"Designer" amphetamines: effects on behavior and monoamines with or without reserpine and/or alpha-methyl-para-tyrosine pretreatment.
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Rats were given single injections of vehicle or one of three doses of (+)-amphetamine (AM), 4-methoxyamphetamine (MA) or 4-ethoxyamphetamine (EA) after pretreatment with vehicle or reserpine, and vehicle or alpha-methyl-para-tyrosine (AMPT). EA is a "designer" drug that was recently seized from an illicit laboratory in Canada. Locomotion of the rats was recorded after treatment with the drugs, and whole brain levels of the drugs as well as monoamine neurotransmitters and their major acidic metabolites were then determined. Neither of the ring-substituted AM analogues influenced locomotion. AM induced locomotion in a dose-dependent manner, and this effect was blocked by AMPT but potentiated by reserpine. Brain concentrations of EA were lower than those of the other two drugs. The brain levels of monoamines and their metabolites indicate that AM releases a newly synthesized pool of dopamine which is transferred to vesicles after re-uptake. A very low dose of AM, but not higher doses, was found to elevate serotonin (5-hydroxytryptamine: 5-HT) levels independently of effects on catecholamines. Both MA and EA affected monoamine metabolites in a manner consistent with actions as reversible inhibitors of monoamine oxidase-an effect which has been previously demonstrated to be true for MA. Both drugs increased 5-HT levels at a very low dose, as did AM, but also increased noradrenaline levels at this dose. It is concluded that EA is not a psychomotor stimulant, but is similar in many of its effects to MA, a potent hallucinogen. (+info)
Alterations in body temperature, corticosterone, and behavior following the administration of 5-methoxy-diisopropyltryptamine ('foxy') to adult rats: a new drug of abuse.
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Many drugs are used or abused in social contexts without understanding the ramifications of their use. In this study, we examined the effects of a newly popular drug, 5-methoxy-diisopropyltryptamine (5-MEO-DIPT; 'foxy' or 'foxy-methoxy'). Two experiments were performed. In the first, 5-MEO-DIPT (0, 10, or 20 mg/kg) was administered to rats four times on a single day and animals were examined 3 days later. The animals that received 5-MEO-DIPT demonstrated hypothermia during the period of drug administration and delayed mild hyperthermic rebound for at least 48 h. Corticosterone levels in plasma were elevated in a dose-dependent manner compared to saline-treated animals with minor changes in 5-HT turnover and no changes in monoamine levels. In experiment 2, rats were examined in behavioral tasks following either 0 or 20 mg/kg of 5-MEO-DIPT. The animals treated with 5-MEO-DIPT showed hypoactivity and an attenuated response to (+)-methamphetamine-induced stimulation (1 mg/kg). In a test of path integration (Cincinnati water maze), 5-MEO-DIPT-treated animals displayed deficits in performance compared to the saline-treated animals. No differences were noted in the ability of the animals to perform in the Morris water maze or on tests of novel object or place recognition. The data demonstrate that 5-MEO-DIPT alters the ability of an animal to perform certain cognitive tasks, while leaving others intact and disrupts the endocrine system. 5-MEO-DIPT may have the potential to induce untoward effects in humans. (+info)
Retail marijuana purchases in designer and commercial markets in New York City: sales units, weights, and prices per gram.
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This paper documents the bifurcation of the market for commercial marijuana from the market for designer marijuana in New York City. Commercial marijuana is usually grown outdoors, imported to NYC, and of average quality. By contrast, several varities of designer marijuana are usually grown indoors from specially bred strains and carefully handled for maximum quality. The mechanisms for marijuana sales include street/park sellers, delivery services, private sales, and storefronts. Retail sales units vary from 5 dollars to 50 dollars and more, but the actual weights and price per gram of retail marijuana purchases lacks scientific precision. Ethnographic staff recruited marijuana purchasers who used digital scales to weigh a purposive sample of 99 marijuana purchases. Results indicate clear differences in price per gram between the purchases of commercial (average 8.20 dollars/g) and designer (average 18.02 dollars/g) marijuana. Designer purchases are more likely to be made by whites, downtown (Lower East Side/Union Square area), via delivery services, and in units of 10 dollar bags, 50 dollar cubes, and eighth and quarter ounces. Commercial marijuana purchases are more likely to be made by blacks, uptown (Harlem), via street dealers, and in units of 5 dollar and 20 dollar bags. Imported commercial types Arizona and Chocolate were only found uptown, while designer brand names describing actual strains like Sour Diesel and White Widow were only found downtown. Findings indicate clear divisions between commercial and designer marijuana markets in New York City. The extent that these differences may be based upon different THC potencies is a matter for future research. (+info)
Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.
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We evolved muscarinic receptors in yeast to generate a family of G protein-coupled receptors (GPCRs) that are activated solely by a pharmacologically inert drug-like and bioavailable compound (clozapine-N-oxide). Subsequent screening in human cell lines facilitated the creation of a family of muscarinic acetylcholine GPCRs suitable for in vitro and in situ studies. We subsequently created lines of telomerase-immortalized human pulmonary artery smooth muscle cells stably expressing all five family members and found that each one faithfully recapitulated the signaling phenotype of the parent receptor. We also expressed a G(i)-coupled designer receptor in hippocampal neurons (hM(4)D) and demonstrated its ability to induce membrane hyperpolarization and neuronal silencing. We have thus devised a facile approach for designing families of GPCRs with engineered ligand specificities. Such reverse-engineered GPCRs will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo. (+info)
Matrix effect and cross-reactivity of select amphetamine-type substances, designer analogues, and putrefactive amines using the Bio-Quant direct ELISA presumptive assays for amphetamine and methamphetamine.
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The aim of this study was to evaluate the Bio-Quant Direct ELISA assays for amphetamine and methamphetamine in the routine presumptive screening of biological fluids. Standard concentration curves of the target analytes were assayed to assess sensitivity, and known concentrations of common amphetamine-type substances (ephedrine, pseudoephedrine, phentermine), designer analogues (MDA, MDMA, MDEA, MBDB, PMA, 4-MTA, 2CB), and putrefactive amines (phenylethylamine, putrescine, tryptamine, tyramine) were analyzed to determine cross-reactivity. Results of the standard curve studies show the capacity of both Direct ELISA kits to confidently detect down to 3 ng/mL interday (PBS matrix; CVs 6.3-15.5%). Cross-reactivity relative to that of 50 ng/mL preparations of the target compounds demonstrated that the Direct ELISA kit for amphetamine also detected MDA (282%), PMA (265%), 4-MTA (280%), and phentermine (61%), and the Direct ELISA for methamphetamine also assayed positive for MDMA (73%), MDEA (18%), pseudoephedrine (19%), MBDB (8%), and ephedrine (9%). Matrix studies demonstrated that both ELISA kits could be applied to screening of blood, urine, and saliva to a concentration of 6 ng/mL or lower. In conclusion, the Bio-Quant Direct ELISA kits for amphetamine and methamphetamine are fast and accurate and have demonstrated themselves to be useful tools in routine toxicological testing. (+info)
Identification of cytochrome P450 enzymes involved in the metabolism of the new designer drug 4'-methyl-alpha-pyrrolidinobutyrophenone.
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The involvement of human hepatic cytochrome P450 (P450) isoenzymes in the metabolism of the new designer drug 4'-methyl-alpha-pyrrolidinobutyrophenone (MPBP) to 4'-(hydroxymethyl)-alpha-pyrrolidinobutyrophenone (HO-MPBP) was studied using insect cell microsomes with cDNA-expressed human P450s and human liver microsomes (HLM). Incubation samples were analyzed by liquid chromatography-mass spectrometry. Only CYP2D6, CYP2C19, and CYP1A2 were capable of catalyzing MPBP 4'-hydroxylation. According to the relative activity factor approach, these enzymes accounted for 54, 30, and 16% of net clearance. At 1 microM MPBP, the chemical inhibitors quinidine (CYP2D6), fluconazole (CYP2C19), and alpha-naphthoflavone (CYP1A2) reduced metabolite formation in pooled HLM by 83, 53, and 47%, respectively, and at 50 microM MPBP by 41, 47, and 45%, respectively. In experiments with HLM from CYP2D6 and CYP2C19 poor metabolizers, HO-MPBP formation was found to be 78 and 79% lower in comparison with pooled HLM, respectively. From these data, it can be concluded that polymorphically expressed CYP2D6 is mainly responsible for MPBP hydroxylation. (+info)
Designer bugs: structural engineering to build a better mouse model.
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Many animal models of bacterial diseases are hampered by differences in tissue tropism and the course of pathogenesis. In a recent issue of Cell, by rationally mutating a surface invasion protein (InlA) to have higher binding affinity for its cognate host receptor (E-cadherin), Wollert et al. were able to "murinize"Listeria monocytogenes, creating a strain capable of invading intestinal epithelial cells in mice, mimicking the route of infection in humans. (+info)