Conselho Nacional de Desenvolvimento Científico e Tecnológico / Amphetamine compounds and its derivatives are widely used in clinical medicine, but it is known that frames can cause dependence, tolerance and withdrawal. Furthermore, these drugs can alter metabolism and the functions of central neurotransmitters causing oxidative imbalances. In this sense it is already documented that exercise improves the conditions of well-being and self-esteem, and improve the plasticity and thus neuronal protection. In this context, the present study aimed to evaluate the influence of regular and continuous exercise on anxiety and behavioral parameters related to relapse to the use of amphetamine in an animal model of conditioned place preference (CPP). Male Wistar rats were conditioned to the use of AMPH or vehicle for 14 days and then half of each group was subjected to aerobic, regular and continuous physical activity for 5 weeks, while the others were not exercised. At the end of the last exercise session, the animals were re-conditioned to the use of AMPH/vehicle for more 3 days. After this phase, the animals were subjected to behavioral testing CPP to evaluate relapse to drug use, and the elevated plus maze to measure anxiety parameters. Hippocampal oxidative status was evaluated by levels of generation of reactive species (RS), carbonyl protein (CP), and activity levels of catalase (CAT) and Na+K+-ATPase, respectively. It was observed that the per amphetamine was able to develop is the CPP in the animals, however after the completion of 5 weeks of aerobic exercise, there was a reduction in the rate preferably compared to sedentary rats indicating a lower rate of relapse to amphetamine. In addition, exercise was shown to be beneficial to reduce the degree of anxiety and oxidative damage in these animals by amphetamine. Thus, regular and continuous exercise is a promising tool in the treatment of dependence and relapse to the indiscriminate use of drugs. / Compostos anfetamínicos e seus derivados são amplamente utilizados na clínica médica, porém podem provocar quadros de dependência, tolerância e abstinência. Além disso, estas drogas são capazes de afetar as funções e o metabolismo de neurotransmissores do sistema nervoso central (SNC) provocando desequilíbrios oxidativos. Neste sentido, já é documentado que o exercício físico melhora as condições de bem estar e auto-estima, favorecendo a plasticidade e, consequentemente, a proteção neuronal. Nesse contexto, o presente estudo visou avaliar a influência do exercício físico regular e contínuo sobre parâmetros comportamentais e de ansiedade relacionados à recaída ao uso de anfetamina em modelo animal de preferência condicionada de lugar (PCL). Ratos Wistar adultos foram condicionados com anfetamina no protocolo de PCL ou veículo por 14 dias e, na sequência, metade de cada grupo foi submetida à atividade física aeróbica regular e contínua por 5 semanas, enquanto os demais não foram exercitados. Ao término da última sessão de exercício físico, os animais foram re-condicionados ao uso de anfetamina ou veículo por mais 3 dias. Após esta fase, os animais foram submetidos aos testes comportamentais de PCL para avaliar sintomas de recaída pela preferência à droga, sendo também avaliados parâmetros de ansiedade em labirinto em cruz elevado. O status oxidativo na região do hipocampo foi avaliado através da geração de espécies reativas (RS), dos níveis de proteína carbonilada (PC) e atividade das enzimas catalase (CAT) e Na+K+-ATPase. Observou-se que a anfetamina per se foi capaz de desenvolver a PCL nos animais. Entretanto, após 5 semanas de exercício físico aeróbico regular e contínuo, os animais expostos à anfetamina mostraram menor PCL pela droga quando comparados ao grupo sedentário, indicando menor índice de recaída à anfetamina. Além disso, o exercício físico regular e contínuo exerceu influência favorável ao reduzir o nível de ansiedade e os danos oxidativos cerebrais, os quais foram associados ao condicionamento com anfetamina. Desse modo, o exercício físico regular e contínuo é uma ferramenta promissora no tratamento de dependência e recaída ao uso abusivo de drogas.

Le système sérotoninergique central a longtemps été associé au contrôle du comportement alimentaire et à la modulation des effets des drogues psychostimulantes sur le comportement.Le récepteur 5-HT2C est présent dans les centres hypothalamiques et particulièrement dans le noyau arqué dans l’hypothalamus (ARC) qui contrôle la régulation homéostatique de la prise alimentaire. On le retrouve aussi dans l’aire tegmentaire ventrale (VTA), une région importante dans la motivation de plusieurs comportements notamment la consommation alimentaire.Dans cette étude, l’hypothèse testée est, d’une part, que le récepteur 5-HT2C exprimé dans le VTA jouerait un rôle dans le contrôle de l’activité locomotrice induite par l’amphétamine et d’autre part qu’il exercerait son effet hypophagique a travers l’ARC.Des micro-injections localisées dans le VTA et dans l’ARC ont été réalisées afin d’évaluer les effets d’un agoniste sélectif du récepteur 5-HT2C, AR231630, sur l’hyperlocomotion stimulée par l’amphétamine ainsi que sur la prise alimentaire chez le rat.Dans les tests sur l’activité locomotrice, AR231630, lorsque qu’injecté dans la VTA, et non pas dans l’ARC, réduit de façon dose-dépendante l’ambulation provoquée par l’amphétamine.Dans les tests sur le comportement alimentaire, l’injection du composé AR231630 dans l’ARC n’induit pas de réduction de la prise alimentaire, contrairement au VTA.Une expérience suivante montre que les effets inhibants de l’administration périphérique d’AR231630 (5mg/kg) sur l’alimentation sont spécifiquement inversés par un prétraitement dans le VTA avec un antagoniste sélectif du récepteur 5-HT2C, SB242084.Ces résultats suggèrent que les récepteurs 5-HT2C dans le VTA participent à la fois au comportement alimentaire et à la fonction de la récompense, et ce, potentiellement par le même mécanisme. / Central serotonin systems have long been associated with the control of ingestive behavior, and the modulation of behavioral effects of psychostimulants.The 5-HT2C receptor is present in hypothalamic centers particularly the arcuate nucleus (ARC) controlling homeostatic regulation of food intake as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding.In the present study, the hypothesis was tested that the 5-HT2CR in the VTA may control amphetamine-evoked locomotor activity and 5-HT2CR in the ARC may regulate food consumption. Localized microinjections into the VTA or into the ARC were used to assess the effects of a highly selective 5-HT2C agonist, AR231630, on the locomotor stimulant effect of amphetamine as well as food intake. In the tests for locomotor activity, AR231630 into the VTA, but not into the ARC, dose-dependently reduced locomotor activity elicited by amphetamine. Unexpectedly, in tests for food intake, intra-ARC injection of AR231630 did not reduce food intake even at doses of 10ug, whereas intra-VTA injection of 10ug AR231630 did. A subsequent experiment determined that the suppressant effect of peripheral administration of AR231630 (5 mg/kg) on feeding was partially reversed by pretreatment with the selective 5-HT2CR antagonist SB242084 into the VTA (5ug). These findings suggest that 5-HT2CR in the VTA participates in both food intake and brain reward function, and possibly through the same pathway.

Drugs of abuse have a long history in humanity. Currently however, a subject of great interest is the phenylalkylamine family of drugs. Not only is the abuse liability of interest but also the potential therapeutic expansion of the capabilities of this family of drugs by utilizing the unique stereospecific effects of the newly discovered hybrid compounds. Based upon prior data of N-Alkyl 4-MA the enantiomers of N-Methyl, N-Ethyl, and N-Propyl were analyzed in hDAT, hNET, and hSERT. It was found that there was a negative correlation between chain length and potency and dopaminergic component. In agreement with the currently established paradigm it was also found that in almost all cases the S(+) enantiomer was the more potent.

Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D₂-like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats.

Objective: The aim was to summarize the clinical literature on interactions between common illicit drugs and prescription therapies. Methods: Medline, Iowa Drug Information Service, International Pharmaceutical Abstracts, EBSCO Academic Search Premier, and Google Scholar were searched from date of origin of database to March 2011. Search terms were cocaine, marijuana, cannabis, methamphetamine, amphetamine, ecstasy, N-methyl-3,4- methylenedioxymethamphetamine, methylenedioxymethamphetamine, heroin, gamma-hydroxybutyrate, sodium oxybate, and combined with interactions, drug interactions, and drugdrug interactions. This review focuses on established clinical evidence. All applicable full-text English language articles and abstracts found were evaluated and included in the review as appropriate. Results: The interactions of illicit drugs with prescription therapies have the ability to potentiate or attenuate the effects of both the illicit agent and/or the prescription therapeutic agent, which can lead to toxic effects or a reduction in the prescription agent's therapeutic activity. Most texts and databases focus on theoretical or probable interactions due to the kinetic properties of the drugs and do not fully explore the pharmacodynamic and clinical implications of these interactions. Clinical trials with coadministration of illicit drugs and prescription drugs are discussed along with case reports that demonstrate a potential interaction between agents. The illicit drugs discussed are cocaine, marijuana, amphetamines, methylenedioxymethamphetamine, heroin, and sodium oxybate. Conclusion: Although the use of illicit drugs is widespread, there are little experimental or clinical data regarding the effects of these agents on common prescription therapies. Scientific Significance: Potential drug interactions between illicit drugs and prescription drugs are described and evaluated on the Drug Interaction Probability Scale by Horn and Hansten.

The large-scale abuse and addiction of narcotics such as amphetamine and cocaine have become a global problem. In this project, we innovatively use graphene quantum dots (GQDs) as a fluorescent sensor to detect and quantify amphetamine and cocaine. This technology will have broad forensic application prospects. Compared with metallic quantum dots, graphene quantum dots are green and safe, with excellent bio-compatibility and low toxicity. We used undoped and N-doped GQDs as fluorescent sensing probes for the detection of amphetamine and cocaine, respectively. Using FTIR and FL as characterization methods, the fluorescence luminescence of GQDs under multiple excitation wavelength bands was studied and compared with the fluorescence after adding drugs. The experimental results show that the N-doped GQDs has a higher response to the binding substance. The detection concentration of amphetamine ranges from 5 µM to 5 mM, and the detection concentration of cocaine ranges from 10 µM-10 mM. Within this range, the fluorescence peak intensity ratio and the drug concentration have a two-stage linear negative correlation. / Storskaligt missbruk och missbruk av narkotika som amfetamin och kokain har blivit ett globalt problem. I detta projekt använder vi innovativt grafenkvantprickar (GQDs) som en fluorescerande sensor för att detektera och kvantifiera amfetamin och kokain. Denna teknik kommer att ha breda rättsmedicinska applikationsmöjligheter. Jämfört med traditionella kvantprickar är grafenkvantprickar gröna och säkra, med utmärkt biokompatibilitet och låg toxicitet. Vi använde odopade och N-dopade GQD: er som fluorescerande avkännande sonder för detektion av amfetamin respektive kokain. Med användning av FTIR och FL som karakteriseringsmetoder studerades fluorescens luminiscens hos GQD under flera exciteringsvåglängdsband och jämfördes med fluorescensen efter tillsats av läkemedel. De experimentella resultaten visar att den N-dopade GQD har ett högre svar på den bindande substansen. Detekteringskoncentrationen av amfetamin sträcker sig från 5 µM till 5 mM, och detektionskoncentrationen av kokain varierar från 10 µM-10 mM. Inom detta område har fluorescens toppintensitetsförhållandet och läkemedelskoncentrationen en tvåstegs linjär negativ korrelation.

Neonatal administration of quinpirole produces significant increases in D2 receptor sensitivity that persists into adulthood. This phenomenon, known as D2 receptor priming, is consistent with pathology in schizophrenia. Rats were administered quinpirole or saline postnatally and raised to adulthood. In adulthood, rats were administered d-amphetamine sulfate or saline every other day and were placed in a locomotor arena where activity was measured over 7 trials. Results showed that D2-primed rats receiving amphetamine were higher in locomotor activity across all days of testing compared to other groups. This effect was more prominent in males than in females. After sensitization, cerebrospinal fluid was taken via microdialysis from the nucleus accumbens core and was analyzed for dopamine content. Analysis revealed D2 priming produced a 300% increase of dopamine release in the nucleus accumbens core in response to amphetamine compared to controls. These results suggest that increases in D2 sensitivity may lead to increased reaction to amphetamine in psychotic individuals.

No description available.

Rationale. Adolescence may be a period of susceptibility to the effects of drugs of abuse. This vulnerability may result from a convergence of psychological processes that contribute to drug addiction including impulsive action and incentive motivation during adolescence. Objectives. I examined age differences in incentive motivation, as measured by responding for a conditioned reinforcer (CR) previously paired with natural or drug rewards, and age and sex differences in impulsive action, as measured by responding on a differential reinforcement of low rates of responding (DRL) schedule or premature responding on the 2-Choice Serial Reaction Time Test (2-CSRTT), in Sprague-Dawley rats. The effects of drugs that affect these behaviours in adulthood and that act on neurochemical systems still developing during adolescence were also examined. Methods. In a first set of experiments (Chapter 3), I compared male adolescents and adults on responding for a CR previously paired with sucrose and the effect of amphetamine on this behaviour. In a second set of experiments (Chapter 4), I examined age differences in responding for a CR previously paired with passive or self-administered intravenous (IV) nicotine infusions. Subsequently, I investigated age and sex differences in responding on a DRL schedule in response to amphetamine (Chapter 5) and 2-CSRTT performance in response to amphetamine, nicotine and Ro 63-1908 (a glutamate N-Methyl-D-aspartic acid [NMDA] receptor subunit antagonist; Chapter 6). Results. Compared to adults, adolescents responded more for a CR previously paired with sucrose or passive, but not self-administered, IV nicotine infusions. Amphetamine only enhanced responding for a CR previously paired with sucrose. Adolescents responded more than adults on a DRL schedule, while adolescents made the most premature responses in the 2-CSRTT. No consistent sex differences were observed during the acquisition of either behaviour. Amphetamine increased premature responding most in adolescent males and adult females in the 2-CSRTT but not in responding on the DRL schedule. No consistent age or sex differences were observed for Ro 63-1908 or nicotine. Conclusions. Adolescents show enhanced impulsivity and incentive motivation than adults depending on the behavioural measure. Dopamine may contribute to age and sex differences in these behaviours.

L’habenula, un noyau épithalamique, est située au centre de la voie dorsale diencéphalique. Cette voie relie les structures limbiques et les ganglions de la base aux cellules monoaminergiques du mésencéphale. En particulier, l’habenula latérale (HbL) projette directement aux cellules dopaminergiques et GABAergiques de l’aire tegmentale ventrale (ATV). L’ATV est le site d’origine de la voie mésolimbique dopaminergique, une voie impliquée de façon cruciale dans la manifestation des comportements dirigés. L’importance de cette projection habenulaire pour le comportement demeure encore méconnue. Ainsi, l’objectif de cette étude est d’approfondir notre compréhension du rôle de régulation de l’HbL sur les comportements dépendants de la neurotransmission dopaminergique. MATÉRIEL ET MÉTHODES: Des rats adultes mâles Sprague-Dawley ont été anesthésiés avec de l’isofluorane et installés sur un appareil stéréotaxique. L’acide iboténique, une neurotoxine agoniste des récepteurs glutamatergiques, était infusée bilatéralement dans l’HbL (0,25 μg/0,25 μl/côté). Les rats du groupe contrôle recevaient des infusions NaCl 0,9%. Les rats de l’expérience d’autostimulation intracérébrale (ASIC) étaient aussi implantés d’une électrode monopolaire dans le mésencéphale postérieur. Un groupe de rats était testé pour leur réponse de locomotion à l’amphétamine (0; 0,5 ou 1 mg/kg, intrapéritonéal), dix jours suivant la lésion de l’HbL. La locomotion était mesurée dans des chambres d’activité, chacune équipée de deux faisceaux parallèles infrarouges. Le jour du test, les rats étaient pesés et placés dans la chambre d’activité puis leur activité locomotrice de base était mesurée pendant une heure. Les rats recevaient ensuite une dose d’amphétamine ou le véhicule (NaCl 0,9%) par voie intrapéritonéale et l’activité locomotrice était mesurée pendant deux heures supplémentaires. Un groupe de rats distinct a été utilisé dans l’expérience d’ASIC. Commençant sept jours suivant la lésion, les rats étaient entraînés à appuyer sur un levier afin de s’autoadministrer des stimulations électriques, au cours de sessions quotidiennes. Nous avons ensuite mesuré chacun des taux de réponses d’une série de stimulations aux fréquences décroissantes. À partir d’une courbe réponses-fréquences, le seuil de récompense était inféré par la fréquence de la stimulation nécessaire pour produire une réponse semi-maximale. Les seuils de récompense étaient stabilisés à un niveau similaire pour l’ensemble des rats. Enfin, l’effet sur la récompense de l’amphétamine était testé aux mêmes doses employées pour l’expérience de locomotion. RÉSULTATS: Une lésion neurotoxique de l’HbL n’a pas altéré les niveaux de base de l’activité locomotrice dans chaque groupe. Cependant, une telle lésion a potentialisé l’effet de locomotion de l’amphétamine (1 mg/kg) pendant la première heure suivant son administration, et une tendance similaire était observable pendant la seconde heure. À l’inverse, nous n’avons observé aucune interaction entre une lésion à l’HbL et l’effet amplificateur sur la récompense de l’amphétamine. CONCLUSION: Nos résultats révèlent une importante contribution fonctionnelle de l’HbL à la locomotion induite par l’activation de la voie mésolimbique dopaminergique avec une dose de 1 mg/kg d’amphétamine. À l’opposé, aucun effet sur la récompense n’a été observé. Ces résultats suggèrent que l’activation psychomotrice et l’amplifiation de la récompense produite par l’amphétamine dépendent de substrats dissociables, chacun étant différentiellement sensible à la modulation provenant de l’HbL. / The habenula, an epithalamic nucleus, is centrally located within the dorsal diencephalic conduction system. This dorsal pathway connects the limbic forebrain and basal ganglia to midbrain monoaminergic cell groups intricately involved in the control of behavior. In particular, the lateral habenula (LHb) projects to, among other sites, the ventral tegmental area (VTA). Indeed, recent work has revealed direct LHb innervation of VTA dopamine as well as GABA cells. Little is known, however, about the behavioral relevance of this innervation but this knowledge is of potential importance, since the VTA gives rise to the mesolimbic dopamine pathway, a system critically involved in goal-directed behavior. Our aim here was to begin to understand the contribution of the LHb to dopamine-dependent behaviors. To do this, we produced neurotoxic lesions of the LHb and measured amphetamine-enhanced locomotion and intracranial self-stimulation (ICSS), two behaviors highly sensitive to mesolimbic dopamine neurotransmission. METRIALS AND METHODS: Adult male Sprague-Dawley rats were anesthetised with isoflurane and mounted onto a stereotaxic apparatus. Ibotenic acid, an excitatory neurotoxin at glutamatergic receptors, was infused bilaterally into the LHb (0.25 μg/0.25 μl/side). Sham-lesioned rats received infusions of 0.9% sterile saline. Rats in the ICSS experiment were additionally implanted with a monopolar stimulation electrode in the posterior mesencephalon. One group of rats was tested for their locomotor response to amphetamine (0, 0.5 or 1 mg/kg, i.p.), ten days after LHb lesion. Locomotion was measured in rectangular activity chambers, each equipped with two parallel infrared photobeams. On test day, rats were weighed, placed in the activity chamber and baseline locomotor activity was measured for 1 hour. Rats then received amphetamine or vehicle (0.9% saline) and locomotor activity was measured for 2 more hours. A separate group of rats was used in the ICSS experiment. Beginning seven days post-lesion, rats were trained to press a lever in order to self-administer trains of stimulation pulses. We then measured response rates at each of a series of pulse frequencies during daily sessions. From these response-frequency curves, we obtained estimates of reward thresholds, defined as the pulse frequency necessary for half-maximal responding. Baseline reward thresholds were matched across all rats and once stable, we tested the reward-enhancing effect of amphetamine, at the same doses tested in the locomotion experiment. RESULTS: Neurotoxic lesions of the LHb did not alter baseline locomotor activity in either group. Amphetamine enhanced locomotor activity throughout the entire 2 hour test. Importantly, the locomotor stimulant effect of amphetamine (1 mg/kg) was significantly greater in lesioned rats during the first hour, and a similar tendency was observed during the second hour. On the other hand, we did not observe any difference in amphetamine-induced enhancement of reward between lesioned and sham rats, at any dose or any time post-injection. CONCLUSION: Our findings reveal an important functional contribution of the LHb to dopamine-mediated locomotion. On the other hand, the clear dissociation between the locomotor-stimulant and rewarding effects of amphetamine suggests that the neural substrates mediating these two are dissociable and differentially sensitive to LHb modulation.