Cagliari buy Ecstasy
Cagliari buy EcstasyCagliari buy Ecstasy
__________________________
📍 Verified store!
📍 Guarantees! Quality! Reviews!
__________________________
▼▼ ▼▼ ▼▼ ▼▼ ▼▼ ▼▼ ▼▼
▲▲ ▲▲ ▲▲ ▲▲ ▲▲ ▲▲ ▲▲
Cagliari buy Ecstasy
The proliferation of novel psychoactive substances NPS in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine 2-Cl-4,5-MDMA has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted. By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine DA and serotonin 5-HT neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens NAc shell and the medial prefrontal cortex mPFC. Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of kHz ultrasonic vocalizations USVs to characterize its affective properties. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users. The opposite was observed on dialysate 5-HT in the NAc shell, with adolescents being more responsive than adults. Data will be helpful to understand and prevent health damage in 2-Cl-4,5-MDMA users of different ages. NPS can be either analogous to existing controlled drugs or new chemicals synthesized to mimic the effects of controlled drugs, thus evading drug control policies. The proliferation of NPS in the global market poses a serious health hazard and raises concerns over uncertainty about their toxicity and clinical treatment of NPS-induced intoxication Al-Banaa et al. NPS have been divided into four main classes based on their psychopharmacological effects: cannabinoids, depressants, hallucinogens, and stimulants Tracy et al. Alternatively, NPS can be categorized into six groups based on their chemical structure: alkylindoles, arylcyclohexylamines, phenethylamines, piperazines, synthetic cathinones, and tryptamines Miliano et al. Phenethylamines may act as either stimulants or hallucinogens but also possess entactogenic effects Schifano et al. Afterward, a case report of a year-old male polydrug user transported to hospital in a state of unconsciousness and hypoxia and displaying bradycardia and hypoventilation raised concerns, since toxicological analysis detected 2-Cl-4,5-MDMA in his urine Maresova et al. Considering the bulk of preclinical studies that demonstrate the existence of severe neurotoxic effects of MDMA Lyles and Cadet, ; Costa and Golembioskwa, and brain dysfunctions, serotonin syndrome, and hepatotoxicity linked to the use and misuse of MDMA Liechti, ; Patel et al. MDMA and analogs are usually consumed for their ability to increase empathy, sociability, and perceptions of sounds and colors and to induce mild hallucinations Green et al. Adolescence is a critical period of brain development, highly sensitive to the rewarding effects of drugs Corongiu et al. We followed this approach because DA transmission in the NAc shell and mPFC crucially mediates the rewarding and addictive properties of drugs of abuse Di Chiara et al. This study also aimed to identify possible differences between the responsiveness of adolescent and adult subjects to the neurochemical and behavioral effects of 2-Cl-4,5-MDMA. A total of 37 adolescent 5—7 weeks and 40 adult 10—12 weeks male Sprague-Dawley rats Envigo, San Pietro al Natisone, Italy were used for in vivo microdialysis or behavioral tests. Tap water and standard laboratory chow were provided ad libitum. All efforts were made to minimize pain and suffering and to reduce to the lesser extent the number of animals used. Quantification was made by comparison of a standard curve performed for each neurotransmitter. After placement in the cages, rats were allowed to habituate for 30 minutes and then administered with vehicle i. Locomotor activity was scored by counting the single or total number of beam interruptions. A further behavioral analysis i. Scoring was performed by recording the percentage of time spent in each behavioral category considered in 10 minutes intervals for the total time of observation 60 minutes. Behavioral items observed were: locomotion, rearing, sniffing up, repetitive and confined sniffing down, gnawing, flat body posture, Straub tail, and hind limb abduction. Intensity gain was always kept at a constant level throughout recordings. Data were tested for normal distribution using Shapiro—Wilk test. The effect of treatment e. To evaluate the effect of age on DA or 5-HT response within each brain area and 2-Cl-4,5-MDMA dose, an overall analysis of DA and 5-HT levels data obtained from each rat during the microdialysis experiment was conducted by calculating the area under the curve AUC , obtained by plotting the values of DA or 5-HT levels vs time with the classical trapezoidal rule and then comparing the obtained values by Holm-Sidak corrected multiple paired t tests. Behavioral scores were analyzed by factorial ANOVA for each behavioral item, with treatment and age as independent factors. Possible preexisting group differences in locomotor activity and USV emissions were analyzed by using unpaired Student's t -test. At first, we studied the effects of 3 i. In parallel, we studied the effect of an i. No significant differences between vehicle and 2-Cl-4,5-MDMA groups were observed in locomotor activity during the 30 minutes time of habituation to the motility cages Figure 5c , d. Upper panels a, b show the time-course of locomotor activity counts following vehicle and 2-Cl-4,5-MDMA administration. Inset panels c, d show activity counts during the 30 minutes of habituation to the motility cages. Lower panels e, f show the percentage of time spent in each behavioral item during the total time of observation 60 minutes. Similarly, no significant differences in calling behavior of the kHz USVs type were observed between vehicle and 2-Cl-4,5-MDMA groups during habituation to the motility cages Figure 6d , e. Abbreviation: USVs, ultrasonic vocalizations. In particular, 2-Cl-4,5-MDMA more markedly increased the extracellular levels of DA in both the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on extracellular levels of 5-HT in the NAc shell, with a more marked increase in adolescent than adult rats. In addition, 2-Cl-4,5-MDMA stimulated locomotor and stereotyped activity in both adolescent and adult rats, although adolescent rats spent higher percentages of time performing locomotion, sniffing up, and Straub tail than adult rats. The main results of this study were obtained by in vivo brain microdialysis that allowed to simultaneously evaluate in the same animal the changes of DA and 5-HT transmission in two brain areas that critically interact to encode motivated behaviors and responsiveness to motivational stimuli De Luca, and whose interplay may differ between adolescence and adulthood. The ability to increase DA in the NAc shell is a common feature of substances with abuse potential and is considered an index of the reinforcing and addictive properties of a drug Carlezon and Wise, ; Di Chiara et al. The quantification of 5-HT from the NAc shell showed a higher responsiveness of adolescent than adult rats, while no age-dependent differences were observed in the mPFC. Notably, the peculiar response of 5-HT transmission in the NAc shell of adolescent rats displayed a prolonged and a 4-fold higher increase in 5-HT release than adult rats, whereas no age-related differences in this response were observed in the mPFC. Reasons for the higher responsiveness of the 5-HT system in adolescent rats may be searched in the light of several factors. It should be considered that 5-HT is one of the first neurotransmitter systems to develop in the mammalian brain and that it plays an important role in brain development Lauder , ; Rubenstein, Animal studies have shown that 5-HT content, SERT levels, and 5-HT binding sites are all generally higher in the developing brain compared with the adult brain and that before puberty they all decline to levels similar to those found in the adult brain Murrin et al. Nonetheless, although the 5-HT system appears to be mature early in life as regard fiber density and 5-HT synthesis, each of 5-HT receptors and enzymes have a unique pattern of development, with some stabilizing before puberty Galineau et al. Serotonergic innervation of the rat cerebral cortex begins to show patterns characteristic of the adult cortex by the end of the third postnatal week Dori et al. While the latter finding is consistent with our results showing no differences in 5-HT release in the mPFC following 2-Cl-4,5-MDMA, the early development of 5-HT neuronal system does not explain the striking differences in 5-HT responsiveness in the NAc shell between adolescent and adult rats. While not neglecting the several changes occurring in the adolescent brain in neuronal systems other than the 5-HT system, which might interact with and affect 5-HT neurotransmission, one likely explanation for the greater increase of 5-HT observed in the NAc shell of adolescent rats might be linked to the contribution of oxytocin OT. The OT system is implicated in social behavior Sanna and De Luca, and, as other neuronal systems, it undergoes changes during brain development with a significant phase of transition following puberty Sannino et al. Other in vivo studies showed that systemic Parsons et al. Of note, repeated treatment with cocaine sensitizes both 5-HT and DA increase in the NAc and dorsal raphe nucleus in response to cocaine challenge Parsons and Justice, a , b ; De Luca et al. Taken together, the above evidence could suggest that an interplay exists between the marked increase of 5-HT outflow and the low increase of DA outflow in the NAc shell of adolescent rats observed here after the administration of 2-Cl-4,5-MDMA. Indeed, adolescence is the phase of neurodevelopment when the PFC matures, being PFC a key regulator of superior brain functions that are altered in psychiatric disorders Renard et al. Furthermore, since in vivo studies have demonstrated the neurotoxicity of molecules structurally-correlated to 2-Cl-4,5-MDMA Cadoni et al. Our results on the behavioral effects of 2-Cl-4,5-MDMA have shown that it stimulates locomotor activity and induces the appearance of stereotypies in both adolescent and adult rats. Regarding locomotor activity, it is well known that activation of DA transmission in the NAc stimulates locomotion through an action on D1 and D2 receptors Sharp et al. Similarly, increased 5-HT transmission by indirect 5-HT agonists is able to stimulate locomotor activity through a 5-HT1B mediated mechanism Geyer, Moreover, adolescent rats displayed a significantly greater increase in the time spent performing locomotion, rearing, and sniffing up compared with adult rats. Regarding stereotypes linked to 5-HT release Straub tail, hind limb abduction, and flat body posture , we observed a comparable hind limb abduction in adolescent and adult rats and a more marked Straub tail in adolescents compared with adults. This effect is similar to what was observed in previous studies after both acute and repeated administration of MDMA Sadananda et al. At the same time, only drugs that markedly activate DA transmission in the NAc shell i. The emission of kHz USVs is considered a behavioral marker of the positive effects that psychoactive drugs may elicit on arousal, affect, and motivation in rats Simola, Nevertheless, it is noteworthy that several drugs that increase the affective and motivational state of rats scarcely stimulate the emission of kHz USVs Wright et al. Accordingly, the lack of effect of 2-Cl-4,5-MDMA on calling behavior should not be simply considered a result indicating that this NPS has no influence on the affective state of rats. Conversely, it may rather support the assumption suggested by microdialysis data that 2-Cl-4,5-MDMA has a psychopharmacological profile different from that of other psychostimulants of abuse. This study has some limitations since it focused mainly on neurochemical and behavioral effects induced by the acute administration of 2-Cl-4,5-MDMA, without addressing the underlying molecular mechanisms, as well as the possible involvement of active metabolites in the findings observed. Moreover, we used only male rats in our study and, therefore, we do not know if our findings can be extended to female rats. Nevertheless, this study completes previous investigations on the pharmacological and toxicological properties of 2-Cl-4,5-MDMA Sogos et al. This feature may influence the pattern of use and misuse of 2-Cl-4,5-MDMA, such as the frequency of ingestion, but also the psychoactive acute effects of this NPS that appear dissimilar from those of other psychostimulant drugs Miliano et al. The data underlying this article will be shared on reasonable request by the corresponding author. A time series analysis. Int J Drug Policy 77 : Google Scholar. Brain Res : 10 — J Pharmacol Exp Ther : — Booij L , Tremblay RE , Szyf M , Benkelfat C Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology. J Psychiatry Neurosci 40 : 5 — J Comp Neurol : 92 — Burgdorf J , Panksepp J Tickling induces reward in adolescent rats. Physiol Behav 72 : — Psychopharmacology : — Brain Res : — Neuropharmacology : — Brain Res : 55 — J Neurosci 16 : — Addict Biol 25 : e Exp Neurol : Neural Regen Res 15 : — J Neurochem 66 : — De Luca MA Habituation of the responsiveness of mesolimbic and mesocortical dopamine transmission to taste stimuli. Front Integr Neurosci 8 : De Luca MA , Bimpisidis Z , Bassareo V , Di Chiara G Influence of morphine sensitization on the responsiveness of mesolimbic and mesocortical dopamine transmission to appetitive and aversive gustatory stimuli. Addict Biol 23 : — Neuropharmacology 47 : — J Clin Med 9 : Nature : — Exp Neurol : 1 — Accessed 2 Feb. Neurosci Lett : — Geyer MA Serotonergic functions in arousal and motor activity. Behav Brain Res 73 : 31 — Pharmacol Rev 55 : — Neurosci Lett : 57 — Neuropharmacology : Ikemoto S , Bonci A Neurocircuitry of drug reward. Neuropharmacology 76 Pt B : — Synapse 36 : — Kalivas PW Neurotransmitter regulation of dopamine neurons in the ventral tegmental area. Brain Res Brain Res Rev 18 : 75 — Br J Pharmacol : — Lancet Psychiatry 1 : — Lauder JM Ontogeny of the serotonergic system in the rat: serotonin as a developmental signal. Ann N Y Acad Sci : — ; discussion Lauder JM Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci 16 : — Pharmacol Biochem Behav : 52 — J Forensic Sci 45 : — Dtsch Med Wochenschr : — Neuropsychopharmacology 22 : — Front Pharmacol 11 : Brain Res Brain Res Rev 42 : — J Anal Toxicol 29 : — Front Neurosci 10 : Front Pharmacol 10 : Murrin LC , Sanders JD , Bylund DB Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: implications for differential drug effects on juveniles and adults. Biochem Pharmacol 73 : — Parsons LH , Justice JB Jr a Perfusate serotonin increases extracellular dopamine in the nucleus accumbens as measured by in vivo microdialysis. Parsons LH , Justice JB Jr b Serotonin and dopamine sensitization in the nucleus accumbens, ventral tegmental area, and dorsal raphe nucleus following repeated cocaine administration. J Neurochem 61 : — J Neurosci 18 : — Expert Opin Pharmacother 5 : — Peters KZ , Naneix F The role of dopamine and endocannabinoid systems in prefrontal cortex development: Adolescence as a critical period. Front Neural Circuits 16 : Phelix CF , Broderick PA Light microscopic immunocytochemical evidence of converging serotonin and dopamine terminals in ventrolateral nucleus accumbens. Brain Res Bull 37 : 37 — Biomedicines 10 : Sci Justice 56 : — Front Neurosci 8 : Psychol Addict Behav 31 : — Rubenstein JL Development of serotonergic neurons and their projections. Biol Psychiatry 44 : — Pharmacol Biochem Behav : — Curr Opin Pharmacol 58 : 8 — Sannino S , Chini B , Grinevich V Lifespan oxytocin signaling: maturation, flexibility, and stability in newborn, adolescent, and aged brain. Dev Neurobiol 77 : — Neuropsychopharmacology 25 : — Schenk S MDMA self-administration in laboratory animals: a summary of the literature and proposal for future research. Neuropsychobiology 60 : — Ann Ist Super Sanita 43 : — World Psychiatry 14 : 15 — Handb Exp Pharmacol : — Simola N Rat ultrasonic vocalizations and behavioral neuropharmacology: from the screening of drugs to the study of disease. Curr Neuropharmacol 13 : — Simola N , Brudzynski SM Rat kHz ultrasonic vocalizations as a tool in studying neurochemical mechanisms that regulate positive emotional states. J Neurosci Methods : 33 — Simola N , Costa G Emission of categorized kHz ultrasonic vocalizations in rats repeatedly treated with amphetamine or apomorphine: possible relevance to drug-induced modifications in the emotional state. Behav Brain Res : 88 — Simola N , Fenu S , Costa G , Pinna A , Plumitallo A , Morelli M Pharmacological characterization of kHz ultrasonic vocalizations in rats: comparison of the effects of different psychoactive drugs and relevance in drug-induced reward. Neuropharmacology 63 : — Simola N , Frau L , Plumitallo A , Morelli M Direct and long-lasting effects elicited by repeated drug administration on kHz ultrasonic vocalizations are regulated differently: implications for the study of the affective properties of drugs of abuse. Int J Neuropsychopharmacol 17 : — Int J Mol Sci 22 : Curr Opin Behav Sci 13 : — J Child Neurol 15 : — Behav Brain Res : 64 — Pharmacol Ther : BMJ : i United Nations Publication , 87 — Google Preview. Neuropharmacology 65 : 58 — Epub Sep 7. Erratum in: Neuropharmacology. Van Bockstaele EJ , Pickel VM Ultrastructure of serotonin-immunoreactive terminals in the core and shell of the rat nucleus accumbens: cellular substrates for interactions with catecholamine afferents. J Comp Neurol : — Wahlstrom D , Collins P , White T , Luciana M Developmental changes in dopamine neurotransmission in adolescence: behavioral implications and issues in assessment. Brain Cogn 72 : — Prog Brain Res : — Williams SN , Undieh AS Brain-derived neurotrophic factor signaling modulates cocaine induction of reward-associated ultrasonic vocalization in rats. J Psychopharmacol 20 : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign in through your institution. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Interest Statement. Data Availability. Author Contributions. Journal Article. Gessica Piras , Gessica Piras. Department of Biomedical Sciences, University of Cagliari. Oxford Academic. Cristina Cadoni. Francesca Caria. Nicholas Pintori. Enrica Spano. Maksims Vanejevs. Latvian Institute of Organic Synthesis. Anastasija Ture. Graziella Tocco. Nicola Simola. Maria Antonietta De Luca. Editorial decision:. Corrected and typeset:. Select Format Select format. Permissions Icon Permissions. Abstract Background. Graphical Abstract. Open in new tab Download slide. Addiction , dopamine , novel psychoactive substances , serotonin , ultrasonic vocalizations. Significance Statement. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Effect of the UK Psychoactive Substances Act on episodes of toxicity related to new psychoactive substances as reported to the National Poisons Information Service. Google Scholar Crossref. Search ADS. Topographical dopamine and serotonin distribution and turnover in rat striatum. Serotonin-facilitated dopamine release in vivo: Pharmacological characterization. Google Scholar PubMed. Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology. Ultrastructural localization of tyrosine hydroxylase in rat nucleus accumbens. Behavioural sensitization after repeated exposure to Delta 9-tetrahydrocannabinol and cross-sensitization with morphine. Widespread reduction of dopamine cell bodies and terminals in adult rats exposed to a low dose regimen of MDMA during adolescence. Mapping of locomotor behavioral arousal induced by microinjections of dopamine within nucleus accumbens septi of rat forebrain. Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex. Adolescence versus adulthood: differences in basal mesolimbic and nigrostriatal dopamine transmission and response to drugs of abuse. Neuronal and peripheral damages induced by synthetic psychoactive substances: an update of recent findings from human and animal studies. The novel psychoactive substance methoxetamine induces persistent behavioral abnormalities and neurotoxicity in rats. Serotonin enhances striatal dopamine outflow in vivo through dopamine uptake sites. De Luca. Influence of morphine sensitization on the responsiveness of mesolimbic and mesocortical dopamine transmission to appetitive and aversive gustatory stimuli. Di Chiara. Abuse of licit and illicit psychoactive substances in the workplace: medical, toxicological, and forensic aspects. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Regional differences in the ontogeny of the serotonergic projection to the cerebral cortex. Ontogeny of the dopamine and serotonin transporters in the rat brain: an autoradiographic study. Experimental strategies to discover and develop the next generation of psychedelics and entactogens as medicines. Neurotransmitter regulation of dopamine neurons in the ventral tegmental area. Mephedrone, compared with MDMA ecstasy and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats. Changes in the adolescent brain and the pathophysiology of psychotic disorders. Ontogeny of the serotonergic system in the rat: serotonin as a developmental signal. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Sex differences in abuse-related neurochemical and behavioral effects of 3,4-methylenedioxymethamphetamine MDMA in rats. The identification of 2-chloro-4,5-methylenedioxymethylamphetamine in an illicit drug seizure. Neuropharmacology of New Psychoactive Substances NPS : focus on the rewarding and reinforcing properties of cannabimimetics and amphetamine-like stimulants. Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: implications for differential drug effects on juveniles and adults. Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Serotonin1B receptors in the ventral tegmental area modulate cocaine-induced increases in nucleus accumbens dopamine levels. Perfusate serotonin increases extracellular dopamine in the nucleus accumbens as measured by in vivo microdialysis. Serotonin and dopamine sensitization in the nucleus accumbens, ventral tegmental area, and dorsal raphe nucleus following repeated cocaine administration. The role of dopamine and endocannabinoid systems in prefrontal cortex development: Adolescence as a critical period. Light microscopic immunocytochemical evidence of converging serotonin and dopamine terminals in ventrolateral nucleus accumbens. The synthesis and characterisation of MDMA derived from a catalytic oxidation of material isolated from black pepper reveals potential route specific impurities. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology. Age of initiation and substance use progression: A multivariate latent growth analysis. Lifespan oxytocin signaling: maturation, flexibility, and stability in newborn, adolescent, and aged brain. Serotonin-dopamine interactions in the control of conditioned reinforcement and motor behavior. MDMA self-administration in laboratory animals: a summary of the literature and proposal for future research. A direct comparison of amphetamine-induced behaviors and regional brain dopamine release in the rat using intracerebral dialysis. Rat ultrasonic vocalizations and behavioral neuropharmacology: from the screening of drugs to the study of disease. Rat kHz ultrasonic vocalizations as a tool in studying neurochemical mechanisms that regulate positive emotional states. Emission of categorized kHz ultrasonic vocalizations in rats repeatedly treated with amphetamine or apomorphine: possible relevance to drug-induced modifications in the emotional state. Pharmacological characterization of kHz ultrasonic vocalizations in rats: comparison of the effects of different psychoactive drugs and relevance in drug-induced reward. Direct and long-lasting effects elicited by repeated drug administration on kHz ultrasonic vocalizations are regulated differently: implications for the study of the affective properties of drugs of abuse. Human neuronal cell lines as an in vitro toxicological tool for the evaluation of novel psychoactive substances. Developmental changes in cerebrospinal fluid concentrations of monoamine-related substances revealed with a Coulochem electrode array system. Amphetamine-induced 50 kHz calls from rat nucleus accumbens: a quantitative mapping study and acoustic analysis. Adolescent neurodevelopment and substance use: Receptor expression and behavioral consequences. Van Bockstaele. Ultrastructure of serotonin-immunoreactive terminals in the core and shell of the rat nucleus accumbens: cellular substrates for interactions with catecholamine afferents. Developmental changes in dopamine neurotransmission in adolescence: behavioral implications and issues in assessment. Serotonin, norepinephrine and associated neuropeptides: effects on somatic motoneuron excitability. Brain-derived neurotrophic factor signaling modulates cocaine induction of reward-associated ultrasonic vocalization in rats. Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population. Failure of rewarding and locomotor stimulant doses of morphine to promote adult rat kHz ultrasonic vocalizations. Endogenous serotonin stimulates striatal dopamine release in conscious rats. For commercial re-use, please contact reprints oup. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals. Issue Section:. Download all slides. Supplementary data. Views More metrics information. Total Views Email alerts Article activity alert. Advance article alerts. New issue alert. In progress issue alert. Receive exclusive offers and updates from Oxford Academic. Citing articles via Google Scholar. Working memory performance predicts, but does not reduce, cocaine- and cannabinoid-seeking in adult male rats. More from Oxford Academic. Medicine and Health. Science and Mathematics. Authoring Open access Purchasing Institutional account management Rights and permissions. Get help with access Accessibility Contact us Advertising Media enquiries.
TEXAS TECH UNIVERSITY
Cagliari buy Ecstasy
You have full access to this open access article. MDMA 3,4-methylenedioxymethamphetamine is a psychostimulant popular as a recreational drug because of its effect on mood and social interactions. MDMA is often ingested with caffeine. The aim of the present study was to determine the changes in DA and 5-HT release in the mouse striatum induced by MDMA and caffeine after their chronic administration. Furthermore, the effect of caffeine on MDMA-induced changes in striatal dynorphin and enkephalin and on behavior was assessed. DNA damage was assayed with the alkaline comet assay. The behavioral changes were measured by the open-field OF test and novel object recognition NOR test. Our data provide evidence that long-term caffeine administration has a powerful influence on functions of dopaminergic and serotonergic neurons in the mouse brain and on neurotoxic effects evoked by MDMA. This effect is intensified by inhibition of monoamine oxidase type B MAO-B located in the outer membrane of the mitochondria of serotonergic neurons Leonardi and Azmitia MDMA has been shown to elicit long-lasting neurotoxic effects which vary depending on gender and strain of animals Brodkin et al. Similarly, the damage in serotonergic system was also observed in non-human primates and in the human brain Green et al. Numerous complex mechanisms have been identified as contributors to the neurotoxic effects of MDMA. Oxidative stress and excitotoxicity represent important mechanisms causing neuronal damage by MDMA Cadet et al. MDMA has also been shown to trigger neuroinflammation which seems to be linked with glial activation, in particular microglial activation Costa et al. Other putative mechanisms of MDMA neurotoxicity include hyperthermia, metabolic toxic products, and apoptosis Capela et al. Toxic and inflammatory effects of MDMA are exacerbated by its co-administration with other psychoactive substances Khairnar et al. Caffeine is commonly consumed with MDMA in energy drinks to reduce drowsiness and fatigue, or it is present in illicit drug preparations, e. Molecular mechanism of caffeine action in the brain is based on adenosine receptor antagonism. The targets of caffeine actions include G-protein-coupled adenosine A1 and A2A receptors. It is also suggested that adenosine A1 receptors present on glutamatergic neurons may be involved in striatal DA release Borycz et al. On the other hand, medium-sized spiny neurons projecting to the globus pallidus express D2 receptor Gerfen et al. By contrast, caffeine increases the activity of both types of neurons Johansson et al. Caffeine augmented many effects associated with MDMA use. MDMA-induced hyperthermia and tachycardia but not hyperlocomotion were promoted by caffeine in rats. The results of Khairnar et al. The abovementioned data suggest that caffeine increases MDMA-related neurotoxicity. On the other hand, the results of Ruiz-Medina et al. This raises the question about a long-term caffeine effect on MDMA neurotoxicity. Both drugs were administrated repeatedly in a way mimicking recreational use by young people in dance clubs. In addition, because caffeine could affect behavioral responses, we assessed the effect of chronic caffeine administration on some behavioral parameters associated with MDMA administration. Caffeine and MDMA were dissolved in 0. All injections were done via intraperitoneal ip route, and control animals received their respective vehicles. This cycle of treatments was repeated 3 times as shown on the diagram below. Animals were anesthetized with ketamine 7. After 1 h of the washout period, three basal dialysate samples were collected every 30 min; then, animals were injected with a challenging dose of an appropriate drug as indicated in the figure captions and fraction collection continued for min. At the end of the experiment, the mice were sacrificed and their brains were histologically examined to validate the probe placement. The mobile phase was composed of 0. The flow rate during analysis was set at 0. The chromatographic data were processed by Chromeleon v. Animals were sacrificed by decapitation 3 h after cessation of treatment with drugs. Brains were separated, and several brain regions striatum, frontal cortex were dissected in anatomical borders. Briefly, tissue samples of brain structures were homogenized in ice-cold 0. The mobile phase consisted of 0. The potential of a 3-mm glassy carbon electrode was set at 0. Animals were killed 60 days after termination of drug treatments. The whole cortex was separated in anatomical borders. Next, the brain tissue was minced with surgical scalpel and homogenized in a manual homogenizer with homogenizing solution containing 0. The pellet was resuspended in 0. The nuclei were obtained as a transparent sediment at the bottom. The suspension was mixed with LMA agarose and transferred immediately onto Comet slides. The buffer was drained, and the slides were immersed in alkaline unwinding solution and were left for 45 min in the dark. Next, electrophoresis was run at 21 V for 30 min. The slides were then covered with dye and allowed to dry completely at room temperature in the dark. On the next day, the slides were examined under a fluorescent microscope. DNA damage was presented as an olive tail moment. Olive tail moment is defined as the product of the tail length and the fraction of total DNA in the tail. Tail moment incorporates a measure of both the smallest detectable size of migrating DNA reflected in the comet tail length and the number of damaged pieces represented by the intensity of DNA in the tail. Brains were removed from the skull, and tissue samples including the striatum were collected. The expression of the HPRT1 transcript was quantified at a stable level between the experimental groups to control for variations in cDNA amounts. Cycle threshold values were calculated automatically by iCycler IQ 3. For each mouse, three sections were collected from each of the brain regions analyzed at the following coordinates: from 2. Free-floating sections were rinsed in 0. After completion of incubation with the primary antibody, sections were rinsed three times in 0. After incubation with the secondary antibody, sections were rinsed and immediately mounted onto glass slides coated with gelatin in Mowiol mounting medium. Images of single wavelengths were obtained with an epifluorescence microscope Axio Scope A1, Zeiss, Oberkochen, Germany connected with a digital camera 1. Sections were captured in black and white 8-bit monochrome, and the density of fibers was determined in fixed regions using a threshold level that was kept constant across all images. The pixels were converted into square micrometers by employing a suited calibration, in order to represent the area occupied by a specific immunoreaction product in square micrometers. The final values are expressed as a percentage of the respective vehicle group. No significant differences in the density of immunoreacted fibers were seen between the three coronal sections. For each level of the striatum and mPFC, the obtained value was first normalized with respect to the vehicle, then, values from different levels were averaged. The arena was dimly illuminated with an indirect light of 18 lx. The mice were selected from separate housing cages. Each mouse was diagonally placed in the middle of the box. The behavior of the animals line crossing, center square duration, rearing, stretch attend postures was measured over a 5-min period. The test box was wiped clean between each trial. The laboratory room was dark, and only the center of the open field was illuminated with a W bulb placed 75 cm above the platform. On the first day of the experiment adaptation , mice were placed in the open field for 10 min. On the next day, the animals were placed in the open field for 5 min with two identical objects white tin, 5 cm wide and 14 cm high or green pyramid 5 cm wide and 14 cm high. The time of object interest was measured for each of the two objects separately. Then, 1 h after the first session, the mice were again placed in a free field for 5 min with two different objects, one from the previous session old and the other new white box and green pyramid. The time of object interest was measured for each of the two objects separately sniffing, touching, or climbing. Co-administration of both drugs produced a significantly stronger effect on extracellular DA level than each of the drugs given separately Fig. Time of drug injections is indicated with thick arrows. However, the increase produced by a combination of both drugs was weaker as compared to the effect of MDMA or caffeine given separately Fig. The increase in 5-HT release to ca. The basal extracellular level of 5-HT was decreased from 1. It is clear that the effect of the challenging doses of both psychostimulant drugs on DA release was weaker in groups pretreated chronically with caffeine and MDMA vs. In contrast, the effect of the challenging doses of caffeine and MDMA on 5-HT release was stronger in animals receiving chronic treatment of psychostimulants vs. The increase in DA tissue content was higher in the group treated concomitantly with caffeine and MDMA than in animals receiving these drugs separately Table 2. Caffeine and MDMA given acutely or chronically produced oxidative damage of DNA in nuclei from the mouse cortex as measured 2 months after cessation of treatment Fig. The damage of DNA was stronger after combination of both drugs administered acutely or chronically Fig. The extent of DNA damage was smaller after all treatments when it was measured 24 h after termination of drug administration data not shown. Data represent an olive tail moment. The loss of DNA integrity persisted 60 days after drug administration. Data represent mRNA levels with respect to the control group. Caffeine did not affect those parameters. Bars represent the time of walking and number of crossings a , and time of exploration of novel object b. Our findings indicate that caffeine increased the response of DA neurons to the challenging dose of MDMA while decreasing the response of serotonergic neurons. Furthermore, exploratory and locomotor activities of mice decreased by MDMA were not affected by caffeine, but exploration of novel object in the NOR test was diminished in animals treated with MDMA and caffeine. The pattern of 5-HT release was different showing more stable increase throughout the whole collection time. Moreover, MDMA applied in a single higher dose i. When MDMA was applied chronically 2 days of binge administration per week; this cycle was repeated three times , a weaker response of DA neurons to the challenging dose of MDMA but a stronger response of 5-HT ones was observed. Interestingly, the basal extracellular level of DA in mice receiving MDMA chronically was nearly twofold higher than in control animals, while extracellular 5-HT level was potently decreased. It may be speculated that persistent outflow of DA due to loss of DA uptake capacity may be a cause of increased basal extracellular DA level. Considerable evidence from the literature indicates that internalization of DAT occurs in response to amphetamine treatment Saunders et al. In fact, we observed a decrease in DAT density in the striatum and frontal cortex following chronic exposure to MDMA, which is in line with studies of Saunders et al. This is probably due to compensatory upregulation of 5-HT release machinery resulting from low synaptic 5-HT levels. For instance, Koch and Galloway , Reveron et al. However, some studies report that the activation of 5-HT1A Ichikawa et al. Thus, it may be suggested that long-term exposure to MDMA leads to neuroadaptative changes in sensitivity of serotonin receptors, which may result in differential response of DA and 5-HT neurons, as it is observed in our study. Some data suggest a role of postsynaptic 5-HT2A receptors located on glutamatergic neurons in the neurochemical effects mediated by MDMA. Stimulation of 5-HT2A receptors located on glutamatergic cells in the frontal cortex may elicit an increase in glutamate level leading indirectly to a rise in DA and 5-HT release Alex and Pehek However, it remains unclear how glutamate and GABA release may be involved in upregulation of serotonergic neurons and cause very potent response to the challenging dose of MDMA, as we observed in the present study. However, in contrast to animals pretreated with saline in which caffeine potentiated MDMA-induced increase in 5-HT release, caffeine inhibited the MDMA effect on 5-HT release in animals receiving both psychostimulants repeatedly. It is accepted that the mechanism underlying caffeine influence on neurotransmitter release is related to the blockade of adenosine A1 and A2A receptors. Caffeine may increase DA and glutamate release in the striatum via blockade of inhibitory A1 receptors as was evidenced by a number of studies Borycz et al. The lack of A2A receptors on the striatal monoaminergic neuronal terminals suggests that their role in the control of DA and 5-HT release may be secondary and related to the changes in the activity of striatal output pathways elicited by postsynaptic A2A receptors. These data indicate synergistic interaction between caffeine and MDMA. The difference in results reported by the above-cited studies may be related by way of drug application systemic vs. It may be speculated that persistent blockade of adenosine receptors by caffeine can be responsible for this effect. In the study of Okada et al. However, under A1 receptor blockade by caffeine, the inhibitory effects of A3 receptor were unmasked in addition to the effect of A2 receptor blockade by caffeine Okada et al. Furthermore, it was also demonstrated that 5-HT reuptake activity might be modulated by A3 receptor Okada et al. Thus, the described mechanism of adenosine receptor involvement in the control of 5-HT release and their blockade by caffeine may be responsible for the diminished 5-HT release in response to MDMA and caffeine co-administration. The neurotoxic effect of MDMA in mice seems to be related to dopaminergic and serotonergic systems. The involvement of free radicals in MDMA-induced dopaminergic neurotoxicity in mice was also shown by Peraile et al. Those authors demonstrated that oxidative stress was related with lipid peroxidation and with an increase in superoxide dismutase and decrease in catalase activity. Hydroxyl radical formation together with products of tryptamine oxidation was proposed as the mechanism of MDMA-induced depletion of brain 5-HT by Shankaran et al. Moreover, it was suggested that 5-HT depletion was dependent on 5-HT transporter activity. Barbosa et al. Oxidative damage produced by MDMA may be associated with neuronal cell bodies. Most of the literature has described the striatum as the main target of MDMA neurotoxicity. Here, we provide evidence that other regions are also targets of MDMA neurotoxicity. DNA damage may be a molecular basis for MDMA-induced neuroplasticity with subsequent behavioral and cognitive deficits. At the same time, it slightly but significantly reversed the decrease in striatal DOPAC content and increased DA striatal tissue level. However, it was neuroprotective for DA fibers in the striatum. On the other hand, it potentiated the decrease in cortical SERT fiber density. Thus, caffeine seems to be neuroprotective for striatal dopaminergic fibers, but it seems to increase neurotoxic damage of cortical 5-HT terminals. Moreover, besides damage of cortical 5-HT terminals, caffeine increased MDMA-induced oxidative damage of cortical DNA which suggests degeneration of neuronal cells in this brain region. The neurotoxic effect exerted on cortical neuronal cell bodies may lead to neuroadaptive change of cortical pathways projecting to nigral or raphe nuclei. Thus, overall caffeine effect seems to be partly neuroprotective and partly neurotoxic. This dual action is dependent on doses, the brain region examined, and the schedule of administration as reported by numerous literature. When caffeine was given chronically, it increased activity of antioxidant enzymes superoxide dismutase SOD and catalase CAT in several regions of the rat brain Noschang et al. Aoyama et al. On the other hand, caffeine exhibited prooxidant properties in vitro Azam et al. The neurotoxic potential of caffeine given acutely was evidenced in the mouse brain by enhanced astroglia and microglia reactivities by MDMA Khairnar et al. In contrast, chronic low doses of caffeine exerted anti-inflammatory effects and prevented MDMA-induced neuroinflammatory reaction Ruiz-Medina et al. Study of Frau et al. Thus, caffeine shows differential effects, neuroprotective or neurotoxic, when co-administered with MDMA indicating that the mechanism of action of psychoactive drug combination needs further clarification. This is in line with findings of Benedetto di et al. These data confirm also the role of D1 receptor in MDMA effects, in particular in the development of neurotoxicity after long-term administration Granado et al. The overstimulation of a direct GABAergic pathway with normal functioning of an indirect GABAergic pathway may be responsible for deficit in locomotor activity of mice observed in our study. On the other hand, caffeine co-administered chronically with MDMA decreased the time of exploration of unknown object in the novel object recognition test. It is likely that a combination of both psychostimulants induced deficit in cognitive functions of mice, as also demonstrated by Costa et al. Structural synaptic plasticity of the medial prefrontal cortex was correlated with changes in response to novelty in rats developmentally treated with cocaine Caffino et al. It may be suggested that damage of serotonergic terminals in cortical regions or possible oxidative damage of glutamatergic pathways projecting to the VTA or raphe cell bodies may be responsible for the effect of psychostimulants on cognitive functions. The role of glutamatergic pathway damage by oxidative stress in the hippocampus and cognitive impairment was also shown in mice by Frenzilli et al. Anxiety-like behavior in rats was related to oxidative damage of DNA in the hippocampus by chronic caffeine Noschang et al. The alterations in the brain antioxidant system were suggested to affect the cognitive functions of rats after chronic caffeine ingestion Abreu et al. In conclusion, our data provide evidence that long-term caffeine administration has a powerful influence on dopaminergic and serotonergic neuron functions disturbed by MDMA in the mouse brain and on neurotoxic effects evoked by MDMA. Caffeine potentiates MDMA effect on dopaminergic system and inhibits its effect on serotonergic neurons. Exacerbation of MDMA-evoked oxidative stress may cause damage of serotonergic terminals. Pharmacol Biochem Behav — Pharmacol Ther — Neuroscience — Ann Neurol — J Neurochem — Br J Pharmacol — Neuropsychopharmacology — Article Google Scholar. Ann Med Interne Paris Suppl. Google Scholar. Neurotox Res — Brain Res — NeuroToxicology — J Neurosci — Mov Disord — Psychopharmacology — J Comp Neurol — Trends Pharmacol Sci — Article PubMed Google Scholar. Prog Brain Res — PubMed Google Scholar. Behav Pharmacol — Science — Pharmacol Rep — Pharmacol Rev — Eur J Pharmacol — J Neurol Sci — J Caffeine Res — J Neural Transm — Neuropharmacology — Neurochem Res — J Pharmacol Exp Ther — Neurosci Lett — Eur J Neurosci —9. Academic Press, San Diego. Peacock A, Bruno R, Ferris J, Winstock A Energy drink use frequency among an international sample of people who use drugs: associations with other substance use and well-being. Drug Alcohol Depend — Reveron ME, Maier EY, Duvauchelle CL Behavioral, thermal and neurochemical effects of acute and chronic 3,4-methylenedioxymethamphetamine ecstasy self-administration. Behav Brain Res — JAMA — Biol Psychol — Synapse — Eur J Neurosci — Proc Natl Acad Sci — Shankaran M, Yamamoto BK, Gudelsky GA Involvement of the serotonin transporter in the formation of hydroxyl radicals induced by 3,4-methylenedioxymethamphetamine. Prog Neurobiol — Aust J Pharm — Brit Aust J Pharm — Download references. You can also search for this author in PubMed Google Scholar. Reprints and permissions. Neurotox Res 33 , — Download citation. Received : 04 August Revised : 04 October Accepted : 18 October Published : 13 November Issue Date : April Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Neurotoxicity Research Aims and scope Submit manuscript. Download PDF. Abstract MDMA 3,4-methylenedioxymethamphetamine is a psychostimulant popular as a recreational drug because of its effect on mood and social interactions. Molecular changes in the nucleus accumbens and prefrontal cortex associated with the locomotor sensitization induced by coca paste seized samples Article 07 February Long-term disruption of tissue levels of glutamate and glutamatergic neurotransmission neuromodulators, taurine and kynurenic acid induced by amphetamine Article 14 March Use our pre-submission checklist Avoid common mistakes on your manuscript. Brain Microdialysis Animals were anesthetized with ketamine 7. Comet Assay Preparation of Nuclear Suspension Animals were killed 60 days after termination of drug treatments. Reaction Protocols Free-floating sections were rinsed in 0. Image Analysis Images of single wavelengths were obtained with an epifluorescence microscope Axio Scope A1, Zeiss, Oberkochen, Germany connected with a digital camera 1. Full size image. Table 3 The density of dopamine transporter DAT and serotonin transporter SERT in the mouse striatum and frontal cortex measured after cessation of treatment with the drugs Full size table. Conclusions In conclusion, our data provide evidence that long-term caffeine administration has a powerful influence on dopaminergic and serotonergic neuron functions disturbed by MDMA in the mouse brain and on neurotoxic effects evoked by MDMA. View author publications. About this article. Copy to clipboard. Search Search by keyword or author Search. Navigation Find a journal Publish with us Track your research.
Cagliari buy Ecstasy
Cannabis and ketamine, in Cagliari consumption among the highest in Italy: the sewers reveal it
Cagliari buy Ecstasy
Cagliari buy Ecstasy
Cannabis and ketamine, in Cagliari consumption among the highest in Italy: the sewers reveal it
Cagliari buy Ecstasy
Cagliari buy Ecstasy
Cagliari buy Ecstasy
Buy marijuana online in Geneve
Cagliari buy Ecstasy