(1/3711) Solid-phase microextraction for cannabinoids analysis in hair and its possible application to other drugs.

This paper describes the application of solid-phase microextraction (SPME) to cannabis testing in hair. Fifty milligrams of hair was washed with petroleum ether, hydrolyzed with NaOH, neutralized, deuterated internal standard was added and directly submitted to SPME. The SPME was analyzed by GC-MS. The limit of detection was 0.1 ng/mg for cannabinol (CBN) and delta9-tetrahydrocannabinol (THC) and 0.2 ng/mg for cannabidiol (CBD). THC was detected in a range spanning from 0.1 to 0.7 ng/mg. CBD concentrations ranged from 0.7 to 14.1 ng/mg, and CBN concentrations ranged from 0.4 to 0.7 ng/mg. The effectiveness of different decontamination procedures was also studied on passively contaminated hair. The proposed method is also suitable for the analysis of methadone in hair; cocaine and cocaethylene can be detected in hair with SPME extraction after enzymatic hydrolysis.  (+info)

(2/3711) Cocaine metabolite kinetics in the newborn.

The study goal was to determine the half-life elimination of cocaine and benzoylecgonine (BZE) in the newborn. Three 0.3-mL blood samples were collected during the first day of life. Urine was collected once daily. Cocaine and BZE concentrations were determined by gas chromatography-mass spectrometry. An extraction method was developed for measuring low concentrations of cocaine and BZE in small (0.1 mL) blood samples. Cocaine had a half-life of 11.6 h in one subject. The half-life of BZE during the first day of life, based on blood data in 13 subjects, was 16 h (95% confidence interval [CI], 12.8 to 21.4 h). The half-life of BZE during the first week of life, based on urine data in 16 subjects, was 11.2 h (95% CI, 10.1 to 11.8 h). The novel extraction method for small blood sample volumes should be applicable to other basic drugs.  (+info)

(3/3711) Identification and quantification of cocaine N-oxide: a thermally labile metabolite of cocaine.

In this article, we report the identification and quantitation of cocaine N-oxide (CNO), a thermally labile oxidative metabolite, from both animal and human samples. The concentration of CNO is similar to the concentrations of cocaine in the samples analyzed. The technique used for the determination of CNO in this study is liquid chromatography-electrospray ionization mass spectrometry, which is necessary because CNO is converted to cocaine upon heating. This includes simple heating of aqueous solutions to temperatures in excess of 100 degrees C and analysis by gas chromatography-mass spectrometry (GC-MS), in which CNO is converted to cocaine in the injection port. The thermal conversion of CNO to cocaine is estimated to cause an over-reporting of cocaine levels by 10-20% when using GC-MS.  (+info)

(4/3711) Acquisition of nicotine discrimination and discriminative stimulus effects of nicotine in rats chronically exposed to caffeine.

Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, with a high frequency of concurrent use in humans. This study examined the effects of chronic caffeine exposure on 1) rates of acquisition of a nicotine discrimination (0.1 or 0.4 mg/kg, s.c., training doses) and 2) the pharmacological characteristics of the established nicotine discrimination in male Sprague-Dawley rats. Once rats learned to lever-press reliably under a fixed ratio of 10 schedule for food pellets, they were randomly divided into two groups; 12 animals were maintained continuously on caffeine added to the drinking water (3 mg/ml) and another 12 control rats continued to drink tap water. In each group of water- and caffeine-drinking rats, there were six rats trained to discriminate 0.1 mg/kg of nicotine from saline and six rats trained to discriminate 0.4 mg/kg of nicotine from saline. Regardless of the training dose of nicotine, both water- and caffeine-drinking groups required a comparable number of training sessions to attain reliable stimulus control, although there was a trend for a slower acquisition in the caffeine-drinking group trained with 0.1 mg/kg of nicotine. Tests for generalization to different doses of nicotine revealed no significant differences in potency of nicotine between water- and caffeine-drinking groups. The nicotinic-receptor antagonist mecamylamine blocked the discriminative effects of 0.1 and 0.4 mg/kg nicotine with comparable potency and efficacy in water- and caffeine-drinking groups. There was a dose-related generalization to both the 0.1 and 0.4 mg/kg nicotine cue (maximum average of 51-83%) in water-drinking rats after i.p. treatment with d-amphetamine, cocaine, the selective dopamine uptake inhibitor GBR-12909, apomorphine, and the selective dopamine D1 receptor agonist SKF-82958, but not in caffeine-drinking rats (0-22%). There was no generalization to the nicotine cues after i.p. treatment with caffeine or the selective D2 (NPA) and D3 (PD 128,907) dopamine-receptor agonists in water- and caffeine-drinking rats. The dopamine-release inhibitor CGS 10746B reduced the discriminative effects of 0.4 mg/kg nicotine in water-drinking rats, but not in caffeine-drinking rats. There was no evidence of development of tolerance or sensitization to nicotine's effects throughout the study. In conclusion, chronic caffeine exposure (average, 135 mg/kg/day) did not affect the rate of acquisition of the nicotine discrimination, but it did reduce the dopaminergic component of the nicotine-discriminative cue. The reduction of the dopaminergic component of the nicotine cue was permanent, as this effect was still evident after the caffeine solution was replaced with water in caffeine-drinking rats. That nicotine could reliably serve as a discriminative stimulus in the absence of the dopaminergic component of its discriminative cue may differentiate nicotine from "classical dopaminergic" drugs of abuse such as cocaine and amphetamine.  (+info)

(5/3711) Effects of stimulants of abuse on extrapyramidal and limbic neuropeptide Y systems.

Neuropeptide Y (NPY), an apparent neuromodulating neuropeptide, has been linked to dopamine systems and dopamine-related psychotic disorders. Because of this association, we determined and compared the effects of psychotomimetic drugs on extrapyramidal and limbic NPY systems. We observed that phencyclidine, methamphetamine (METH), (+)methylenedioxymethamphetamine (MDMA), and cocaine, but not (-)MDMA, similarly reduced the striatal content of NPY-like immunoreactivity from 54% (phencyclidine) to 74% [(+) MDMA] of control. The effects of METH on NPY levels in the nucleus accumbens, caudate nucleus, globus pallidus, and substantia nigra were characterized in greater detail. We observed that METH decreased NPY levels in specific regions of the nucleus accumbens and the caudate, but had no effect on NPY in the globus pallidus or the substantia nigra. The dopamine D1 receptor antagonist SCH-23390 blocked these effects of METH, suggesting that NPY levels throughout the nucleus accumbens and the caudate are regulated through D1 pathways. The D2 receptor antagonist eticlopride did not appear to alter the METH effect, but this was difficult to determine because eticlopride decreased NPY levels by itself. A single dose of METH was sufficient to lower NPY levels, in some, but not all, regions examined. The effects on NPY levels after multiple METH administrations were substantially greater and persisted up to 48 h after treatment; this suggests that synthesis of this neuropeptide may be suppressed even after the drug is gone. These findings suggest that NPY systems may contribute to the D1 receptor-mediated effects of the psychostimulants.  (+info)

(6/3711) Age-related reductions in [3H]WIN 35,428 binding to the dopamine transporter in nigrostriatal and mesolimbic brain regions of the fischer 344 rat.

In the present study, we used the potent cocaine analog [3H]WIN 35, 428 to map and quantify binding to the dopamine transporter (DAT) within the dorsal striatum, nucleus accumbens, substantia nigra, and ventral tegmental area in young (6-month-old), middle-aged (12-month-old), and aged (18- and 24-month-old) Fischer 344 rats. Quantitative autoradiographic analysis of indirect [3H]WIN 35,428 saturation curves revealed two-site binding for all four brain regions in every age group. The percentage of binding to the high- or low-affinity sites did not differ with age or region and was approximately 50%. However, significant age-related decreases in the overall density (Bmax) of [3H]WIN 35,428-binding sites were observed in the striatum, nucleus accumbens, substantia nigra, and ventral tegmental area. The Bmax within all brain regions declined by more than 15% every 6 months, with the Bmax in the aged (24-month-old) group being approximately half that measured in the young adult (6-month-old) group. Competition experiments indicated that nomifensine also exhibited two-site binding to the DAT in Fischer 344 rats. No consistent age-related differences in binding affinities were noted with either [3H]WIN 35,428 or nomifensine. Taken together, these results support the hypothesis that functional DATs within the nigrostriatal and mesolimbic systems are down-regulated with age, without changing their affinity for ligands.  (+info)

(7/3711) A possible mode of cardiovascular actions of dopamine in dogs.

A possible mode of cardiovascular actions of dopamine was studied using ephedrine. In the dog pretreated with repeated administrations of ephedrine (total dose, 40 or 80 mg/kg, i.v.) or with combined administrations of ephedrine (total dose, 90 mg/kg, s.c. and i.v.) and reserpine (2 mg/kg, s.c., 24 hr previously), pressor responses to dopamine were eliminated and reversed to depressor responses whereas depressor responses to dopamine were potentiated. Positive chronotropic effects of dopamine were almost eliminated. Pressor and positive chronotropic effects of tyramine were almost abolished. Sympathomimetic effect of noradrenaline and adrenaline were potentiated while those of isoprenaline were inhibited. In the heart-lung preparation of ephedrine-treated dogs (total dose, 40 mg/kg, i.v.), cardiac stimulating effects of dopamine and tyramine were strongly depressed, and those of noradrenaline, adrenaline and isoprenaline were reduced to some extent. In the open-chest dogs, after pretreatment of cocaine (4 mg/kg, i.v.), pressor, positive inotropic and chronotropic effects of noradrenaline were potentiated, whilst those of tyramine were inhibited. Those of dopamine were not visibly altered, but depressor, negative chronotropic and inotropic effects of dopamine appeared at small doses. In the ephedrine-pretreated dogs, these sympathomimetic effects of dopamine and tyramine after cocaine were strongly depressed and those of noradrenaline were inhibited to a certain degree. The results obtained with ephedrine suggest that dopamine differs from other catecholamines and tyramine in the mode of cardiovascular actions.  (+info)

(8/3711) Pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2-(3H)-furylidene]-1,3-cyclopentanedione (oudenone).

The pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2(3H)-furylidene]-1,3-cyclopentanedione (oudenone) were studied in both anesthetized animals and isolated organs. Oudenone (10--40 mg/kg i.v.) induced an initial rise in blood pressure followed by a prolonged hypotension in the anesthetized rats. In unanesthetized spontaneously hypertensive rats (SHR), oudenone (5--200 mg/kg p.o.) caused a dose-related decrease in the systolic blood pressure. The initial pressor effect was diminished by pretreatments with phentolamine, guanethidine, hexamethonium and was abolished in the pithed rats. In addition, intracisternal administrations of oudenone (100--600 mug/kg) showed a marked increase in blood pressure in the anesthetized rats, suggesting that the pressor effect may be due to centrally mediated actions. Oudenone, given intra-arterially into the femoral artery (400--800 mug/kg), caused a long-lasting vasodilation in anesthetized dogs. At a relatively high dose (40 mg/kg i.v.), oudenone antagonized all pressor responses to autonomic agents and central vagus nerve stimulation in anesthetized rats and dogs, however, oudenone showed no anti-cholinergic,-histaminergic, beta-adrenergic and adrenergic neuron blocking properties.  (+info)