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How can I buy cocaine online in Maldonado

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Adenosine is an endogenous purine nucleoside, which acts as a neuromodulator in the central nervous system. A 2A adenosine and D 2 dopamine receptors are colocalized in the same neurons in discrete brain areas, and the dopaminergic transmission plays a crucial role in the addictive properties of drugs of abuse, such as cocaine. In the present study, we have investigated the specific role of A 2A adenosine receptors in cocaine-induced behavioral responses related to its addictive properties. For this purpose, we have evaluated the acute locomotor effects produced by cocaine and the development of locomotor sensitization by repeated cocaine administration. In addition, we have also examined cocaine acute rewarding properties using the conditioned place preference. Finally, we used the intravenous drug self-administration paradigm to investigate the acquisition of an operant response maintained by cocaine self-administration and the reinforcing efficacy of the drug in these knockout animals. Acute cocaine induced a similar increase of locomotor activity in mice lacking A 2A adenosine receptors and wild-type littermates. Cocaine-induced locomotor sensitization and conditioned place preference were also maintained in A 2A knockout mice. Nevertheless, these knockout mice showed a lower rate of cocaine self-administration than wild-type mice in both fixed ratio 1 and 3 schedules of reinforcement. Moreover, a reduction in the maximal effort to obtain a cocaine infusion was found in A 2A knockout mice under a progressive ratio schedule. In addition, a vertical shift of the cocaine dose—response curve was observed in mice lacking A 2A adenosine receptors in comparison with wild-type littermates. Our study demonstrates that A 2A adenosine receptors play an important role in cocaine addictive properties, and these receptors seem to be required to develop the addictive effects of this drug. Adenosine is an endogenous purine nucleoside, which acts as a neuromodulator in the central nervous system CNS. The physiological effects of adenosine are produced through the activation of four receptor types: A 1 , A 2A , A 2B , and A 3. A 2A adenosine receptors are found at high concentrations in the olfactory tubercle, the striatum, and the nucleus accumbens Nac Moreau and Huber, Dopaminergic transmission in the mesocorticolimbic system plays a crucial role in the modulation of reward-related process Koob, ; Di Chiara, , as well as in the addictive properties of drugs of abuse. There is evidence to support a role for adenosine in mediating different responses induced by several drugs of abuse such as opioids, cannabinoids, and psychostimulants. Thus, adenosine agonists inhibit the expression of morphine withdrawal, while adenosine antagonists increase the incidence of withdrawal signs Kaplan and Sears, ; Salem and Hope, In agreement, mice lacking A 2A adenosine receptors showed an increased morphine withdrawal in comparison with wild-type mice Berrendero et al, However, there are controversial results about the possible involvement of A 2A adenosine receptors in the reinforcing effects induced by psychostimulant drugs. A role for adenosine in reinstatement of cocaine-seeking behavior has also been suggested since caffeine and CGS reinstated this behavior Weerts and Griffiths, In addition, the selective A 2A receptor agonist CGS attenuated the rewarding impact of brain stimulation, whereas the A 2 adenosine antagonist DMPX reversed the reward impairment produced by cocaine withdrawal Baldo et al, Furthermore, CGS also potentiated the discriminative-stimulus actions of cocaine as shown by the leftward shift of the cocaine dose—response curve Justinova et al, Therefore, the specific role of A 2A adenosine receptors in the processes underlying cocaine addiction remains unclear. The generation of A 2A receptor knockout mice with complete and specific inactivation of the A 2A receptor Ledent et al, provides a useful genetic model to clarify the role of A 2A receptors on cocaine pharmacological responses in vivo. The aim of the present study was to investigate the specific role of A 2A adenosine receptors in cocaine-induced behavioral responses related to its addictive properties. Finally, we used the intravenous i. Mice lacking A 2A adenosine receptors were generated as previously reported Ledent et al, In order to homogenize the genetic background of the mice, the first generation heterozygotes were bred for 30 generations on a CD1 background Charles River, France with selection for the mutant A 2A gene at each generation. Beginning with the 30th generation of backcrossed mice, heterozygote—heterozygote matings of A 2A knockout mice produced wild-type and knockout littermates for subsequent experiments. Breeding couples were periodically renovated by crossing heterozygote mice with wild-type CD1 females Charles River, France in order to maintain a genetically diverse outbred background. Food and water were available ad libitum during all experiments except during the exposure to the different behavioral paradigms. Mice were handled for 1 week before starting the experiments. All experiments were performed under blind conditions. Cocaine hydrochloride was obtained from Ministerio Sanidad y Consumo Spain and dissolved in sterile 0. Locomotor activity was measured as number of beam breaks, and two different measures were evaluated: directional or ambulatory movements and small local movements. After completing chronic cocaine administration on day 12, mice remained without any treatment from day 13 to As above, locomotor activity was measured as number of beam breaks, and two different measures were evaluated: directional or ambulatory movements and small local movements. The time spent in each compartment was recorded by computerized monitoring software Smart; Panlab, Barcelone, Spain. Three pairings were performed with cocaine and three pairings with vehicle on alternate days. Treatments were counterbalanced as closely as possible between compartments. Control animals received vehicle every day. A score value was calculated for each mouse as the difference between times spent in the drug-paired compartment during the postconditioning and preconditioning phases. Nose-poking on the active hole resulted in a reinforcer cocaine infusion while nose-poking on the inactive hole had no consequences. The chambers were housed in sound- and light-attenuated boxes equipped with fans to provide ventilation and white noise. A stimulus light, located above the active hole, was paired contingently with the delivery of the reinforcer. Mice were anesthetized under isoflurane anesthesia 1. The catheter tubing was inserted 1. The remaining tubing runs subcutaneously to the cannula, which exits at the midscapular region. After surgery, animals were allowed to recover for 3 days prior to initiation of self-administration sessions. The patency of i. Cocaine self-administration sessions were performed as described previously Soria et al, Briefly, sessions started 3 days after surgery. The swivel was mounted on a counterbalanced arm above the operant chamber. Each daily session started with a priming injection of the drug. First, mice were trained under a fixed ratio 1 FR1 schedule of reinforcement. The stimulus light signaled delivery of the reinforcer. Once mice achieved the acquisition criteria, the reinforcement schedule was changed to fixed ratio 3 FR3. The same criteria as above were used to move mice from FR3 to a progressive ratio PR schedule in which the response requirement to earn an injection escalates according to the following series: The breaking point to extinguish self-administration behavior was determined in each animal. After each session, mice were returned to their home-cages. After acquisition same criteria as above , self-administration of various doses of cocaine 0. Acute effects of cocaine administration and cocaine-induced conditioned place preference scores were compared by two-way ANOVA genotype and treatment as factors of variation between subjects, followed by one-way ANOVA and Tukey post hoc test when required. Data of sensitization study were compared by three-way ANOVA genotype and treatment as between factors and day as within-group factor of variation. Tukey post hoc test was performed when required. For cocaine maintained operant responding, two-way ANOVA was performed on the mean of nose-pokes performed during the last 3 days required to reach the stability criteria, with hole active vs inactive and genotype knockout vs wild-type as factors of variation. This statistical analysis was performed for FR1 and FR3 schedules of reinforcement in cocaine operant responding experiments. The breaking point values obtained on the PR schedule for cocaine self-administration were compared by calculating Mann—Whitney U -test between genotypes. For the cocaine dose—response curve, the number of infusions was compared by repeated measures two-way ANOVA dose as within-subject factor and genotype as between-subject factor. Additionally, one-way ANOVA within subjects was performed to discard a day effect for the Latin square design in the dose—response curve. On days 1—3, animals were exposed to the locomotor activity boxes in order to be habituated to the test environment data not shown. Acute locomotor effects induced by cocaine in A 2A knockout and wild-type mice. White columns represent wild-type mice and black columns represent A 2A adenosine receptor knockout mice. Stars over the bars mean differences vs vehicle group. Chronic cocaine treatment induced a sensitization to its locomotor effects in both genotypes as shown in Figure 2a. Locomotor sensitization to the effects induced by chronic cocaine administration in A 2A knockout and wild-type mice. Mice remained without any treatment from day 13 to On day 20, all the mice received a saline injection and locomotor activity was evaluated again. The figure shows locomotor activity on days 1, 12, 19, and White columns represent saline-treated mice and black columns represent cocaine-treated mice. Acute rewarding responses induced by cocaine were investigated in A 2A knockout and wild-type mice using the place conditioning paradigm. The effects of the A 2A receptor mutation on the reinforcing properties of cocaine were evaluated using the operant self-administration procedure. Knockout mice reached the acquisition criteria faster than wild-type mice 7. The infusion pattern of the cocaine self-administration sessions was also evaluated Figure 4b. A regular and consistent pattern of response was observed in both wild-type and A 2A knockout mice during the whole duration of the self-administration session, which excludes a possible random nose-poking behavior. The decreased breaking point values observed in knockout mice were not due to the relative short time period of the PR session since the analysis of infusion patterns revealed that most of the knockout mice stopped nose-poking before than wild-type animals data not shown. As shown in Figure 5a , a bell-shaped dose—response curve was obtained when different doses of cocaine were tested in wild-type and in A 2A knockout mice. Nevertheless, a vertical shift of this dose—response curve was observed in the knockout group. Figure 5b shows the total cocaine intake received when different doses were tested. Cocaine self-administration 0. The present study demonstrates the involvement of A 2A adenosine receptors in the addictive properties of cocaine. Mice lacking A 2A adenosine receptors showed a decreased rate of self-administration and motivation for cocaine, as well as reduced efficacy of cocaine reinforcing effects. Nevertheless, the increased locomotor activity produced by an acute injection of cocaine, the development of locomotor sensitization by repeated cocaine administration, and cocaine-induced conditioned place preference were maintained in these A 2A knockout mice. Deletion of A 2A adenosine receptors did not modify acute effects induced by cocaine. Our data also confirm the hypolocomotor phenotype described in A 2A knockout mice Ledent et al, since locomotor basal activity of knockout mice was decreased vs wild-type littermates. However, this hypolocomotion did not impair the acute effects induced by cocaine administration. In contrast, other authors have shown that locomotor responses to acute cocaine administration were attenuated in mice lacking A 2A receptors Chen et al, In addition, a recent study demonstrates that conditional A 2A knockout mice showed no sensitization to locomotor effects of amphetamine Bastia et al, Repeated drug exposure is known to induce sensitization to its behavioral stimulant effects Koob, ; Vanderschuren and Kalivas, The mesocorticolimbic dopaminergic system has been proposed as the neural substrate underlying this phenomenon Kalivas et al, , which is also involved in the reinforcing properties of all drugs of abuse Koob and Le Moal, ; Nestler, The locomotor activity displayed by animals in a novel environment has been positively correlated with the sensitivity to both the locomotor and reinforcing effects of psychostimulants such as cocaine Piazza et al, ; Hooks et al, a , b. In the present study, A 2A knockout mice showed similar acute cocaine locomotor effects and cocaine-induced locomotor sensitization as wild-type mice, although cocaine self-administration behavior was different in both genotypes, suggesting separate neuronal substrates for these behavioral responses induced by cocaine. Acute rewarding properties of cocaine were indirectly evaluated using the place conditioning procedure. In agreement with this result, the amount of cocaine self-administered in the first session of the operant self-administration paradigm was similar in both wild-type 9. Although acute rewarding effects are important to initiate the drug addictive process, other factors are also needed to develop this complex behavior Koob and Le Moal, A 2A adenosine receptor knockout mice acquired an operant behavior maintained by i. This result is in agreement with the reduction in the maximal effort required to obtain a cocaine infusion in A 2A knockout mice under a PR schedule of reinforcement. In animal drug self-administration studies, response rates usually show an inverted U-shaped function of drug dose where rate of responding is inversely related to the injection dose Meisch and Lemaire, In the present study, typical inverted U-shaped dose—response curves were obtained in both wild-type and A 2A knockout mice. The possibility that A 2A knockout mice would experience increased reinforcing effects of cocaine, and therefore a reduction in cocaine self-administration, can be ruled out since knockout mice did not show a leftward shift in the dose—response curve. Indeed, the vertical shift obtained indicates a difference in the efficacy, but not in the potency of the reinforcing effects of cocaine. In agreement, A 2A adenosine knockout mice showed a decreased breaking point in the PR schedule and did not exhibit a higher sensitivity to cocaine-induced behavioral effects in the other models evaluated locomotion, sensitization, and conditioned place preference. There is evidence showing that vertical shifts in self-administration dose—response curve predict a drug-vulnerable phenotype predisposed to addiction Piazza et al, Thus, it could be hypothesized that A 2A knockout mice represent a low-vulnerable phenotype to cocaine addiction and the lack of A 2A adenosine receptors could provide resistance against the addictive properties of cocaine. The lower reinforcing efficacy of cocaine found in A 2A adenosine knockout mice that have acquired a stable cocaine self-administration behavior was not due to an impairment of the acute rewarding properties of cocaine, since cocaine-induced conditioned place preference and the cocaine intake in the first session of the self-administration paradigm were not modified in these knockouts. Differences in conditioned place preference and self-administration results are not surprising since the behavior responses evaluated in these two paradigms are not equivalent. While conditioned place preference evaluates the expression of indirect reward, self-administration paradigm is used to directly study the reinforcing effects of a drug. Adenosine and its receptors have been involved in learning and memory processes de Mendonca and Ribeiro, ; Svenningsson et al, ; Hauber and Bareiss, ; Justinova et al, However, the lower rate of cocaine self-administration found in A 2A knockout mice does not appear to be a consequence of learning impairment since operant responding for food is maintained in these animals Soria et al, In addition, A 2A adenosine receptor knockout mice achieved the FR1 acquisition criteria for cocaine self-administration faster than wild-type littermates 7. Moreover, the similar results obtained on cocaine-induced conditioned place preference in both genotypes also support a normal learning and memory response in these knockout mice. Dopamine D 2 -like receptors are known to be particularly important in mediating the abuse-related effects of cocaine Caine et al, Our study does not show this antagonistic interaction since the reinforcing efficacy of cocaine was diminished in A 2A knockout mice. However, other indirect interactions between A 2A and D 2 receptors have also been reported at intracellular levels, which may explain our results. DARPP, a downstream effector molecule of D 2 -like receptors, has been reported to play an important role in mediating the pharmacological effects of a variety of drugs of abuse Nairn et al, In this sense, mice lacking DARPP showed attenuated conditioned place preference to cocaine without involving alteration of dopamine release or reuptake Zachariou et al, Dopamine D1 receptors are also involved in cocaine effects Hummel and Unterwald, In this sense, D1 and A 2A adenosine receptors have an additive effect on DARPP phosphorylation Svenningsson et al, , raising the possibility that D1 receptors could compensate the consequences of the absence of A 2A on intracellular signals implicated in cocaine reward. On the other hand, extracellular signal-regulated kinase ERK pathway activation has been involved in synaptic plasticity related to long-term effects of psychostimulants addiction Valjent et al, , Therefore, a possible explanation for our findings could be that intracellular cascades downstream of dopamine release could be impaired in mice lacking A 2A adenosine receptors producing an alteration in the brain reward function. Therefore, this synergy might be absent in A 2A knockout mice, which would have a negative effect in drug reinforcement properties. In conclusion, the present study demonstrates the important role played by A 2A adenosine receptors in cocaine addictive properties, as revealed by the decreased rate of self-administration and motivation for cocaine, and the lower efficacy of cocaine reinforcing effects found in mice lacking A 2A adenosine receptors. However, acute locomotor effects of cocaine and repeated cocaine-induced locomotor sensitization and conditioned place preference were preserved in these animals. These findings support the hypothesis that separate neuronal substrates mediate cocaine-induced locomotor effects and the self-administration in an operant behavior paradigm Therefore, pharmacological manipulation of these receptors may be a possible target in the treatment of cocaine addiction. Role of adenosine A2 receptors in brain stimulation reward under baseline conditions and during cocaine withdrawal in rats. J Neurosci 19 : — A crucial role for forebrain adenosine A 2A receptors in amphetamine sensitization. Neuropsychopharmacology 30 : — Eur J Neurosci 17 : — Article Google Scholar. Method for training operant responding and evaluating cocaine self-administration behavior in mutant mice. Psychopharmacology : 22— Role of dopamine D2-like receptors in cocaine self-administration: studies with D2 receptor mutant mice and novel D2 receptor antagonists. J Neurosci 22 : — Selective attenuation of psychostimulant-induced behavioral responses in mice lacking A 2A adenosine receptors. Neuroscience 97 : — Adenosine and neuronal plasticity. Life Sci 60 : — Di Chiara G Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res : 75— Adenosine—dopamine receptor—receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci 20 : — Neuropsychopharmacology 23 : S50—S Hauber W, Bareiss A Behav Brain Res : 43— Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine. Synapse 9 : — Individual differences in locomotor activity and sensitization. Pharmacol Biochem Behav 38 : — Hummel M, Unterwald EM D1 dopamine receptor: a putative neurochemical and behavioral link to cocaine action. J Cell Physiol : 17— Involvement of adenosine A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of cocaine and methamphetamine in rats. J Pharmacol Exp Ther : — Cellular mechanisms of behavioral sensitization to drugs of abuse. Ann NY Acad Sci : — Adenosine receptor agonists attenuate and adenosine receptor antagonists exacerbate opiate withdrawal signs. Psychopharmacology : 64— Pharmacol Biochem Behav 68 : — Koob GF Hedonic valence, dopamine and motivation. Mol Psychiatry 1 : — Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24 : 97— Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature : — Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Drug self-administration. In: Haaren F ed. Methods in Behavioral Pharmacology. Chapter Google Scholar. Moreau JL, Huber G Central adenosine A 2A receptors: an overview. Brain Res Brain Res Rev 31 : 65— Neuropharmacology 47 Suppl 1 : 14— Nestler EJ Molecular mechanisms of drug addiction. Neuropharmacology 47 Suppl 1 : 24— Factors that predict individual vulnerability to amphetamine self-administration. Science : — Vertical shifts in self-administration dose—esponse functions predict a drug-vulnerable phenotype predisposed to addiction. J Neurosci 20 : — Poleszak E, Malec D Adenosine receptor ligands and cocaine in conditioned place preference CPP test in rats. Pol J Pharmacol 54 : — The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18 : — Salem A, Hope W Effect of adenosine receptor agonists and antagonists on the expression of opiate withdrawal in rats. Pharmacol Biochem Behav 57 : — Eur J Neurosci 20 : — Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology doi Distribution, biochemistry and function of striatal adenosine A2A receptors. Prog Neurobiol 59 : — DARPP an integrator of neurotransmission. Annu Rev Pharmacol Toxicol 44 : — Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology : 99— Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. Possible role of the extracellular signal-regulated kinase ERK in reward-controlled learning and addiction. Curr Neuropharmacol 1 : — From The Cover: regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. The adenosine receptor antagonist CGS reinstates cocaine-seeking behavior and maintains self-administration in baboons. Psychopharmacology : — Cell : — Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-beta gamma dimers. Biol Psychiatry 51 : — Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Olga Valverde. Reprints and permissions. Soria, G. Neuropsychopharmacol 31 , — Download citation. Received : 01 March Accepted : 18 July Published : 17 August Issue Date : 01 May 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. Naunyn-Schmiedeberg's Archives of Pharmacology Skip to main content Thank you for visiting nature. Download PDF. Abstract Adenosine is an endogenous purine nucleoside, which acts as a neuromodulator in the central nervous system. The non-receptor tyrosine kinase Pyk2 modulates acute locomotor effects of cocaine in D1 receptor-expressing neurons of the nucleus accumbens Article Open access 20 April GPR55 is expressed in glutamate neurons and functionally modulates drug taking and seeking in rats and mice Article Open access 19 February Effects of muscarinic M 1 receptor stimulation on reinforcing and neurochemical effects of cocaine in rats Article 28 April Drugs Cocaine hydrochloride was obtained from Ministerio Sanidad y Consumo Spain and dissolved in sterile 0. Surgery for drug self-administration study Mice were anesthetized under isoflurane anesthesia 1. Drug self-administration procedure Cocaine self-administration sessions were performed as described previously Soria et al, Statistical Analysis Acute effects of cocaine administration and cocaine-induced conditioned place preference scores were compared by two-way ANOVA genotype and treatment as factors of variation between subjects, followed by one-way ANOVA and Tukey post hoc test when required. Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Figure 5. View author publications. Rights and permissions Reprints and permissions. About this article Cite this article Soria, G. Copy to clipboard. This article is cited by Adenosine A2A receptor in schizophrenia: an in vivo brain PET imaging study Tiago Reis Marques Sridhar Natesan Shitij Kapur Psychopharmacology Effects of intra-accumbal or intra-prefrontal cortex microinjections of adenosine 2A receptor ligands on responses to cocaine reward and seeking in rats K. Wydra A. Suder M. 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How can I buy cocaine online in Maldonado

Official websites use. Share sensitive information only on official, secure websites. The potential involvement of the cannabinoid CB 2 receptors CB 2 r in the adaptive responses induced by cocaine was studied in transgenic mice overexpressing the CB 2 r CB 2 xP and in wild-type WT littermates. For this purpose, the acute and sensitized locomotor responses to cocaine, conditioned place preference, and cocaine intravenous self-administration were evaluated. CB 2 xP mice presented cocaine-induced conditioned place aversion and self-administered less cocaine than WT mice. No significant differences in extracellular DA levels in the NAcc were observed between genotypes after cocaine administration. These results revealed that CB 2 r are involved in cocaine motor responses and cocaine self-administration, suggesting that this receptor could represent a promising target to develop novel treatments for cocaine addiction. Keywords: cocaine, cannabinoid, dopamine transporter, sensitization, self-administration, tyrosine hydroxylase. A large body of evidence suggests the involvement of the endocannabinoid system ECS in the development of dependence to different licit and illicit drugs Fattore et al , ; Lupica et al , ; Maldonado et al , ; Parolaro and Rubino, ; Tanda and Goldberg, However, the specific participation of the ECS in cocaine addiction remains unclear. Thus, the administration of a cannabinoid CB 1 receptor CB 1 r antagonist or the deletion of CB 1 r does not alter cocaine self-administration in rodents Cossu et al , , conditioned place preference CPP or behavioral sensitization Lesscher et al , ; Martin et al , Other studies revealed that the administration of a cannabinoid CB 1 r agonist induced relapse to cocaine-seeking behavior De Vries et al , , and CB 1 r antagonists inhibited sensitized locomotor response to a cocaine challenge Filip et al , and cocaine self-administration Soria et al , ; Xi et al , In addition, the deletion of CB 1 r decreased cocaine-induced motor sensitization Corbille et al , , CPP Miller et al , and the breakpoint for cocaine self-administration Soria et al , There is scarce information about the possible involvement of cannabinoid CB 2 receptors CB 2 r in cocaine dependence. Initially, CB 2 r were found in the brain only under pathological conditions Ehrhart et al , ; Guzman et al , ; Ibrahim et al , However, further descriptive studies in rodents reported CB 2 r gene expression in the different areas of brain under baseline conditions, caudate putamen, nucleus accumbens NAcc , cingulate cortex, amygdala, hippocampus, ventromedial hypothalamic nucleus, arcuate nucleus, thalamus, substantia nigra, dorsal raphe, and medial raphe nucleus Garcia-Gutierrez et al , ; Onaivi, ; Van Sickle et al , Furthermore, the presence of CB 2 r in reward-related brain areas such as the ventral tegmental area VTA and the NAcc suggests the participation of this receptor in drug abuse. A number of results support the potential implication of CB 2 r in addictive behaviors. Increased CB 2 r gene expression was reported in the brain of mice after chronic treatment with heroin or cocaine Onaivi et al , In contrast, the same group reported reduced CB 2 r gene expression in striatum and ventral midbrain after chronic ethanol intake in mice Onaivi et al , Furthermore, the pharmacological manipulation of CB 2 r modified ethanol intake only in stressed mice Ishiguro et al , It is possible that CB 2 r and CB 1 r function together regulating dopaminergic circuits involved in drug-induced motivation and reward. Drugs of abuse act directly on dopaminergic terminals or block GABAergic inhibitory neurons on cell bodies of mesolimbic dopaminergic neurons, increasing the release of dopamine DA in the NAcc Nestler, ; Spanagel and Weiss, ; Tanda et al , The regulation of DA neuronal activity involves the participation of the DA transporter DAT , which regulates DA reuptake from the synaptic cleft determining the intensity and duration of DA activity Gainetdinov et al , ; Jaber et al , and TH, the rate-limiting enzyme of DA biosynthesis Jaber et al , ; Jones et al , To explore the potential involvement of CB 2 r in the adaptive responses underlying addictive processes, several behavioral and neurochemical responses induced by cocaine were studied in the wild-type WT and transgenic mice overexpressing CB 2 r CB 2 xP. We evaluated acute dose—response effects of cocaine on motor activity, sensitization to cocaine-induced motor effects, CPP, and intravenous cocaine self-administration under both fixed ratio FR and progressive ratio PR schedules of reinforcement, as well as in vivo microdialysis following acute cocaine administration in both genotypes. In addition, cells expressing CB 2 r were phenotypically characterized using double immunolabeling. All behavioral experiments were performed under blind conditions. The motor response was evaluated in the open-field test. After the last cocaine administration on day 20, mice remained abstinent for the next 6 days. Details of the features of the apparatus and the procedure used are described in Supplementary Information. Details of the features of the apparatus and surgical procedures are described in the Supplementary Information. Four days after surgery, CB 2 xP and WT mice were trained to nose-poke under a FR1 schedule of reinforcement in order to receive cocaine 0. Self-administration sessions starting with a priming injection of the drug 0. After each session, mice were returned to their home-cages. The number of reinforcers was limited to 50 infusions per session. Each infusion was followed by a s time-out period during which an active nose-poke had no consequence. When stability was acquired, mice were tested on a PR schedule of reinforcement, where the requirement to earn an injection escalated according to the following series: 1—2—3—5—12—18—27—40—60—90—————— Soria et al , Food was available ad libitum during the whole experiment. Two days after starting water deprivation, mice were trained to nose-poke for water under a FR1 schedule of reinforcement, as previously described Trigo et al , Mice achieving the acquisition criteria underwent a PR schedule of reinforcement, as reported for drug self-administration. Sections, distributed in eight parallel series, were stored in 0. Two days after surgery, animals were habituated to the microdialysis environment overnight. Four baseline samples were collected in all mice before drug challenge. DA was quantified as previously described Robledo et al , At the end of the experiments, mice were killed and the brains were coronally cut using a cryostat. Only those mice with correct probe placements were used in the study. From these slices, the regions were dissected out as described elsewhere Palkovits, Statistical analyses were performed using Student's t -test by comparing two groups and one-, two-, or three-way analyses of variance ANOVA when comparing three or more groups. When appropriate, post-hoc individual differences between groups were determined using the Newman—Keuls test. Specific statistical analyses of the microdialysis study are described in Supplementary Information. SigmaStat v3. No significant differences NS were found in motor activity between genotypes, during the min baseline session Figure 1a , Student's t -test, NS. The sensitization protocol induced a dose-related enhancement in cocaine-induced motor activity, when compared with saline treatment. Sensitization to motor response induced by cocaine in wild-type WT and CB 2 r overexpressing CB 2 xP mice: Effect of challenge with cocaine after 6 days of withdrawal. Thus, in saline pre-treated mice both doses of cocaine increased motor behavior compared with the saline challenge, but this effect was significantly lower in the CB 2 xP mice as compared with the WT mice. In cocaine pre-treated mice, the cocaine challenge induced a dose-related increase in traveled distance compared with the saline challenge in WT mice. Differences between genotypes were observed and CB 2 xP mice displayed a significantly lower motor response than that observed in WT mice Figure 2b. During the pre-conditioning period phase I , no difference was observed in the time spent in the two compartments by both genotypes Student's t -test; NS. These results ruled out the possibility of initial unconditioned preference for either of the two compartments by any of the genotypes. CB 2 xP mice self-administer less cocaine than WT mice along the different training sessions Figure 4a. A clear discrimination between the active and the inactive holes was observed for WT mice during the acquisition of operant responding for cocaine 0. Mean time to achieve the acquisition criteria for WT mice was 5. CB 2 xP mice trained to self-administer cocaine started to discriminate between the active and the inactive holes on the fourth training session, and discrimination was maintained from the sixth session until the last session see Supplementary Information Figure S1B. One-way ANOVAs were performed comparing genotypes in the active and inactive see Supplementary Figure S2A holes for each of the training sessions see Table 1 for significance values and comparing active and inactive holes on each of the training sessions for WT and CB 2 xP mice see Table 2 for significance values. Mean time to achieve the acquisition criteria for CB 2 xP mice was 7. However, the motivation to obtain cocaine in mice achieving the acquisition criteria was similar in both genotypes Figure 4b. These results suggest a reduction of cocaine reinforcing effects in CB 2 xP mice when compared with WT controls. Mice achieving the criteria for extinction underwent a reinstatement session evaluating cue-induced relapse to cocaine-seeking behavior Figure 4d. No apparent differences between genotypes in the extinction process or in the capacity of cue to induce reinstatement of cocaine-seeking behavior were observed see ANOVAs analyses in Supplementary Information. WT animals started to discriminate between the active and the inactive holes from the third training session data not shown and the discrimination was maintained during the next seven sessions. CB 2 xP mice also showed discrimination from the third until the last training session. In this group, the stability criterion was achieved by all the animals tested and the mean time required to reach it was of 4. In order to evaluate whether WT and CB 2 xP presented differences in the motivation to obtain water, mice achieving the acquisition criteria underwent a PR schedule of reinforcement. No differences between genotypes were observed in the breaking point achieved under the PR schedule Figure 5b. These results show that the reinforcing effects of the natural reinforcer water were not modified in CB 2 xP mice, and the capacity of these mice to acquire an operant responding also remained unaltered. All neurons were CB2r i. CB 2 r immunolabeling was found in the soma of the neuron and in the surrounding neuropile Figure 6a—f , whereas it was observed in the soma and processes of the astrocytes Figure 6g—l. A CB 2 r cell not labeled for NeuN is shown in c arrow. Double labeling yellow cells in i and l shows that most of the GFAP i. GFAP i. CB 2 r immunolabeled cells, most probably neurons, are showed in i and l double arrow. Same scale for b—l. D1Dr i. However, no D1Dr i. For instance, in the hippocampal dentate gyrus Figure 7g—i , some cells were D1Dr i. D2Dr i. Figure 7d—f. In all cases, both D1Dr i. Double labeling yellow cells is shown in c , f , i , and l. Several D1Dr i. Note that most of the D2Dr i. No significant differences in basal extracellular DA levels in the NAcc were observed between genotypes mean of four baseline samples: WT: 4. Following saline administration, no significant differences in DA outflow were observed between treatment groups. CB 2 xP mice pre-treated with saline showed increased TH gene expression compared with WT mice, supporting baseline differences between the two genotypes. Regarding genotype, these results confirmed the lack of significant differences in baseline CB 1 r gene expression between CB 2 xP and WT mice. The present results provide evidence for the relevant role of the cannabinoid CB 2 r in the development of motor sensitization and the reinforcing effects of cocaine. CB 2 xP and WT mice showed similar spontaneous motor activity. This finding was consistent with a previous study from our laboratory Garcia-Gutierrez and Manzanares, The acute administration of cocaine enhanced the motor activity in both genotypes, although the response in CB 2 xP mice was significantly less pronounced. On the other hand, we recently reported that deletion of CB 2 r increased the sensitivity to the motor responses of an acute dose of cocaine in the open field Ortega-Alvaro et al , Repeated exposure to psychostimulants produces sensitization, revealed by progressive enhancement of their hyperlocomotor effects Robinson and Berridge, , This motor sensitization remains after the withdrawal of the chronic psychostimulant treatment Pierce and Kalivas, These results point to the involvement of CB 2 r in the development of cocaine-induced motor sensitization in mice. The discrepancies found in this cocaine-induced motor response may be due to the limiting dose factor together with the specific features of the sensitization protocol. On day 0, mice were habituated to the open field cage for a min period without treatment. This habituation process was not carried out in the dose-response study. Thus, the cocaine dose-response results are not comparable to the results of cocaine sensitization on days 1 and Thus, the expression of cocaine-induced sensitization may also be modulated by CB 2 r in mice. The specific molecular mechanisms by which the overexpression of CB 2 r resulted in decreased cocaine-induced motor response and sensitization remain to be determined. The CB 2 r has been identified in the brain areas regulating motor functions such as caudate-putamen and substantia nigra Garcia-Gutierrez et al , ; Gong et al , , and alterations in dopaminergic and glutamatergic transmission have been closely related with the development of cocaine behavioral sensitization Vanderschuren and Kalivas, Thus, it may be possible that the increased expression of CB 2 r in these brain areas resulted in alterations of the activity of these neurotransmitter systems decreasing motor responses to cocaine. The gene expression of TH and DAT in the VTA were measured in both genotypes, under baseline conditions and following cocaine or saline challenge after 6 days of withdrawal from saline or cocaine chronic treatment. The acute cocaine administration in saline pre-treated groups will help to differentiate the changes in gene expression due to neuroadaptations after chronic cocaine treatment from those produced by a single cocaine injection in saline pre-treated animals. Acute cocaine administration in saline or cocaine pre-treated mice similarly decreased TH gene expression in both genotypes. As DAT deletion facilitates cocaine-induced sensitization Morice et al , , the enhanced DAT gene expression found in transgenic mice might act in an opposite manner, interfering on cocaine-induced sensitization. These changes occurred in a similar manner in both genotypes. On the other hand, CB 1 r gene expression in the NAcc under baseline conditions was similar in both genotypes. Cocaine challenge in WT mice pre-treated with saline significantly decreased CB 1 r gene expression, whereas this effect was not observed in CB 2 xP mice. In contrast, the cocaine challenge in cocaine pre-treated mice significantly decreased CB 1 r gene expression in CB 2 xP but not in WT mice. These results suggest that the pattern of cocaine administration acute or chronic differently affected CB 1 r gene expression in CB 2 xP and WT mice. This fact might be due to potential compensatory mechanisms between CB 1 r and CB 2 r. This study demonstrates the involvement of the cannabinoid CB 2 r in the actions of cocaine in the CPP, as well as in the acquisition of intravenous cocaine self-administration. WT mice did not present a clear CPP for the conditioning compartment, whereas CB 2 xP mice showed cocaine-induced conditioned place aversion. The ratio of mice reaching the acquisition criteria in self-administration studies was reduced and the mean time to achieve these criteria was increased in the CB 2 xP group. The enhanced DAT gene expression might account for the decreased perception of cocaine reinforcing effects in CB 2 xP mice and for the consequent impairment in the acquisition of cocaine self-administration. However, the role of DAT in cocaine reinforcing effects has also been questioned Rocha et al , ; Sora et al , In spite of the decreased acquisition of cocaine self-administration in CB 2 xP mice, no differences in the motivation to obtain cocaine were observed between mice of both genotypes reaching the acquisition criteria. A similar dissociation between rates of acquisition and motivation for drug self-administration has been previously reported in the mice with a different sensitivity to the reinforcing effects of the drug Galeote et al , ; Trigo et al , Thus, CB 2 r overexpression interferes with the acquisition of cocaine self-administration behavior under a continuous schedule of reinforcement, but once this behavior is established, CB 2 r overexpression does not seem to affect performance on a progressive schedule of reinforcement, possibly suggesting that CB 2 r do not critically contribute to the motivational properties of cocaine. The deficits in cocaine self-administration observed in CB 2 xP mice cannot be attributed to possible unspecific learning or motor deficits produced by the CB 2 r overexpression as both genotypes similarly acquired and maintained stable operant responding for water. It has been recently reported Xi et al , that pharmacological activation of CB 2 r attenuated the effects of cocaine on the enhancement of extracellular DA levels in the NAcc of WT mice. WT mice treated with CB 2 r agonists are not necessarily equivalent to mice overexpressing CB 2 r from the behavioral and neurochemical point of view. Besides, the genetic manipulation of the receptor may affect other neurochemical systems coupled with CB 2 r function in a different manner than the administration of the cannabinoid agonist in WT mice. The results of this study also revealed that CB 2 r are found in neurons and astrocytes in both genotypes. In addition, D2Dr i. There is no information available regarding the functional cooperation between the CB 2 r and D2Dr. However, an interaction between 2-arachidonoylglycerol and DA receptors has been described in rat NAcc core neurons mediating an enhancement of firing Seif et al , Taken together, these results might provide a cellular mechanism to understand the important role of NAcc D2Dr and CB 2 r in the behavioral responses associated to the acquisition of drug-seeking behavior. Moreover, DA modulation of excitatory currents in the striatum controlled by the expression of D1Dr or D2Dr is modified by endocannabinoids Andre et al , , suggesting that activation of postsynaptic DA receptors controls endocannabinoid mobilization. The precise molecular mechanisms by which the CB 2 r may interact with the D2Dr remain to be determined. In conclusion, the results presented here demonstrate that overexpression of CB 2 r reduced the effects of cocaine on motor sensitization, CPP and self-administration. The results point out that pharmacological manipulation of the CB 2 r might be considered a new valuable target for the treatment of cocaine dependence. Further studies are needed to explore these hypotheses. DN is a predoctoral FPI fellow. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Find articles by Alexander Ternianov. Find articles by Daniela Navarro. Find articles by Patricia Robledo. Find articles by Pere Berbel. Find articles by Rafael Maldonado. Find articles by Jorge Manzanares. Open in a new tab. Click here for additional data file. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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