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4-Methylaminorex is a potential psychostimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. The racemic mixture of the cis-isomers has been encountered in illicit samples, but previous animal studies suggest that also the trans-isomers could have similar stimulant-like properties. We tested whether the stereoisomers possess rewarding properties and compared their potency using the conditioned place preference method in rats. Furthermore, the involvement of the brain dopaminergic system in the 4-methylaminorex reward was tested with the dopamine D1- and D2-receptor antagonists SCH 23390 and raclopride administered systemically, or with the neurotoxin 6-hydroxydopamine injected into the nucleus accumbens. All the four isomers induced place preference, with no apparent differences in their potency. SCH 23990 and raclopride attenuated 4-methylaminorex-induced increase in place preference, and 6-hydroxydopamine also tended to be efficacious. These findings indicate that all the four stereoisomers of 4-methylaminorex possess rewarding properties and thus abuse potential; the trans-isomers are at least as potent as the cis-isomers. Furthermore, the brain dopaminergic system appears to be involved in the 4-methylaminorex-reward.

4-Methylaminorex is a stimulant drug of abuse that exists as four stereoisomers: cis -4 R ,5 S , cis -4 S ,5 R , trans -4 S ,5 S , and trans -4 R ,5 R. These isomers have previously been shown to differ markedly in various respects. In the present study we assessed the effects of the isomers of 4-methylaminorex (2.5, 5.0, and 10 mg/kg i.p.) on extracellular dopamine and 5-hydroxytryptamine (5-HT) levels in the nucleus accumbens, as well as behavior in the rats simultaneously. The relative concentrations of the isomers in the brain were also measured. The samples were collected by in vivo microdialysis and then analyzed for neurotransmitters with high-performance liquid chromatography/electrochemical detection and for cis - and trans -4-methylaminorex with gas chromatography/mass spectrometry. The behavioral effects of the isomers were assessed from videotapes recorded during the microdialysis experiments. All isomers elevated the extracellular levels of both dopamine and 5-HT, with the exception of trans -4 R ,5 R . The rank order of potency for elevating dopamine was trans -4 S ,5 S > cis -4 S ,5 R ≈ cis -4 R ,5 S > trans -4R,5R, and for elevating 5-HT cis -4 S ,5 R > trans -4 S ,5 S ≈ cis -4 R ,5 S > trans -4 R ,5 R . Analysis of the behavioral data, together with the neurochemical data, suggests that behavioral effects of the isomers of 4-methylaminorex are related to drug-induced dopamine release and, in the case of higher doses of the most efficacious isomers, to 5-HT as well. The brain concentrations of the isomers did not reflect their neurochemical efficacy, which implies that their differences are pharmacodynamic rather than pharmacokinetic.

Rationale: It has previously been demonstrated that the 5-HT3 receptors located in the mesolimbic brain areas are able to modulate the dopaminergic effects of various abused drugs, including cocaine (COC). Objectives: The present experiments investigated the role of 5-HT3 receptors in the actions of selected monoamine uptake inhibitors. Methods: The ability of the 5-HT3 receptor antagonist MDL 72222 (MDL; 0.1 and 1.0 mg/kg) to modify the neurochemical and behavioral changes induced by COC (20 mg/kg), mazindol (MAZ; 10 mg/kg), and methylphenidate (MP; 5.0 or 10, and 20 mg/kg) was assessed with an in vivo microdialysis technique, a conditioned place preference method, and motor activity measurements. Results: MDL robustly attenuated the elevation of extracellular dopamine levels in the nucleus accumbens, acquisition of place preference, and motor activity induced by COC and MAZ, but not those induced by MP, the only drug with no significant effect on 5-HT. In contrast, expression of COC-induced place preference was not attenuated by MDL. Conclusions: These results show that COC- and MAZ-induced reward-related neurochemical and behavioral effects, preferentially those implicated in development of conditioned reward, are modified by the 5-HT3 blockade. In contrast to COC and MAZ, the changes induced by MP, which has less effect on the serotonergic system, remain unchanged. Thus it appears that involvement of a serotonergic component in the mechanism of action of a drug could be a prerequisite for effective antagonism by 5-HT3 receptor blockers.

The 4-methylaminorex (4-MAX) is an amphetamine-related psychostimulant drug that has appeared on the clandestine market with a street name of “U4Euh”. This compound exists as four stereoisomers, trans-4R,5R, trans-4S,5S, cis-4R,5S and cis-4S,5R, of which the cis forms have been classified as Schedule I substances in the US. The increasing variety of designer drugs has highlighted the importance of detection, identification, and quantitative measurement of these drugs, including 4-MAX, in biological samples. In the present study, the isomers of 4-MAX were detected in urine of rats treated with the drugs by some but not all of the on-site immunoassays tested, mainly as amphetamine or methamphetamine. To facilitate identification of 4-MAX by laboratories specialized in drug analysis, the electron-ionization mass spectrum and TLC data for underivatized 4-MAX using a routine laboratory drug-screening procedure is provided. In addition, a GC/MS method is described for the quantitative determination of cis- and trans-4-MAX as tert-butyldimethylsilyl-derivatives in plasma, urine and tissue.

Use of antioxidative agents is required in automated LC assay of microdialysis samples, due to rapid degradation of the monoamine neurotransmitters and their metabolites. Addition of oxalic acid prevented degradation of dopamine, serotonin, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid efficiently: after a 24-h incubation at room temperature the decreases in peak heights were less than 10%. The long-term stability of the analytes, however, was still enhanced when acetic acid and l -cysteine were included in the solution. Using this antioxidative solution, the monoamine neurotransmitters and their metabolites could be determined with an automated LC assay even at room temperature.

Drugs such as benzodiazepines, which enhance the effects of inhibitory neurotransmitter gamma-amino butyric acid (GABA), are known to modulate the mesocorticolimbic dopaminergic system, which is considered to mediate the rewarding effects of psychostimulants. The effects of diazepam, a benzodiazepine that binds unspecifically to omega 1- (omega1-) and omega2-receptors, and zolpidem, a nonbenzodiazepine drug that binds preferentially to omega1-receptors, on cocaine- and amphetamine-induced place preference were evaluated in Wistar rats. In tests using the counterbalanced method, neither diazepam (0.2, 1, and 5 mg/kg) nor zolpidem (2.5, 5, and 10 mg/kg) alone induced place preference or place aversion. Diazepam pretreatment prevented both cocaine- and amphetamine-induced (15 and 9 mg/kg, respectively) place preference; however, at doses that were earlier shown to cause sedation and amnesia, zolpidem failed to prevent either cocaine- or amphetamine-induced place preference. These results suggest that diazepam interferes with the rewarding properties of the psychostimulants, whereas zolpidem is less effective in this respect, possibly due to differential distribution of omega1- and omega2-receptors in the brain.

Problems related to illegal amphetamine use have become a major public health issue in many developed countries. To date, evidence on the effectiveness of psychosocial treatments has remained modest, and no pharmacotherapy has proven effective for amphetamine dependence.Individuals meeting DSM-IV criteria for intravenous amphetamine dependence (N=53) were randomly assigned to receive aripiprazole (15 mg/day), slow-release methylphenidate (54 mg/day), or placebo for 20 weeks. The study was terminated prematurely due to unexpected results of interim analysis. An intention-to-treat analysis was used. The primary outcome measure was the proportion of amphetamine-positive urine samples.Patients allocated to aripiprazole had significantly more amphetamine-positive urine samples than patients in the placebo group (odds ratio=3.77, 95% CI=1.55-9.18), whereas patients who received methylphenidate had significantly fewer amphetamine-positive urine samples than patients who had received placebo (odds ratio=0.46, 95% CI=0.26-0.81).Methylphenidate is an effective treatment for reducing intravenous drug use in patients with severe amphetamine dependence.

The impact of alcohol use on the course of adolescent depression over one-year was investigated by following 197 consecutive adolescent outpatients with unipolar depression in a naturalistic treatment setting. Their baseline alcohol consumption was categorized in three groups: excessive use (defined as weekly drunkenness), regular use (monthly use, not weekly drunkenness), and no/occasional use (abstinence/less than monthly use). During the monthly BDI follow-up, the excessive users achieved remission less frequently, and after one year, had poorer psychosocial functioning than the no/occasional users. In conclusion, excessive alcohol use negatively affects the course of adolescent depression and psychosocial functioning. Weekly drunkenness seems to be of predictive value and this can be examined with a few simple questions. Means of reducing alcohol consumption among depressed adolescents are worth further investigations.

OBJECTIVE: To investigate the association among acne, depressive symptoms and suicidal ideation in Finnish male military conscripts. METHODS: Consecutive 165 acne patients and 150 patients with mild knee symptoms for comparison were enrolled in the study conducted in the Central Military Hospital, Helsinki, Finland. They filled out the following questionnaires: General Health Questionnaire (GHQ-12), Beck Depression Inventory (BDI), Alcohol Use Disorders Identification Test and Rosenberg Self-Esteem Scale. The Leeds acne grading scale was used to estimate the severity of acne. RESULTS: Sixteen (9.7%) acne patients and 20 (13.3%) comparison patients had at least moderate level of depressive symptoms (BDI score 10; P > 0.05, between groups). Suicidal ideation (BDI suicidal item score 1) was reported by 24 (14.5%) acne patients and 16 (10.7%) comparison patients (P > 0.05, between groups). When comparing the mild facial acne patients (Leeds score 0-3) with those with moderate-severe facial acne (Leeds score 4), there were no statistical differences in depressive symptoms (9.5% vs. 10.0%) or suicidal ideation (13.7% vs. 15.7%). No linear relationship was observed between the BDI and facial Leeds scores (P > 0.05). Risk factors for suicidal ideation among the acne patients were depression and alcohol risk use. CONCLUSION: Young male patients with acne do not suffer more depressive symptoms or suicidal ideation than patients with mild knee symptoms, and the severity of acne is not associated with the presence of depressive symptoms. The risk factors for suicidal ideation among acne patients seem to be similar to those found in the general population. Language: en

1-Benzylpiperazine (also known as ‘Legal X’, ‘Legal E’, or ‘A2’) is a psychoactive compound increasingly encountered on the clandestine market. Previous experimental data suggest that the compound possesses addictive properties. In the present study, we used the conditioned place preference method in the rat to test whether 1-benzylpiperazine possesses rewarding properties. Furthermore, the mechanisms of the 1-benzylpiperazine reward were investigated using selected dopamine and serotonin receptor antagonists. 1-Benzylpiperazine (1.25, 5, and 20 mg/kg) induced dose-dependently place preference. This place preference was attenuated by the antagonists SCH23390 (0.2 mg/kg; dopamine D1-like receptors) and MDL72222 (1.0 mg/kg; serotonin3 receptors), but not by raclopride (0.8 mg/kg; dopamine D2-like receptors) or ketanserin (2 mg/kg; preferentially serotonin2 receptors). Our results show that 1-benzylpiperazine possesses rewarding properties in the rat, which suggests the compound to be susceptible to human abuse. The brain dopaminergic and serotonergic systems appear to be involved in the 1-benzylpiperazine reward.

Betaine, i.e., trimethylglycine, is linked to homocysteine metabolism. A 3-mo daily betaine supplementation decreased even normal plasma total homocysteine (tHcy) concentrations in humans. The pharmacokinetic characteristics and metabolism of betaine in humans have not been investigated in detail. The aim of this study was to assess the pharmacokinetics of orally administered betaine and its acute effect on plasma tHcy concentrations. Healthy volunteers (n = 10; 3 men, 7 women) with normal body weight (mean +/- SD, 69.5 +/- 17.0 kg), 40.8 +/- 12.4 y old, participated in the study. The betaine doses were 1, 3, and 6 g. The doses were mixed with 150 mL of orange juice and ingested after a 12-h overnight fast by each volunteer according to a randomized double-blind crossover design. Blood samples were drawn for 24 h and a 24-h urine collection was performed. Orally administered betaine had an immediate and dose-dependent effect on serum betaine concentration. Single doses of 3 and 6 g lowered plasma tHcy concentrations (P = 0.019 and P < 0.001, respectively), unlike the 1-g dose. After the highest dose, the concentrations remained low during the 24 h of monitoring. The change in plasma tHcy concentration was linearly associated with betaine dose (P = 0.006) and serum betaine concentration (R2 = 0.17, P = 0.025). The absorption and elimination of betaine were dose dependent. The urinary excretion of betaine seemed to increase with an increasing betaine dose, although a very small proportion of ingested betaine was excreted via urine. In conclusion, a single dose of orally administered betaine had an acute and dose-dependent effect on serum betaine concentration and resulted in lowered plasma tHcy concentrations within 2 h in healthy subjects.

4-Methylaminorex, a potential psychostimulant drug of abuse, exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R, which were shown previously to possess stereospecific effects. This study characterized their pharmacokinetic and tissue distribution profiles, and metabolic turnover to norephedrine and norpseudoephedrine, in male Wistar rats. The rats received each isomer intravenously, intraperitoneally, or orally, followed by blood sample collection via cannula (pharmacokinetic study), or tissue sample collection at predetermined time points (tissue distribution study). The samples were analyzed for cis- and trans-isomers, and when appropriate for norephedrine and norpseudoephedrine, with gas chromatography/mass spectrometry. Trans-4S,5S-, cis-4R,5S-, and cis-4S,5R-isomers behaved comparably kinetically (volume of distribution 1.7-2.3 l/kg, distribution half-life 3.8-7.0 min, elimination half-life 35-42 min, and bioavailability 32-57% intraperitoneally or 4-16% orally), whereas trans-4R,5R-isomer differed from the others, with a longer elimination half-life (118-169 min) and higher bioavailability (100% intraperitoneally or 83% orally). The highest isomer concentrations were observed in the kidney followed most frequently by the liver, brain, muscle, and last by fat and blood. The elimination half-lives of the stereoisomers from the tissues were generally similar to those in blood. No pharmacologically significant amounts of norephedrine or norpseudoephedrine were detected in blood or the brain. In conclusion, differences between the stereoisomers of 4-methylaminorex in the pharmacokinetics and tissue distribution are described. However, these differences are not compatible with, and thus may not account for, the distinct behavioral and neurochemical effects of the stereoisomers demonstrated previously. Furthermore, metabolic turnover to norephedrine and norpseudoephedrine does not seem to contribute significantly to 4-methylaminorex pharmacology.

We assessed the prevalence and associations of symptoms of insomnia in patients with acute ischemic stroke, and evaluated whether mianserin as a sedative antidepressant is beneficial in the treatment of poststroke insomnia. One hundred consecutively hospitalized patients were randomized to receive 60 mg/day of mianserin (n = 51) or placebo for 1 year in a double-blind trial with a 6-month follow-up after the therapy. Symptoms of insomnia were assessed with the three insomnia-related items of the Hamilton Depression Scale; patients were defined as insomniacs if any of these items was positive. Complaints of insomnia occurred in 68% of patients on admission, and in 49% at 18 months, and they were as frequent in all subgroups of patients. From 2 months, symptoms of insomnia were associated independently with depression. Living alone before stroke (at 0 and 2 months) and age (at 12 months) were other independent predictors of insomnia. The rate of recovery as evaluated by the insomnia score was more rapid in patients on mianserin than in those on placebo. At 2 months, the scores were significantly different favoring mianserin treatment (1.3 vs. 0.8, p = 0.02). We conclude that insomnia is a common complaint after ischemic stroke. Mianserin had a beneficial influence on the recovery from symptoms of insomnia, even though the intensity of poststroke depression was low.

The flavanones naringenin and hesperetin exhibit estrogenic, anticarcinogenic and antioxidative properties. Orange juice and grapefruit juice contain high amounts of these compounds, and therefore their intake from the diet can be relatively high. No data are available regarding plasma concentrations or plasma kinetics of flavanones. The objectives of this study were to develop methods allowing the analysis of naringenin and hesperetin from plasma and urine and to study their plasma kinetics and urinary excretion. We also wanted to assess whether plasma or urine flavanone concentrations can be used as biomarkers of intake. Healthy volunteers ingested orange juice (five women and three men) or grapefruit juice (two women and three men) once (8 mL/kg). Eleven blood samples and urine were collected between 0 and 24 h after juice administration. Flavanones were analyzed by HPLC with electrochemical detection. Naringenin and hesperetin were bioavailable from the studied juices, but interindividual variation in bioavailability was remarkable. The resulting plasma concentrations were comparatively high, and the peak plasma concentrations (C(max)) were 0.6 +/- 0.4 micromol/L (means +/- SD) for naringenin from orange juice and 6.0 +/- 5.4 micromol/L for naringenin from grapefruit juice. The corresponding value for hesperetin from orange juice was 2.2 +/- 1.6 micromol/L. The elimination half-lives were between 1.3 and 2.2 h, and therefore plasma concentrations reflect short-term intake. The relative urinary excretion varied depending on the flavanone source and dose and was 30.2 +/- 25.5% and 1.1 +/- 0.8% for naringenin from grapefruit juice and orange juice, respectively, and 5.3 +/- 3.1% for hesperetin from orange juice. The considerable difference in the relative urinary excretion of naringenin from the two juices was most likely caused by dose-dependent renal clearance rather than differences in bioavailability (as indicated by the similar C(max)-to-dose ratios). The results indicate that urine flavanone concentrations are not good biomarkers of dietary intake. We conclude that because of the relatively high concentrations of flavanones in plasma after ingestion of orange juice or grapefruit juice, considerable health effects could ensue in individuals consuming them regularly.

The acute effects of amphetamine derivatives on extracellular concentration of serotonin (5-HT) and dopamine in the nucleus accumbens were studied with in vivo microdialysis using conscious, freely moving rats. 5-HT, dopamine, and their major metabolites were measured by HPLC with electrochemical detection. Amphetamine (1.0-9.0 mg/kg) elevated dopamine levels considerably, but failed to affect the levels of 5-HT, except at the highest dose administered. 3,4-Methylenedioxyamphetamine (MDA, 1.0-9.0 mg/kg) and 3,4-methylenedioxymethamphetamine (MDMA, 1.0-9.0 mg/kg) elevated both 5-HT and dopamine levels dose dependently. The failure of 2,5-dimethoxy-4-methylamphetamine (DOM, 0.5-1.0 mg/kg) to affect the 5-HT levels suggests that extracellular levels of 5-HT play a minor role in hallucinogenic activity. The strong effects of MDA and MDMA on levels of 5-HT indicate that their actions on serotonergic mechanisms are different from those of the hallucinogens. In addition, methylenedioxyamphetamines may act via dopaminergic mechanisms similar to those of amphetamine.