Augmenter la vitesse d’injection de la cocaïne favorise l’apparition de comportements de consommation caractéristiques de la toxicomanie

Nombreux individus vont expérimenter avec les drogues d’abus, mais peu vont devenir toxicomanes. Plusieurs facteurs sont impliqués dans la transition d’un usage récréatif à l’addiction. Les drogues, les conditionnements et les voies d’administration qui mènent à l’augmentation rapide du taux drogue dans le cerveau favorisent cette évolution. La raison est méconnue. Nous avons émis l’hypothèse que l’injection rapide de drogue promeut des changements dans le cerveau qui mènent à l’augmentation de la consommation et de la motivation à obtenir la drogue. Nous avons comparé la consommation lors de conditions à ratio fixe (FR) et à ratio progressif (PR) chez des rats s’auto-administrant la cocaïne administrée par voie intraveineuse (i.v.) en 5 ou 90 secondes (s). Tous les rats ont été entrainés à peser sur un levier afin de s’auto administrer des injections de cocaïne de 0.25 ou 0.5 mg/kg par voie intraveineuse injectée en 5 s sous FR avant d’être divisés en groupes s’auto administrant la cocaïne injectée en 5 ou 90 s pendant 1 heure (h)/session. Pour étudier les différences potentielles en consommation, l’accès à la cocaïne à été augmenté à 6 h/session. Les différences en motivation ont été détectées par l’auto administration de la cocaïne sous PR en fonction de la dose et de la vitesse d’infusion. L’accès à la drogue pendant 1 h/session n’a pas influencé la consommation. Lorsque l’accès a été prolongé à 6 h, tous les animaux ont augmenté leur consommation, mais l’augmentation était plus prononcée chez les rats s’injectant la cocaïne en 5 s. De plus, la vitesse d’injection a influencé la motivation pour obtenir la drogue. Lors de conditions à PR, la courbe dose-réponse pour le nombre d’infusions prises a été déplacée vers le haut pour les rats s’auto administrant des injections de cocaïne en 5 s versus 90 s. De plus, des différences qualitatives on été observées en PR. La consommation de cocaïne des rats s’injectant des infusions en 5 s était dépendante de la dose, tandis que les rats s’auto administrant la drogue en 90 s ont pris la même quantité de drogue, peu importe la dose. Finalement, les rats s’auto administrant des infusions de cocaïne 0.5 mg/kg en 5 s ont consommé plus de cocaïne que les rats prenant des infusions en 90 s, peu importe si elle était injectée en 5 ou 90 s le jour du test. Ainsi, nos résultats montrent que l’injection rapide de drogue dans le cerveau mène à l’augmentation de la consommation et de la motivation pour obtenir la cocaïne, deux symptômes qui caractérisent la toxicomanie.While many people will experiment with drugs of abuse, few will become addicts. Many factors have been implicated in the transition from recreational drug use to addiction. Drugs, formulations and routes of administration that lead to the rapid rise of drug levels in the brain are thought to facilitate this evolution. The reason for this remains unknown. We hypothesized that the rapid delivery of drugs might promote certain changes in the brain leading to increased drug intake and greater motivation to obtain the drug. In order to assess the effects of the speed of administration, we compared drug intake under fixed (FR) and progressive (PR) ratio conditions in rats self-administering intravenous (i.v.) cocaine injections delivered over either 5 or 90 seconds (s). Rats were trained to press a lever for 0.25 or 0.5 mg/kg cocaine injections delivered over 5 s under a FR schedule of reinforcement, before being divided into groups self-administering cocaine delivered over either 5 or 90 s for 1 hour (h)/session. To assess potential differences in drug consumption, access to cocaine was increased to 6 h/session. To assess differences in motivation for cocaine, drug self-administration was determined under a PR schedule of reinforcement both as a function of dose and infusion rate. When animals were given access to i.v. cocaine for 1 h/session, the infusion speed did not influence drug consumption. However, when access to the drug was prolonged to 6 h/session, all animals augmented their drug intake, though the increase was greater in animals self-administering the drug delivered more rapidly (over 5 vs. 90 s). The speed of drug delivery also influenced the motivation for cocaine. Under PR conditions, the dose response curve for the number of self-administered infusions was shifted upward in the 5-s animals relative to those in the 90-s group. Moreover, qualitative differences were observed in cocaine intake under PR conditions. Whereas the intake of rats self-administering cocaine delivered over 5 s was dose-dependent, drug consumption in rats injecting the drug over 90 s did not vary with the dose. Finally, rats self-administering 0.5 mg/kg cocaine infusions delivered over 5 s took more cocaine than the rats receiving it over 90 s, regardless of whether cocaine was delivered over 5 or 90 s during PR testing. Thus, our results show that increasing the speed at which cocaine is delivered to the brain leads to greater drug intake and increased willingness to expend effort to obtain the drug, two important symptoms of addiction

Augmenter la vitesse d’infusion de la cocaïne par voie intraveineuse induit des changements neurochimiques, neurobiologiques et comportementaux chez le rat : implications pour la toxicomanie

Plusieurs individus consomment la cocaïne, mais peu développent des troubles liés à l’usage de la drogue. Les facteurs pharmacocinétiques de la drogue et le patron de consommation sont importants dans ce processus. Les drogues et les voies d’administration qui produisent l’augmentation rapide des niveaux de drogue dans le cerveau faciliteraient cette transition. Similairement, l’accès intermittent à la cocaïne, qui induit des fluctuations de drogue dans le cerveau, serait impliqué aussi. Le travail présenté ici regarde de près comment la vitesse d’administration et la fréquence de consommation induisent des comportements et de la neuroplasticité caractéristiques à la toxicomanie chez le rat. Dans une première étude, nous avions déterminé les effets de la cocaïne sur les niveaux de drogue et de dopamine dans le striatum dorsal par microdialyse. La gamme de vitesses utilisée (5-90 secondes (s)) n’a pas modifié la concentration maximale de ces deux molécules, mais les infusions rapides ont fait que ces concentrations maximales soient atteintes plus rapidement. Ainsi, les différences induites par la vitesse d’administration sur le comportement et la neuroplasticité seraient dues à la vitesse à laquelle la drogue arrive au cerveau, et non à la quantité de drogue qu’y parvient. Nos travaux précédents montrent que les infusions rapides de cocaïne augmentent la motivation pour la drogue. Afin de mieux comprendre les mécanismes qui sous-tendent cette augmentation, nous avions examiné la neuroplasticité induite par l’infusion rapide de cocaïne chez des animaux montrant une motivation excessive pour la drogue sous ratio progressif. Premièrement, nous avions étudié les effets de la vitesse d’infusion sur l’expression corticostriatale de l’ARN messager (ARNm) du brain-derived neurotrophic factor (BDNF) et TrkB, son récepteur, chez des rats ayant un historique de consommation en continu (6 heures/session). Seulement les rats s’injectant des infusions rapides de drogue (infusées en 5 s) ont montré des altérations dans les niveaux de BDNF et TrkB, telles que l’augmentation des niveaux de l’ARNm de BDNF dans les cortex orbitofrontal, frontal et pariétal et la baisse des niveaux de l’ARNm de TrkB dans les cortex cingulé, frontal et pariétal et le striatum dorsal versus les rats s’auto-administrant des infusions plus lentes (infusées en 90 s). Ensuite, nous avions utilisé un modèle d’accès intermittent, où la concentration de cocaïne dans le cerveau fluctue durant la session, pour déterminer les effets de la vitesse d’infusion sur l’expression de l’ARN messager c-fos, un marqueur d’activité neuronale. Il a été récemment reporté dans la littérature que les consommateurs de cocaïne expérimentés ne consomment pas de façon continue, mais préfèrent espacer leur consommation, donc un modèle d’accès intermittent serait plus approprié pour l’étude de la toxicomanie. Ainsi, un premier groupe d’animaux a eu un accès intermittent à des infusions rapides de cocaïne, un modèle considéré pertinent à la toxicomanie, tandis que l’autre a eu accès à des infusions lentes en continu, qui permet une consommation importante sans provoquer des symptômes caractéristiques à la toxicomanie. Le groupe pertinent à la toxicomanie était plus motivé pour la drogue. De plus, ce groupe a montré une augmentation de l’expression de c-fos dans plusieurs structures corticostriatales. Ces résultats suggèrent que les infusions rapides et intermittentes de cocaïne facilitent le développement de neuroplasticité dans le cerveau, qui peut ensuite changer le comportement. De plus, le cortex orbitofrontal et le striatum dorsal seraient potentiellement impliqués. Ces deux structures sont interconnectées et sont engagées dans la toxicomanie. Nous avions déconnecté temporairement et pharmacologiquement ce circuit et avions observé une baisse significative de la motivation pour la drogue. En conclusion, les facteurs pharmacocinétiques sont importants dans le développement de modèles animaux adéquats de la toxicomanie. Une meilleure compréhension des mécanismes impliqués pourrait éventuellement améliorer le développement de pharmacothérapies pour la prévention et le traitement de la toxicomanie.Many individuals will experiment with cocaine during their lifetime; yet, few will transition from occasional drug use to addiction. Pharmacokinetic factors of the drug and the way it is consumed are important in this process. Drugs and routes of administration that produce the rapid rise of drug levels in the brain are believed to facilitate this transition. Similarly, intermittent access to the drug, which provokes fluctuations of cocaine concentrations in the brain rather than maintaining continuous high levels, may also be involved. The work presented in this thesis examines how speed of drug delivery and frequency of intake may induce addiction-like symptoms in a rat model of cocaine self-administration and promote neuroplasticity. In a first study, microdialysis was used to determine the effects of rate of cocaine infusion on cocaine and dopamine levels in the dorsal striatum of awake, freely-moving rats. Over the range of infusion rates used (5-90 seconds), cocaine and dopamine concentrations did not significantly vary. Instead, rapid cocaine infusions lead to the faster rate of onset of both molecules in the brain, implying that differences in cocaine-induced behaviour and neuroplasticity are not due to how much drug reaches the brain but on how fast the drug does so. Previous work from our laboratory showed that rapid cocaine infusions increase motivation for cocaine, a symptom of addiction. Therefore, we examined potential changes in the brain caused by rapid cocaine infusions in animals showing excessive motivation for the drug as assessed under a progressive ratio schedule of reinforcement. First, we investigated the effects of cocaine infusion rate on corticostriatal expression of brain-derived neurotrophic factor (BDNF) and TrkB mRNA in rats with a history of chronic and continuous exposure to cocaine under long access conditions (6 hours/session) and found that only rats self-administering rapid cocaine injections had altered BDNF and TrkB mRNA levels. Next, new evidence suggested that experienced cocaine users do not consume the drug continuously, but rather space out each intoxicating event. Therefore, using an intermittent access model of self-administration, where brain cocaine levels fluctuate within the session, we examined the effects of rate of infusion on c-fos mRNA expression, a marker of neuronal activity. A first group of rats had intermittent access to rapid cocaine infusions, a model we consider as addiction-relevant, while the second had access to slow and continuous cocaine, which promotes significant cocaine intake without promoting addiction-like behaviour. Animals in the addiction-relevant group presented greater motivation for cocaine and showed greater c-fos mRNA expression in various corticostriatal regions. Together, these results suggest that rapid and intermittent cocaine infusions facilitate the development of drug-induced neuroplasticity which may cause addiction-like behaviour, and particularly implicate the orbitofrontal cortex and the dorsal striatum. These two interconnected structures are both involved in addiction. Therefore, we temporarily and pharmacologically disconnected this circuit and found that it reduces motivation for cocaine. In conclusion, we show that pharmacokinetic factors are important when developing animal models of addiction, and that better understanding the mechanisms involved can potentially improve prevention and treatment therapies

How fast and how often: the pharmacokinetics of drug use are decisive in addiction

How much, how often and how fast a drug reaches the brain determine the behavioural and neuroplastic changes associated with the addiction process. Despite the critical nature of these variables, the drug addiction field often ignores pharmacokinetic issues, which we argue can lead to false conclusions. First, we review the clinical data demonstrating the importance of the speed of drug onset and of intermittent patterns of drug intake in psychostimulant drug addiction. This is followed by a review of the preclinical literature demonstrating that pharmacokinetic variables play a decisive role in determining behavioural and neurobiological outcomes in animal models of addiction. This literature includes recent data highlighting the importance of intermittent, ‘spiking’ brain levels of drug in producing an increase in the motivation to take drug over time. Rapid drug onset and intermittent drug exposure both appear to push the addiction process forward most effectively. This has significant implications for refining animal models of addiction and for better understanding the neuroadaptations that are critical for the disorder

Varying the rate of intravenous cocaine infusion influences the temporal dynamics of both drug and dopamine concentrations in the striatum

The faster drugs of abuse reach the brain, the greater is the risk of addiction. Even small differences in the rate of drug delivery can influence outcome. Infusing cocaine intravenously over 5 vs. 90â 100 s promotes sensitization to the psychomotor and incentive motivational effects of the drug and preferentially recruits mesocorticolimbic regions. It remains unclear whether these effects are due to differences in how fast and/or how much drug reaches the brain. Here, we predicted that varying the rate of intravenous cocaine infusion between 5 and 90 s produces different rates of rise of brain drug concentrations, while producing similar peak concentrations. Freely moving male Wistar rats received acute intravenous cocaine infusions (2.0 mg/kg/infusion) over 5, 45 and 90 s. We measured cocaine concentrations in the dorsal striatum using rapidâ sampling microdialysis (1 sample/min) and highâ performance liquid chromatographyâ tandem mass spectrometry. We also measured extracellular concentrations of dopamine and other neurochemicals. Regardless of infusion rate, acute cocaine did not change concentrations of nonâ dopaminergic neurochemicals. Infusion rate did not significantly influence peak concentrations of cocaine or dopamine, but concentrations increased faster following 5â s infusions. We also assessed psychomotor activity as a function of cocaine infusion rate. Infusion rate did not significantly influence total locomotion, but locomotion increased earlier following 5â s infusions. Thus, small differences in the rate of cocaine delivery influence both the rate of rise of drug and dopamine concentrations, and psychomotor activity. A faster rate of rise of drug and dopamine concentrations might be an important issue in making rapidly delivered cocaine more addictive.Varying the rate of i.v. cocaine delivery between 5 and 90 s determines the drug’s effects on brain and behaviour. We show that injecting cocaine between 5 and 90 s in rats alters the rates of rise of cocaine and dopamine in the dorsal striatum, without significantly changing peak concentrations. Faster injections also increase locomotor behaviour earlier than slower injections. Thus, beyond achieved dose, differences in the rates of rise of cocaine and dopamine can determine outcome.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151808/1/ejn13941-sup-0002-reviewer-Comments.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151808/2/ejn13941.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151808/3/ejn13941-sup-0001-FigS1-S3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151808/4/ejn13941_am.pd

Cues paired with either rapid or slower self-administered cocaine injections acquire similar conditioned rewarding properties.

The faster drugs of abuse reach the brain, the more addictive they can be. It is not known why this is. Environmental stimuli associated with drugs can promote the development and persistence of addiction by invigorating and precipitating drug-seeking behaviour. We determined, therefore, whether cues associated with the self-administration of rapidly delivered cocaine (injected intravenously over 5 versus 90 seconds) would acquire greater conditioned rewarding properties, as assessed by the performance of an operant response reinforced solely by the cues. Rats nose-poked for intravenous cocaine infusions delivered either over 5 or 90 seconds. Discrete visual cues accompanied each infusion. The rats could then press a lever to obtain the cues--now a conditioned reward--or an inactive lever. Rats in both the 5- and 90-second groups pressed more on the active versus inactive lever following extensive (24 sessions) but not following limited (3 sessions) self-administration training. There were no group differences in this behaviour. Following withdrawal from cocaine self-administration, lever discrimination progressively abated in both groups and was lost by withdrawal day 30. However, the rewarding properties of the cues were not "forgotten" because on withdrawal days 32-33, amphetamine selectively enhanced active-lever pressing, and did so to a similar extent in both groups. Thus, cues paired with rapid or slower cocaine delivery acquire similar conditioned rewarding properties. We conclude, therefore, that the rapid delivery of cocaine to the brain promotes addiction by mechanisms that might not involve a greater ability of drug cues to control behaviour

The self-administration of rapidly delivered cocaine promotes increased motivation to take the drug: contributions of prior levels of operant responding and cocaine intake

Abstract Rationale Rapid drug delivery to the brain might increase the risk for developing addiction. In rats, increasing the speed of intravenous cocaine delivery (5 vs. 90 s) increases drug intake and the subsequent motivation to self-administer cocaine. Increased motivation for cocaine could result not only from more extensive prior drug intake and operant responding for drug, but also from neuroplasticity evoked by rapid drug uptake. Objective We determined the contributions of prior drug intake and operant responding to the increased motivation for cocaine evoked by rapid delivery. We also investigated the effects of cocaine delivery speed on corticostriatal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) mRNA. Methods Rats self-administered cocaine (0.25 mg/kg/infusion) delivered over 5 or 90 s during short-access (1 h/session; ShA) or long-access (6 h; LgA) sessions. Motivation for cocaine was then assessed by measuring responding under a progressive ratio schedule of reinforcement. Next, BDNF and TrkB mRNA levels were measured in 5-and 90-s rats. Results Five-second ShA and 5-s-LgA rats were more motivated for cocaine than their 90-s counterparts. This effect was dissociable from previous levels of drug intake or of operant responding for cocaine. In parallel, only rats selfadministering rapid cocaine injections had altered BDNF and TrkB mRNA levels in corticostriatal regions. Conclusions Rapid drug delivery augments the motivation for cocaine independently of effects on the levels of drug intake or operant responding for drug. We suggest that rapid delivery might increase the motivation for drug by promoting neuroplasticity within reward pathways. This neuroplasticity could involve increased regulation of BDNF/TrkB

MinogianisDataFiles.xlsx

<p><a>The faster drugs of abuse reach the brain, the greater is the risk of addiction. Even small differences in the rate of drug delivery can influence outcome. Infusing cocaine intravenously over 5 versus 90-100 seconds promotes sensitization to the psychomotor and incentive motivational effects of the drug and preferentially recruits mesocorticolimbic regions. It remains unclear whether these effects are due to differences in how fast and/or how much drug reaches the brain.</a> <a>Here, we predicted that varying the rate of intravenous cocaine infusion between 5-90 seconds produces different rates of rise of brain drug concentrations, while producing similar peak concentrations. Freely-moving male Wistar rats received acute intravenous cocaine infusions (2.0 mg/kg/infusion) over 5, 45 and 90 seconds. </a><a>We measured cocaine concentrations in the dorsal striatum using rapid-sampling microdialysis (1 sample/minute) and high-performance liquid chromatography-tandem mass spectrometry. We also measured extracellular concentrations of dopamine and other neurochemicals. Regardless of infusion rate, acute cocaine did not change concentrations of non-dopaminergic neurochemicals. Infusion rate did not significantly influence peak concentrations of cocaine or dopamine, but concentrations increased faster following 5-second infusions. </a><a>We also assessed psychomotor activity as a function of cocaine infusion rate. Infusion rate did not significantly influence total locomotion, but locomotion increased earlier following 5-second infusions. Thus, small differences in the rate of cocaine delivery influence both the rate of rise of drug and dopamine concentrations and psychomotor activity. A faster rate of rise of drug and dopamine concentrations might be an important issue in making rapidly delivered cocaine more addictive.</a></p

Dataset for: Varying the rate of intravenous cocaine infusion influences the temporal dynamics of both drug and dopamine concentrations in the striatum

The faster drugs of abuse reach the brain, the greater is the risk of addiction. Even small differences in the rate of drug delivery can influence outcome. Infusing cocaine intravenously over 5 versus 90-100 seconds promotes sensitization to the psychomotor and incentive motivational effects of the drug and preferentially recruits mesocorticolimbic regions. It remains unclear whether these effects are due to differences in how fast and/or how much drug reaches the brain. Here, we predicted that varying the rate of intravenous cocaine infusion between 5-90 seconds produces different rates of rise of brain drug concentrations, while producing similar peak concentrations. Freely-moving male Wistar rats received acute intravenous cocaine infusions (2.0 mg/kg/infusion) over 5, 45 and 90 seconds. We measured cocaine concentrations in the dorsal striatum using rapid-sampling microdialysis (1 sample/minute) and high-performance liquid chromatography-tandem mass spectrometry. We also measured extracellular concentrations of dopamine and other neurochemicals. Regardless of infusion rate, acute cocaine did not change concentrations of non-dopaminergic neurochemicals. Infusion rate did not significantly influence peak concentrations of cocaine or dopamine, but concentrations increased faster following 5-second infusions. We also assessed psychomotor activity as a function of cocaine infusion rate. Infusion rate did not significantly influence total locomotion, but locomotion increased earlier following 5-second infusions. Thus, small differences in the rate of cocaine delivery influence both the rate of rise of drug and dopamine concentrations and psychomotor activity. A faster rate of rise of drug and dopamine concentrations might be an important issue in making rapidly delivered cocaine more addictive