed by loss of (CF3)2CHOH from its molecular anion. The recoveries of THC and THCA were 74% and 17%, respectively. The lower and upper limits of quantitation were 0.5 and 100 ng/mL for THC and 2.5 ng/mL and 100 ng/mL for THCA. The within-run accuracy and precision for THC (measured at 0.5, 1, 10 and 75 ng/mL) ranged from 98 to 106% (% target) and 4.1 to 9.5 (%CV), respectively. For THCA, the within-run accuracy and precision (measured at 2.5, 5, 10, and 75 ng/mL) ranged from 89 to 101% and 4.3 to 7.5%, respectively. The between-run accuracy and precision for THC ranged from 92 to 110% and 0.4 to 12.4%, respectively. The between-run accuracy and precision for THCA ranged from 97 to 103% and 6.5 to 12.3%, respectively. In processed samples stored in reconstituted form at -20 degrees C, THC and THCA were stable for at least three days. THC and THCA stored in plasma were stable following three freeze/thaw cycles. THC and THCA in whole blood at room temperature for 6 h, or in plasma stored at room temperature for 24 h, did not show significant change. Storage in polypropylene containers for 7 days at -20 degrees C and the presence of 1% sodium fluoride or the cannabinoid receptor antagonist, SR141716, at 1 microg/mL did not interfere with the quantitation of THC and THCA. In three individuals who smoked marijuana under controlled dosing conditions, peak THC concentrations of 151, 266, and 99 ng/mL were seen in the first plasma samples drawn immediately after the end of smoking, and corresponding peak THCA concentrations of 41, 52, and 17 ng/mL occurred at 0.33 to 1 h after cessation of smoking. (+info)