Papers by Marcello Solinas
Journal of Neural Transmission, 2018
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
The Journal of Neuroscience, 2002
An increase in the extracellular concentration of dopamine in the nucleus accumbens (NAc) is beli... more An increase in the extracellular concentration of dopamine in the nucleus accumbens (NAc) is believed to be one of the main mechanisms involved in the rewarding and motor-activating properties of psychostimulants such as amphetamines and cocaine. Using in vivo microdialysis in freely moving rats, we demonstrate that systemic administration of behaviorally relevant doses of caffeine can preferentially increase extracellular levels of dopamine and glutamate in the shell of the NAc. These effects could be reproduced by the administration of a selective adenosine A1 receptor antagonist but not by a selective adenosine A2A receptor antagonist. This suggests that caffeine, because of its ability to block adenosine A1 receptors, shares neurochemical properties with other psychostimulants, which could contribute to the widespread consumption of caffeinecontaining beverages.
Opiate Receptors and Antagonists, 2009
... Eur J Pharmacol 1995;282:R12. 53. Tanda G, Loddo P, Di Chiara G. Dependence of mesolimbic do... more ... Eur J Pharmacol 1995;282:R12. 53. Tanda G, Loddo P, Di Chiara G. Dependence of mesolimbic dopamine transmission on delta 9-tetrahydrocannabinol. Eur J Pharmacol 1999;376:236. 54. Hirschhorn ID, Rosecrans JA. ... 76. Killian AK, Bonese K, Schuster CR. ...
The Journal of Neuroscience, 2006
The recent findings thatΔ9tetrahydrocannabinol (Δ9THC), the active agent in marijuana and hashish... more The recent findings thatΔ9tetrahydrocannabinol (Δ9THC), the active agent in marijuana and hashish, (1) is self-administered intravenously, (2) potentiates the rewarding effects of electrical brain stimulation, and (3) can establish conditioned place preferences in laboratory animals, suggest that these drugs activate biologically primitive brain reward mechanisms. Here, we identify two chemical trigger zones for stimulant and rewarding actions ofΔ9THC. Microinjections ofΔ9THC into the posterior ventral tegmental area (VTA) or into the shell of the nucleus accumbens (NAS) increased locomotion, and rats learned to lever-press for injections ofΔ9THC into each of these regions. Substitution of vehicle for drug or treatment with a cannabinoid CB1receptor antagonist caused response cessation. Microinjections ofΔ9THC into the posterior VTA and into the posterior shell of NAS established conditioned place preferences. Injections into the core of the NAS, the anterior VTA, or dorsal to the V...
Journal of Neuroscience, 2005
Anandamide, an endogenous ligand for brain cannabinoid CB 1 receptors, produces many behavioral e... more Anandamide, an endogenous ligand for brain cannabinoid CB 1 receptors, produces many behavioral effects similar to those of ⌬ 9tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Reinforcing effects of THC have been demonstrated in experimental animals, but there is only indirect evidence that endogenous cannabinoids such as anandamide participate in brain reward processes. We now show that anandamide serves as an effective reinforcer of drug-taking behavior when self-administered intravenously by squirrel monkeys. We also show that methanandamide, a synthetic long-lasting anandamide analog, similarly serves as a reinforcer of drug-taking behavior. Finally, we show that the reinforcing effects of both anandamide and methanandamide are blocked by pretreatment with the cannabinoid CB 1 receptor antagonist rimonabant (SR141716). These findings strongly suggest that release of endogenous cannabinoids is involved in brain reward processes and that activation of cannabinoid CB 1 receptors by anandamide could be part of the signaling of natural rewarding events.
Psychopharmacology, 2010
Rational-Although THC-induced elevations in accumbal dopamine levels are believed to play an impo... more Rational-Although THC-induced elevations in accumbal dopamine levels are believed to play an important role in the abuse-related effects of cannabis, little direct evidence has been provided that the dopaminergic system is involved in the psychotropic effects of THC. Objectives-To investigate whether drugs activating or blocking the dopaminergic system modulate the discriminative effects of THC. Methods and Results-In rats that had learned to discriminate 3 mg/kg of THC from vehicle injections, the indirect dopaminergic agonists cocaine and amphetamine, the D 1 -receptor agonist SKF-38393, and the D 2 -receptor agonists quinpirole and apomorphine did not produce significant THC-like discriminative effects. However, both cocaine and amphetamine and D 2 -, but not the D 1 -, receptor agonists, augmented THC discrimination. Neither the D 1 -receptor antagonist SCH-23390 nor the D 2 -receptor antagonist raclopride reduced the discriminative effects of THC, even at doses that significantly depressed baseline operant responding. However, the D 2 -, but not the D 1 -, antagonist counteracted the augmentation of THC's discriminative effects produced by cocaine and amphetamine. We hypothesized that release of anandamide by activation of D 2 receptors was responsible for the observed augmentation of THC discrimination. This hypothesis was supported by two findings. First, the cannabinoid CB 1 -receptor antagonist rimonabant blocked quinpirole-induced augmentation of THC discrimination. Second, inhibition of anandamide degradation by blockade of fatty acid amide hydrolase (FAAH) augmented the THClike effects of quinpirole. Conclusions-Dopamine does not play a major role in THC discrimination. However, activation of the dopaminergic system positively modulates the discriminative effects of THC, possibly through D 2 -induced elevations in brain levels of anandamide.
Proceedings of the National Academy of Sciences, 2005
Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression,... more Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, Δ 9 -tetrahydrocannabinol, acts by binding to brain CB 1 cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB 1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and...
Pharmacological Research, 2007
Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredie... more Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), produces rewarding effects in humans and non-human primates. Over the last several decades, an endogenous system comprised of cannabinoid receptors, endogenous ligands for these receptors and enzymes responsible for the synthesis and degradation of these endogenous cannabinoid ligands has been discovered and partly characterized. Experimental findings strongly suggest a major involvement of the endocannabinoid system in general brain reward functions and drug abuse. First, natural and synthetic cannabinoids and endocannabinoids can produce rewarding effects in humans and laboratory animals. Second, activation or blockade of the endogenous cannabinoid system has been shown to modulate the rewarding effects of noncannabinoid psychoactive drugs. Third, most abused drugs alter brain levels of endocannabinoids in the brain. In addition to reward functions, the endocannabinoid cannabinoid system appears to be involved in the ability of drugs and drug-related cues to reinstate drug-seeking behavior in animal models of relapse. Altogether, evidence points to the endocannadinoid system as a promising target for the development of medications for the treatment of drug abuse.
Neuropsychopharmacology, 2004
Second-order schedules of drug self-administration were developed to incorporate the effects of d... more Second-order schedules of drug self-administration were developed to incorporate the effects of drug-related environmental stimuli into an animal model of drug abuse, making it more similar to human situations. Ironically, little is known about how human subjects behave under these schedules. In this study, human volunteers with a history of cocaine use worked on a second-order schedule in which every 100th lever response produced an auditory-visual brief stimulus (2 s). The first stimulus produced after 1 h was extended to 10 s and paired with an intravenous injection of cocaine (25 mg). Up to three injections were allowed per session. In different phases of the experiment, presentation of the brief stimulus was discontinued and/or saline solution (placebo) was injected instead of cocaine. Injections of cocaine were found to maintain responding even when the brief stimulus was not presented. Placebo injections alone did not maintain responding. In contrast, the brief stimulus maintained high levels of responding under placebo conditions, even though selfreports indicated that subjects could clearly discriminate that they were not receiving cocaine. These results demonstrate that drugrelated environmental stimuli can maintain persistent drug seeking during periods of drug unavailability. As this procedure directly measures the effects of stimuli on drug seeking, it may provide a valuable complement to indirect measures, such as self-reports of craving, that are often used with human subjects. The similarity of the response patterns in humans and animals also supports the use of second-order schedules in animals as a valid model of human drug seeking.
Neuropsychopharmacology, 2004
One concern about the widespread use of cannabis is that exposure to its active ingredient, D-9-t... more One concern about the widespread use of cannabis is that exposure to its active ingredient, D-9-tetrahydrocannabinol (THC), might increase future reinforcing effects of other abused drugs such as heroin. In this study, we investigated the effects of pre-exposure to THC on subsequent intravenous self-administration of heroin by Sprague-Dawley rats. In one group of rats, we studied (1) acquisition of heroin self-administration behavior using a continuous-reinforcement (fixed-ratio (FR) 1) schedule, (2) heroin dose-response relationships using an FR1/variable-dose schedule, and (3) reinforcing efficacy of heroin using a progressive-ratio schedule. The number of rats pre-exposed to THC that subsequently learned to self-administer 50 mg/kg injections of heroin within 10 daily sessions did not differ from vehicle-pretreated controls. In contrast, rats pre-exposed to THC subsequently self-administered significantly more heroin injections per session and showed significantly shorter post-injection pauses over a range of heroin doses (12.5-100 mg/kg/injection) using the variable-dose schedule. Interestingly, the maximum effort rats would exert to receive an injection of the different doses of heroin under the progressive-ratio schedule was not altered by THC pre-exposure. In a second group of rats, we varied the 'price' of heroin (responses required/dose), by manipulating FR response requirements at different doses of heroin across sessions, to calculate demand and response output curves. Again, consumption was significantly higher in the THC-treated rats at the lowest prices of heroin (FR1/ 100 mg/kg and FR1/50 mg/kg) but there were no differences in the reinforcing efficacy of heroin between THC-and vehicle-pretreated rats. Altogether, these results demonstrate that pre-exposure to THC alters some pharmacological effects of heroin that determine frequency of heroin taking, but offer no support for the hypothesis that pre-exposure to THC alters heroin's efficacy as a reinforcer.
Neuropsychopharmacology, 2005
Strong functional interactions exist between endogenous cannabinoid and opioid systems. Here, we ... more Strong functional interactions exist between endogenous cannabinoid and opioid systems. Here, we investigated whether cannabinoidopioid interactions modulate motivational effects of food reinforcement. In rats responding for food under a progressive-ratio schedule, the maximal effort (break point) expended to obtain 45 mg pellets depended on the level of food deprivation, with free-feeding reducing break points and food-deprivation increasing break points. Delta-9-tetrahydrocannabinol (THC; 0.3-5.6 mg/kg intrapeitoneally (i.p.)) and morphine (1-10 mg/kg i.p.) dose-dependently increased break points for food reinforcement, while the cannabinoid CB1 receptor antagonist rimonabant (SR-141716A; 0.3-3 mg/kg i.p.) and the preferential mu-opioid receptor antagonist naloxone (0.3-3 mg/kg i.p.) dose-dependently decreased break points. THC and morphine only increased break points when food was delivered during testing, suggesting that these treatments directly influenced reinforcing effects of food, rather than increasing behavior in a nonspecific manner. Effects of THC were blocked by rimonabant and effects of morphine were blocked by naloxone, demonstrating that THC's effects depended on cannabinoid CB1 receptor activation and morphine's effects depended on opioid-receptor activation. Furthermore, THC's effects were blocked by naloxone and morphine's effects were blocked by rimonabant, demonstrating that mu-opioid receptors were involved in the effects of THC and cannabinoid CB1 receptors were involved in the effects of morphine on food-reinforced behavior. Thus, activation of both endogenous cannabinoid and opioid systems appears to jointly facilitate motivational effects of food measured under progressive-ratio schedules of reinforcement and this facilitatory modulation appears to critically depend on interactions between these two systems. These findings support the proposed therapeutic utility of cannabinoid agonists and antagonists in eating disorders.
Neuropsychopharmacology, 2005
Accumulating evidence suggests that the endogenous cannabinoid system is involved in the reinforc... more Accumulating evidence suggests that the endogenous cannabinoid system is involved in the reinforcing effects of heroin. In rats intravenously self-administering heroin, we investigated effects of cannabinoid CB 1 receptor agonists and compounds that block transport or metabolism of the endogenous cannabinoid anandamide. The natural cannnabinoid CB 1 receptor agonist delta-9-tetrahydrocannabinol (THC, 0.3-3 mg/kg i.p.) did not alter self-administration of heroin under a fixed-ratio one (FR1) schedule, except at a high 3 mg/kg dose which decreased heroin self-administration. Under a progressive-ratio schedule, however, THC dose-dependently increased the number of 50 mg/kg heroin injections self-administered per session and the maximal ratio completed (break-point), with peak increases at 1 mg/kg THC. In addition, 1 mg/kg THC increased break-points and injections self-administered over a wide range of heroin injection doses (25À100 mg/kg), indicating an increase in heroin's reinforcing efficacy and not its potency. The synthetic cannabinoid CB 1 receptor agonist WIN55,212-2 (0.3-3 mg/kg i.p.) had effects similar to THC under the progressive-ratio schedule. In contrast, AM-404 (1-10 mg/ kg i.p.), an inhibitor of transport of anandamide, and URB-597 (0.01-0.3 mg/kg i.p.), an inhibitor of the enzyme fatty acid amide hydrolase (FAAH) that degrades anandamide, or their combination, did not increase reinforcing efficacy of heroin at any dose tested. Thus, activation of cannabinoid CB 1 receptors facilitates the reinforcing efficacy of heroin and this appears to be mediated by interactions between cannabinoid CB 1 receptors and mu-opioid receptors and their signaling pathways, rather than by an opioid-induced release of endogenous cannabinoids.
Neuropsychopharmacology, 2008
It is known that negative environmental conditions increase vulnerability to drugs, whereas littl... more It is known that negative environmental conditions increase vulnerability to drugs, whereas little is known on whether positive environmental conditions such as enriched environments (EE) have protective effects against addiction. We have previously found that EE consisting of bigger cages containing several toys that were changed once per week reduce cocaine-induced increases in locomotor activity. Here, we also show that the rewarding effects of cocaine are blunted in mice reared from weaning to adulthood in EE compared to mice reared in standard environments (SE). In addition, although both EE and SE mice develop behavioral sensitization to cocaine, EE mice show less activation in response to repeated administration of cocaine injections and reduced responses to cocaine challenges. In vivo microdialysis experiments demonstrate that the protective effects of EE do not depend on reduced cocaine-induced increases in the dopamine levels in the ventral or dorsal striatum. On the other hand, they were associated with reduced cocaine-induced expression of the immediate early gene zif-268 in the nucleus accumbens (shell and core) of EE mice. Finally, basal levels of Delta-Fos B, a transcription factor known to be increased by sustained activation of striatal neurons, are higher in the striatum of EE compared to SE mice and repeated administration of cocaine increases Delta-Fos B levels in SE mice but decreases them in EE mice. Altogether our results demonstrate that exposure to complex environments during early stages of life produce dramatic changes in the striatum that result in reduced reactivity to drugs of abuse.
Neuropsychopharmacology, 2006
The hypothesis that prior cannabis exposure increases the likelihood of becoming addicted to othe... more The hypothesis that prior cannabis exposure increases the likelihood of becoming addicted to other drugs can be evaluated by giving rats a history of tetrahydrocannabinol (THC) exposure, then allowing them to self-administer other drugs. In Experiment 1, THC preexposure did not alter the acquisition of cocaine self-administration or the amount of cocaine taken under a fixed-ratio 1 (FR1) schedule, with one response required for each injection. Under a progressive-ratio schedule, with the response requirement increasing exponentially with each injection, cocaine-seeking was significantly reduced in THC-exposed rats, suggesting that the regimen of THC exposure used in the present study caused cocaine to be devalued as a reinforcer. In contrast, in an earlier study that used the same regimen, a history of THC exposure did not alter the value of heroin as a reinforcer under the progressive-ratio schedule, but it increased heroin self-administration under the FR1 schedule. Experiment 2 examined how this regimen of THC pre-exposure alters the locomotor effects of cocaine and heroin. THC pre-exposure produced cross-tolerance to the motor-depressant effects of heroin; this may explain the shortened post-injection pauses exhibited by THC-exposed rats under FR1 heroin self-administration. When given cocaine, THCexposed rats exhibited normal increases in locomotion, but they avoided the center of the open field, suggesting that this THC preexposure regimen enhances the anxiogenic effects of cocaine. This enhanced anxiogenic effectFwhich was verified in Experiment 3 using another model of anxiety, the light-dark testFmay explain the reduced reinforcing value of cocaine observed in THC-exposed rats in Experiment 1.
Neuropsychopharmacology, 2009
Whereas earlier studies have focused on the preventive effects of enriched environments (EE) in d... more Whereas earlier studies have focused on the preventive effects of enriched environments (EE) in drug addiction, in a recent study we suggested that EE can also have 'curative' effects. In fact, we found that cocaine addiction-related behaviors can be eliminated by housing cocaine-treated mice in EE during periods of forced abstinence. However, those results were obtained with two simple models of addiction, conditioned place preference (CPP), and behavioral sensitization. In this study, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of EE on cocaine addiction in a reinstatement model of relapse. Singly housed rats learned to self-administer cocaine during 10 consecutive daily sessions (0.6 mg/injection, 6 h/day). They were then housed three per cage in either standard environments (SE) or EE and were kept abstinent in the animal facility until testing for extinction and reinstatement. We found that 30 days of EE significantly and consistently reduced cocaine seeking during a 6-h extinction session. In addition, EE significantly reduced cue-and stress-induced reinstatement. Surprisingly, given our earlier results in mice with CPP, EE did not reduce cocaine-induced reinstatement regardless of the level of exposure to cocaine and the duration of the period of abstinence and exposure to EE. Altogether, these results support the hypothesis that EE can reduce cocaine-induced craving and highlight the importance of positive life conditions in facilitating abstinence and preventing relapse to cocaine addiction.
Neuropharmacology, 2012
Cannabinoid receptor agonists are known to stimulate feeding in humans and animals and this effec... more Cannabinoid receptor agonists are known to stimulate feeding in humans and animals and this effect is thought to be related to an increase in food palatability. On the other hand, highly palatable food stimulates dopamine (DA) transmission in the shell of the n.accumbens and this effect undergoes one trial habituation. In order to investigate the relationship between the affective properties of tastes and the response of accumbens shell DA we studied the effect of delta-9tetrahydrocannabinol (THC) on behavioral taste reactivity to intraoral infusion of appetitive (sucrose solutions) and aversive (quinine and saturated NaCl solutions) tastes and on the response of in vivo dopamine (DA) transmission n.accumbens shell to intraoral sucrose. Rats were implanted with intraoral cannulae and the effect of systemic administration of THC on the behavioral reactions to intraoral infusion of sucrose and of quinine or saturated NaCl solutions were scored. THC increased the hedonic reactions to sucrose but did not affect the aversive reactions to quinine and NaCl. The effects of THC were fully blocked by the CB1 receptor inverse agonist/antagonist rimonabant given at doses that do not affect taste reactivity to sucrose. In rats implanted with microdialysis probes and with intraoral cannulae, THC, made sucrose effective in raising dialysate DA in the shell of the n.accumbens. As in the case of highly palatable food (Fonzies, sweet chocolate), the stimulatory effect of sucrose on shell DA under THC underwent one trial habituation. Altogether, these findings demonstrate that stimulation of CB1 receptors specifically increases the palatability of hedonic taste without affecting that of aversive tastes. Consistent with the ability of THC to increase sucrose palatability is the observation that under THC pretreatment sucrose acquires the ability to induce a release of DA in the shell of the accumbens and this property undergoes adaptation after repeated exposure to the taste (habituation).
Neuropharmacology, 2014
Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in t... more Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ 9tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB 1 and CB 2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG
Learning & Memory, 2009
Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a canna... more Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB1-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for α-type peroxisome proliferator-activated nuclear receptors, PPAR-α) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-α agonist WY14643, and these enhancements were blocked by the PPAR-α antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-α, either directly by administering a PPAR-α agonist or indirectly by administering a FAAH inhibitor.
Journal of Pharmacology and Experimental Therapeutics, 2007
Anandamide is an endogenous ligand for brain cannabinoid CB 1 receptors, but its behavioral effec... more Anandamide is an endogenous ligand for brain cannabinoid CB 1 receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of ␦-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3Ј-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dra-matically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and methanandamide were blocked by the CB 1 receptor antagonist rimonabant, but not the vanilloid VR 1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide (AM-404) and N-(3furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide. The endogenous cannabinoid (CB) system, which is targeted by the psychoactive ingredient in cannabis, ␦-9-tetrahydrocannabinol (THC), comprises receptors termed CB 1 and CB 2 (and others not yet identified) endogenous compounds that activate these receptors and enzymes involved in the synthesis and degradation of these endogenous cannabinoids
Journal of Pharmacology and Experimental Therapeutics, 2003
Adenosine, by acting on adenosine A 1 and A 2A receptors, is known to antagonistically modulate d... more Adenosine, by acting on adenosine A 1 and A 2A receptors, is known to antagonistically modulate dopaminergic neurotransmission. We have recently reported that non-selective adenosine receptor antagonists (caffeine and DMPX) can partially substitute for the discriminative-stimulus effects of methamphetamine. In the present study, by using more selective compounds, we investigated the involvement of A 1 and A 2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of both cocaine and methamphetamine. The effects of the A 1 receptor agonist CPA (0.01 -0.1 mg/kg) and antagonist CPT (1.3 -23.7 mg/kg) and the A 2A receptor agonist CGS 21680 (0.03 -0.18 mg/kg) and antagonist MSX-3 (1 -56 mg/kg) were evaluated in rats trained to discriminate either 1 mg/kg methamphetamine or 10 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. The A 1 and A 2A receptor antagonists (CPT and MSX-3) both produced high levels of drug-lever selection when substituted for either methamphetamine or cocaine and significantly shifted dose-response curves of both psychostimulants to the left. Unexpectedly, the A 2A receptor agonist CGS 21680 also produced drug-appropriate responding (although at lower levels) when substituted for the cocaine-training stimulus and both CGS 21680 and the A 1 receptor agonist CPA significantly shifted the cocaine dose-response curve to the left. In contrast both agonists did not produce significant levels of drug-lever selection when substituted for the methamphetaminetraining stimulus and failed to shift the methamphetamine dose-response curve. Therefore, adenosine A 1 and A 2A receptors appear to play important but differential roles in the modulation of the discriminative-stimulus effects of methamphetamine and cocaine.
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Papers by Marcello Solinas