Psychostimulant Properties Research Articles

Isopropylphenidate: An Ester Homolog of Methylphenidate with Sustained and Selective Dopaminergic Activity and Reduced Drug Interaction Liability

The most widely utilized pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD) is the psychostimulant methylphenidate (MPH). Most MPH formulations consist of the racemic mixture of d-threo-(R, R)-MPH and l-threo-(S, S)-MPH isomers. MPH is characterized by its low bioavailability and short half-life (2-3 hours). Additionally, significant inter-individual variability in MPH pharmacokinetics has been consistently documented. Accordingly, efforts have been directed at developing alternatives to MPH as therapeutic agents. A wide range of MPH analogues (dl-α-[2-piperidyl]-phenylacetic acid esters) have been synthesized with the dopamine transporter (DAT) and norepinephrine transporter (NET) as principle neuropharmacological targets. The present study investigated the metabolic profiles and pharmacological activity of the isopropyl ester derivative of MPH, dl-isopropylphenidate (IPH), both in vitro and in vivo. The synthesis, monoaminergic transporter binding, cellular uptake profiles, and assessment of metabolic hydrolysis and transesterification in the presence of ethanol are described using MPH as a comparator. Additionally, an in vivo assessment of IPH stimulant effects (vs. saline) in rats was performed with locomotor activity as a pharmacodynamic outcome. IPH displayed unique pharmacological characteristics including greater DAT than NET binding and cellular uptake activity, and greater resistance to hydrolysis and transesterification via carboxylesterase 1 relative to MPH. Further, sustained psychostimulant properties offer the prospect of an enhanced duration of action. Our findings are consistent with IPH exhibiting attributes distinguishing it from MPH and warranting further study and development of IPH as a novel psychotherapeutic agent.

Chronic khat (Catha edulis) and alcohol marginally alter complete blood counts, clinical chemistry, and testosterone in male rats

IntroductionKhat (Catha edulis) is a recreational psychoactive drug with psychostimulant properties. While the use of this drug is widespread in eastern Africa, including the Horn of Africa, surveys and anecdotal data show that its use has become cosmopolitan, with users now living in Europe and North America as well. Recent data in Uganda suggest an increasing pattern of simultaneous khat and ethanol use particularly among young adults. However, the effects of this pattern of use remain largely unknown, even though long-term use of either drug alone is known to be harmful. The aim of this study was to examine the toxic effects of simultaneous chronic administration of khat and ethanol on hematological parameters, clinical chemistry, and testosterone in a rat model.MethodsAdult male Sprague-Dawley rats were randomly assigned to one of six dose groups: 2 g/kg khat; 4 g/kg khat; 4 g/kg ethanol; combined khat and ethanol (4 g/kg each); control; and an untreated group. Treatments were given by gavage twice daily for 28 days, followed by determination of hematological parameters, blood clinical chemistry, and testosterone.ResultsEthanol alone significantly reduced platelet counts compared to control-, untreated and low-dose khat-treated rats; conversely low-dose khat significantly increased both the hemoglobin and hematocrit values, while ethanol alone also significantly increased the hemoglobin value compared to controls. Simultaneous khat and ethanol administration per se did not produce more toxic consequences in chronic use than either drug alone.ConclusionChronic short-term khat use and ethanol dependence individually produce noteworthy effects on the blood, but not on clinical chemistry or testosterone. Chronic short-term combined khat and ethanol use does not produce more toxic effects compared to use of either drug alone. This provides an opportunity for appropriate clinical interventions to avert the chronic long-term effects that result from use of these drugs of abuse.

Caffeine and Substance Use Disorders

Caffeine and Substance Use Disorders

Contribution of Caffeine to the Psychostimulant, Neuroinflammatory and Neurotoxic Effects of Amphetamine-Related Drugs

Association of amphetamine-related drugs with beverages containing high levels of caffeine is becoming very popular among adolescents and young adults. This review by examining the psychostimulant properties and the neuroinflammatory and neurotoxic effects of this drug association provides a new vision of the risks correlated to multiple substances consumption. In preclinical studies, caffeine amplifies the effects of amphetamine-related drugs on behavioral parameters, such as locomotor activity, operant behavioral tests, and discriminative stimulus effects, and promotes long-term modifications in the brain. Preclinical data also demonstrate that caffeine contributes to increase the acute toxicity, seizures, hyperthermia, and tachycardia elicited by amphetamine-related drugs in rats. These effects, together with the results showing that caffeine potentiates the loss of central serotonin and dopamine and the induction of neuroinflammation by amphetamine-related drugs, emphasize that, depending on the condi...

Viral-Mediated Knockdown of mGluR7 in the Nucleus Accumbens Mediates Excessive Alcohol Drinking and Increased Ethanol-Elicited Conditioned Place Preference in Rats

Whether metabotropic glutamate 7 (mGluR7) -activation enhances or diminishes the reinforcing properties of psychostimulants remains unclear. We have previously shown that systemic mGluR7 activation reduced alcohol consumption and preference as well as locomotor-stimulating and rewarding properties of ethanol. In this study, we further examined the contribution of mGluR7 on the effect of ethanol within the nucleus accumbens (NAcc), a neural target for many drugs of abuse. Using short hairpin RNA (shRNA)-expressing lentiviral vectors (LV) to alter locally the activity of mGluR7 in male rats, we have shown that blocking mGluR7 expression increased ethanol consumption and preference in a two-bottle choice drinking paradigm with no effect either on saccharin or on quinine used for taste discrimination. In addition, mGluR7 knockdown increases preference for environments previously paired with low doses of ethanol in the conditioned place preference (CPP) test, as it shifted the dose-response curve for ethanol CPP to the left, indicating alterations in the rewarding effects of alcohol. More importantly, mGluR7 blockade in the dorsal striatum (DS) neither affected ethanol consumption nor ethanol-elicited CPP. These results show that levels of mGluR7 in the NAcc regulate responsiveness to alcohol. Taken together, these findings clearly demonstrate that mGluR7 signaling within the NAcc is a key modulator of functional responses to ethanol and offer an important target for regulating the addictive effects of alcohol.

Mephedrone (“bath salt”) pharmacology: insights from invertebrates

Psychoactive bath salts (also called meph, drone, meow meow, m-CAT, bounce, bubbles, mad cow, etc.) contain a substance called mephedrone (4-methylcathinone) that may share psychostimulant properties with amphetamine and cocaine. However, there are only limited studies of the neuropharmacological profile of mephedrone. The present study used an established invertebrate (planarian) assay to test the hypothesis that acute and repeated mephedrone exposure produces psychostimulant-like behavioral effects. Acute mephedrone administration (50–1000 μM) produced stereotyped movements that were attenuated by a dopamine receptor antagonist (SCH 23390) (0.3 μM). Spontaneous discontinuation of mephedrone exposure (1, 10 μM) (60 min) resulted in an abstinence-induced withdrawal response (i.e. reduced motility). In place conditioning experiments, planarians in which mephedrone (100, 500 μM) was paired with the non-preferred environment during conditioning displayed a shift in preference upon subsequent testing. These results suggest that mephedrone produces three behavioral effects associated with psychostimulant drugs, namely dopamine-sensitive stereotyped movements, abstinence-induced withdrawal, and environmental place conditioning.

Responses of dopaminergic, serotonergic and noradrenergic networks to acute levo-tetrahydropalmatine administration in naïve rats detected at 9.4 T

Aim The aim of this study was to understand the neuropharmacological characteristics of levo-tetrahydropalmatine ( l-THP), a recently found potential treatment for drug addiction, and discover its neural correlates and sites of action. Methods High-field pharmacological magnetic resonance imaging (phMRI) was used to detect activation induced by acute l-THP administration in the naïve rat brain at dose levels of 5, 10, 20 and 40 mg/kg. Results Interestingly, the pharmacological profile of l-THP selectively binds to the receptors of the dopaminergic, serotonergic and noradrenergic systems. Using the phMRI method, it was demonstrated that l-THP selectively activated the key brain regions of the dopaminergic, serotonergic and noradrenergic systems in a dose-dependent manner. Conclusion Numerous studies suggest a critical role of monoamines in the behavioral, pharmacological and addictive properties of psychostimulants. It is suggested that l-THP holds great potential to be a therapeutic medication for drug addiction.

Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1

The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that is functionally activated by amphetamine-based psychostimulants, including amphetamine, methamphetamine and MDMA. Previous studies have shown that in transgenic mice lacking the TAAR1 gene (TAAR1 knockout; KO) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type (WT) mice. Further, the psychostimulant effects of cocaine can be diminished by selective activation of TAAR1. These findings suggest that TAAR1 might be implicated in the rewarding properties of psychostimulants. To investigate the role of TAAR1 in the rewarding effects of drugs of abuse, the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and TAAR1 KO mice. In locomotor activity studies, both single and repeated exposure to d-amphetamine or methamphetamine generated significantly higher levels of total distance traveled in TAAR1 KO mice compared to WT mice. In conditioned place preference (CPP) studies, TAAR1 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training. In morphine-induced CPP, both WT and KO genotypes displayed similar levels of CPP. Results from locomotor activity studies suggest that TAAR1 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants. That methamphetamine-but not morphine-induced CPP was augmented in TAAR1 KO mice suggests a selective role of TAAR1 in the conditioned reinforcing effects of methamphetamine. Collectively, these findings provide support for a regulatory role of TAAR1 in methamphetamine signaling.

ChemInform Abstract: Vesicular Monoamine Transporters: Structure‐Function, Pharmacology, and Medicinal Chemistry

AbstractReview: 168 refs.

Lobeline Attenuates the Locomotor-Activating Properties of Repeated Morphine Treatment in Rats

Purpose: Lobeline perturbs intra- and extracellular neurotransmitter levels and diminishes the in vitro and in vivo effects of psychostimulants. More recently, lobeline was shown to bind to μ opiate receptors, block the effects of opiate receptor agonists, and decrease heroin self-administration in rats. The present study determined the effect of lobeline on morphine-induced changes in locomotor behavior in rats. Methods: For 12 consecutive days (Days 1 - 12), male rats were administered lobeline (0.3 or 1 mg/kg) followed by morphine (5 or 10 mg/kg) and locomotor activity was measured. On Day 13, the effect of lobeline on the expression of morphine-induced increases in activity was determined. Results: With repeated morphine treatment, an increase in locomotor activity was observed. In a dosedependent manner, lobeline decreased the morphine-induced increase in activity. Acute lobeline challenge on Day 13 also attenuated the expression of this morphine-induced increase in activity. Conclusion: These results are consistent with previous work where lobeline blocks the locomotoractivtating properties of psychostimulants, and these findings support an emerging literature suggesting that lobeline produces its behavioral effects through an interaction with μ opiate receptors. Keywords: Behavior, Morphine, Locomotor activity, Behavioural sensitization, μ Opiate receptors

Khat (Catha edulis) and ethanol co-dependence modulate seizure expression in a pentylenetetrazol seizure model

Ethnopharmacological relevanceKhat is a plant with psychostimulant properties whose parts, mainly leaves and twigs, are chewed for its euphoriant effects. Khat use and ethanol abuse are increasingly becoming global health concerns especially among many disadvantaged social groups. The present studies were undertaken to investigate seizure susceptibility and responses following chronic co-administration of khat and ethanol. Materials and methodsJuvenile male Sprague-Dawley (SD) rats were administered khat, ethanol or combined khat and ethanol twice daily for 28 days by gavage. Khat-treated animals received 2g/kg or 4g/kg body weight continuously for the study period. Ethanol-treated animals received 20% ethanol at a dose of 4g/kg body weight. The convulsant, pentylenetetrazol (PTZ), was administered intraperitoneally at a dose of 40mg/kg body weight. Seizure responses were recorded. ResultsTwice-daily dosing of khat did not produce inhibition of weight gain. Khat alone, combined khat and 20% ethanol, but not 20% ethanol alone, significantly reduced the latency to seize. Khat treatment at 2g/kg but not 4g/kg body weight also significantly increased the duration of seizures. Conversely, combined khat and ethanol reduced the duration of seizures compared to controls. Ethanol alone reduced the seizure severity while khat alone, and combined khat and ethanol, produced close to the maximum seizure severity. ConclusionsThese data suggest that combined moderate to high dose khat and ethanol co-dependence produce a greater deleterious CNS effect than either drug alone. Future studies will address neurochemical effects, in addition to neuroadaptations, resulting from coabuse of these drugs.

Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behaviour

The serotonergic system appears crucial for (±)-3,4-methylenedioxymethamphetamine (MDMA) reinforcing properties. Current evidence indicates that serotonin 5-HT2A receptors (5-HT2ARs) modulate mesolimbic dopamine (DA) activity and several behavioural responses related to the addictive properties of psychostimulants. This study evaluated the role of 5-HT2ARs in MDMA-induced reinforcement and hyperlocomotion, and the reinstatement of MDMA-seeking behaviour. Basal and MDMA-stimulated extracellular levels of DA in the nucleus accumbens (NAc) and serotonin and noradrenaline in the prefrontal cortex were also assessed. Self-administration of MDMA was blunted in 5-HT2AR knockout (KO) mice compared to wild-type (WT) littermates at both doses tested (0.125 and 0.25 mg/kg per infusion). Horizontal locomotion was increased by MDMA (10 and 20 mg/kg i.p.) to a higher extent in KO than in WT mice. DA outflow in the NAc was lower in KO compared to WT mice under basal conditions and after MDMA (20 mg/kg) challenge. In WT mice, MDMA (5 and 10 mg/kg i.p.) priming did not reinstate MDMA-seeking behaviour, while cue-induced reinstatement was prominent. This cue-induced reinstatement was blocked by administration of the selective 5-HT2AR antagonist, SR46349B (eplivanserin) at a dose of 0.5 mg/kg, but not at 0.25 mg/kg. Our results indicate that 5-HT2ARs are crucial for MDMA-induced reinforcement and cue-induced reinstatement of MDMA-seeking behaviour. These effects are probably due to the modulation of mesolimbic dopaminergic activity.

Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry.

Vesicular monoamine transporters (VMAT) are responsible for the uptake of cytosolic monoamines into synaptic vesicles in monoaminergic neurons. Two closely related VMATs with distinct pharmacological properties and tissue distributions have been characterized. VMAT1 is preferentially expressed in neuroendocrine cells and VMAT2 is primarily expressed in the CNS. The neurotoxicity and addictive properties of various psychostimulants have been attributed, at least partly, to their interference with VMAT2 functions. The quantitative assessment of the VMAT2 density by PET scanning has been clinically useful for early diagnosis and monitoring of the progression of Parkinson's and Alzheimer's diseases and drug addiction. The classical VMAT2 inhibitor, tetrabenazine, has long been used for the treatment of chorea associated with Huntington's disease in the United Kingdom, Canada, and Australia, and recently approved in the United States. The VMAT2 imaging may also be useful for exploiting the onset of diabetes mellitus, as VMAT2 is also expressed in the β-cells of the pancreas. VMAT1 gene SLC18A1 is a locus with strong evidence of linkage with schizophrenia and, thus, the polymorphic forms of the VMAT1 gene may confer susceptibility to schizophrenia. This review summarizes the current understanding of the structure-function relationships of VMAT2, and the role of VMAT2 on addiction and psychostimulant-induced neurotoxicity, and the therapeutic and diagnostic applications of specific VMAT2 ligands. The evidence for the linkage of VMAT1 gene with schizophrenia and bipolar disorder I is also discussed.

Application of the conditioned taste aversion paradigm to assess discriminative stimulus properties of psychostimulants in rats

BackgroundThe conditioned taste aversion (CTA) paradigm is one of the reliable methods to evaluate the discriminative stimulus properties of drugs and is characterized by a short conditioning period and no need for special equipment. This method, however, has not yet been fully investigated for psychostimulants such as cocaine and methamphetamine. MethodsIn the present study, rats were trained to discriminate between cocaine and a vehicle using CTA and substitution tests with various psychostimulants were conducted to evaluate the usefulness of the method for assessing the discriminative stimulus properties of this pharmacological class. Male rats received an intraperitoneal (i.p.) injection of cocaine (10mg/kg) 10min prior to access saccharin for 20-min, and immediately after the saccharin access they received an i.p. dose of LiCl (1.8mEq; n=8, Group CL) or the vehicle (n=8, Group CW) on the day of conditioning; on the other days (2 or 3 days between the cocaine conditioning days), they were injected with saline prior to access to saccharin without the LiCl or vehicle injection after the access. ResultsBy the fifteenth cocaine conditioning trial, all animals acquired discrimination. In the substitution test, cocaine dose dependently decreased saccharin consumption. The psychostimulants, methamphetamine, methylphenidate, bupropion and sibutramine, substituted for cocaine, whereas the opioid μ agonist morphine and the cannabinoid agonist, Δ9-tetrahydrocannabinol, did not substitute for cocaine. Mazindol did not substitute for cocaine although it has CNS stimulant activities. ConclusionThese results suggest that discriminative stimulus properties of psychostimulants can be evaluated using the CTA paradigm.

Muhtemelen Sulbutiamin ile Tetiklenen Bir Manik Atak Olgusu

Sulbutiamine is a precursor of thiamine that crosses the blood-brain barrier. The modulatory effects on both dopaminergic and glutamatergic transmissions within the prefrontal cortex could play a pivotal role in the therapeutic action of sulbutiamine. Sulbutiamine is currently used for the treatment of fatigue, exhaustion and asthenia in physical and psychiatric disorders; however, it does not have any psycho-stimulant properties. While sulbutiamine has no anti-depressive effect, it exhibits several psychotropic effects such as a decrease in psycho-behavioural inhibition occurring in major depressive disorder. In this report, we describe a possible case of sulbutiamine-triggered manic attack in a patient with major depressive disorder, who later developed bipolar I disorder with spontaneous manic episodes. To our knowledge, this is the first possible case of sulbutiamine-triggered manic attack at the proper therapeutic dosage of sulbutiamine in a major depressive patient.

Pharmacological recruitment of the GABAergic tail of the ventral tegmental area by acute drug exposure

The tail of the ventral tegmental area (tVTA), also called the rostromedial tegmental nucleus, is a newly defined brain structure and a potential control centre for dopaminergic activity. It was identified by the induction of DeltaFosB following chronic cocaine exposure. In this work, we screened 20 drugs for their ability to induce FosB/DeltaFosB in the tVTA. Immunohistochemistry following systemic drug administration was used to study FosB/DeltaFosB induction in the tVTA of adult rats. Double-staining was used to determine whether dopamine or GABA neurones are involved in this induction. The acute injection of the psychostimulant drugs cocaine, D-amphetamine, (+/-)-3,4-methylenedioxymethamphetamine (MDMA), methylphenidate or caffeine, induced the expression of FosB/DeltaFosB in the tVTA GABAergic cells. No induction was observed following exposure to ethanol, diazepam, γ-hydroxybutyric acid (GHB), morphine, ketamine, phencyclidine (PCP), Δ(9)-tetrahydrocannabinol (THC), sodium valproic acid or gabapentin. To evaluate the role of monoamine transporters in the psychostimulant-induced expression of FosB/DeltaFosB, we tested the antidepressant drugs reboxetine, nortriptyline, fluoxetine and venlafaxine (which target the noradrenaline and/or the 5-hydroxytryptamine transporters), the 5-hydroxytryptamine releasing agent dexfenfluramine, and the dopamine transporter inhibitor GBR12909. Only GBR12909 was able to induce FosB/DeltaFosB expression in the tVTA, showing that this induction is mediated by dopamine. Newly described brain structures may help to increase our knowledge of brain function, pathology and targets for treatments. FosB/DeltaFosB induction in the tVTA is a common feature of drugs sharing psychostimulant properties but not of drugs sharing risk of abuse.

Cannabinoids, Opioids and MDMA: Neuropsychological Interactions Related to Addiction

3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is an amphetamine derivative with psychostimulant properties. This substance is widely used around the world by young adults in recreational settings. One of the most remarkable characteristic of ecstasy users is the concurrent consumption of several other drugs of abuse including psychostimulants, alcohol, tobacco, LSD, cannabis and opioids. This poly-drug pattern of use is now prompting research towards understanding how the combination of MDMA with cannabis and opioids could affect neuropsychobiological processes related to addiction. As with other drugs of abuse, behavioural evidence has been presented supporting the role of the endocannabinoid system as a modulator of the rewarding/reinforcing properties of MDMA. On the other hand, the neurochemical substrate for the complex interactions between the endocannabinoid system and MDMA is poorly understood. MDMA also modulates the activity of the dynorphinergic and enkephalinergic systems in several brain structures related to addiction, as it has been shown for other psychostimulants. The work regarding the contribution of micro- and delta-opioid receptors in the rewarding effects of MDMA shows differential results in pharmacological studies in rats, with respect to studies using knock-out mice. The present review describes the behavioural and neurochemical interactions between MDMA, cannabinoids and opioids with respect to addiction processes.

Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

Muscarinic M(5) receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M(5) receptors modulate their activity. Previous studies showed that M(5) receptor knockout (M (5) (-/-) ) mice are less sensitive to the reinforcing properties of addictive drugs. Here, we investigate the role of M(5) receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M (5) (-/-) mice backcrossed to the C57BL/6NTac strain. Sensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M (5) (-/-) mice, while the effects of cocaine were similar in M (5) (-/-) and wild-type mice. Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M (5) (-/-) mice. The different effects of amphetamine and cocaine in M (5) (-/-) mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M(5) receptor. These results support the concept that the M(5) receptor modulates effects of addictive drugs.

Cyclin-Dependent Kinase 5 Inhibitors: Inhibition of Dopamine Transporter Activity

Cyclin-dependent kinase (Cdk) 5 reduces the rewarding properties of psychostimulants by dampening postsynaptic dopamine (DA) receptor signaling. Cdk5 is also present in midbrain DA neurons, where the DA transporter (DAT) is localized and limits DA neurotransmission by removing extracellular DA. Here, we tested the hypothesis that Cdk5 could also affect the disposition of DA by regulating DAT activity. Incubation of rat dorsal striatal (dSTR) synaptosomes with the Cdk5 inhibitors roscovitine, olomoucine, and 4-{[(7-oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)methyl]amino}-N-(2-pyridyl)benzenesulfonamide (GW8510) or the inactive congener iso-olomoucine resulted in a rapid, concentration-dependent inhibition of specific [3H]DA uptake. However, roscovitine was the only inhibitor that did not also decrease [3H]2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (WIN35,428) binding to dSTR DATs. Roscovitine-induced inhibition of dSTR [3H]DA uptake was explained by decreased maximal uptake velocity, without a change in cell-surface DAT levels. Roscovitine did not enhance [3H]DA release mediated by either DAT reverse-transport or Ca(2+) channels in dSTR slices. Instead, roscovitine enhanced spontaneous [3H]DA outflow and inhibited DAT-mediated [3H]DA reaccumulation into dSTR slices. To explore the involvement of Cdk5 in roscovitine-induced down-regulation of DAT activity, Cdk5 protein was knocked down via Cdk5-small interfering RNA by as much as 86% in porcine aortic endothelial cells stably expressing human (h)DATs. However, Cdk5 depletion did not alter hDAT activity. Taken together, our results suggest that roscovitine inhibits DAT activity independently of Cdk5; therefore, results obtained with such inhibitors should be interpreted with caution. Our study is the first to demonstrate that Cdk5 inhibitors reduce brain DAT activity via a mechanism that is independent of DAT trafficking and reverse-transport.

Khat Use: Lifestyle or Addiction?

The khat plant contains psychoactive alkaloids with psychostimulant properties, and has been used for centuries as a recreational and religious drug, mainly in some African and Middle Eastern countries. With changing migrationpatterns, epidemiological and clinical outcomes may have changed. The aim of this article is to review current knowledge on pharmacological, epidemiological and clinical aspects of khat use. Khat use is still highly prevalent in the countries mentioned, and in African and Yemeniemigrant groups. Preclinical and clinical data confirm its addictivepotential as well as possible psychological, psychiatric and medical consequences related to stimulant use; however, existing epidemiological studies do not focus on the prevalence of problematic use or dependence. There are no indications of high prevalence of khat use in other cultural and ethnic groups. Data are lacking on possible increased psychotogenic risks when khat is used outside of the original cultural context. As with alcohol use in many countries, khat use can be considered as a lifestyle in some specific countries, covering the spectrum from nonproblematic use to problematic use and dependence. Khat dependence is associated with high morbidity and societal and economical costs.