PMC:3780360 / 33557-62054 JSONTXT

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of the eCBS with Biological and Behavioral Correlates of Psychostimulants Addiction\n\nHuman studies\nHuman studies aimed at understanding the interaction of the ECBS with biological and behavioral correlates of addiction to psychostimulants have mostly focused on ECBS-related risk factors leading to drug dependence. Interestingly, cannabis use is strongly associated with the abuse and/or dependence of several class of drugs including psychostimulants such as cocaine (222). Moreover, exogenous cannabinoids have been shown to modulate the acute rewarding effects of cocaine. These lines of evidence may suggest an association between ECBS and liability to psychostimulant by pointing toward a possible involvement of the ECBS in the motivational effects mediated by psychostimulants (223) [reviewed in Ref. (224)]. Based on these observations, scientific efforts have been devoted to investigate the influence of various genetic (e.g., ECBS-related genes) and environmental characteristics (e.g., previous or current exposure to cannabinoid agonists) in individual progression from occasional use to psychostimulant addiction.\n\n“The gateway theory” and addiction to psychostimulants\nAssociation of prior or concomitant cannabis consumption with other illicit drugs including psychostimulants such as methamphetamine and cocaine, forms the basis of a well-known hypothesis – “ the gateway theory,” which suggests a causal role for cannabis in the development of subsequent drug use and addiction (225). While data indicate that smoking cannabis is positively associated with cocaine consumption, it would be inappropriate to assume that cannabis per se leads to cocaine use. A study from Lynskey et al. in human twins reveals that early cannabis use in life increases the odds of subsequent cocaine use, supporting the causative model of the “gateway theory.” However, results of this study have been refuted by Kandel et al. (226) which argues that several additional genetic, social, and environmental factors, such as life experiences, might link cannabis use with subsequent cocaine consumption (227, 228). Actual neurobiological causal mechanisms underlying this “gateway theory” remain mostly unidentified. Interestingly, Tomasiewicz and colleagues show that Δ9-THC exposure induces epigenetic dysregulation of the endogenous opioid proenkephalin in adolescents; these findings indicate that cannabis exposure, in and of itself, can be considered as a risk factor that acts “above the genome” and can “write” on the existing epigenetic background of adolescent neurodevelopment. Thus, in adolescents, Δ9-THC exposure-mediated epigenetic effects may act in concert with other environmental or social factors to augment future behavioral responses to drugs of abuse via stable and long-term regulation of genes at the transcriptional level. However, while these data establish a direct link between Δ9-THC-induced changes in proenkephalin expression and susceptibility to opiate drugs, no studies have confirmed that this mechanism can be applied to psychostimulants (229).\n\nGenetic determinants of the ECBS and psychostimulant addiction\nIt is worth mentioning that not every subject who experiences the pleasurable effects of psychostimulants will become a chronic user. Indeed it is more likely that additional factors such as: (1) genetic variabilities (e.g., polymorphisms in the catechol O-methyltransferase gene (Val158met) and in the serotonin transporter gene (5-HTTLPR) (230, 231); (2) monoamine receptors deficiency – either genetically or as a result of their drug excesses – also contribute to the psychostimulants addiction process (232–235) (see Table 1). In the ECBS, different genetic variants of the CB1 receptors – CNR1 – and FAAH genes have been associated with increased susceptibility to drug addiction. Indeed, genetic analyses demonstrate that the CNR1 gene exhibits elevated numbers of (AAT)n triplet repetition in a sample of 192 non-Hispanic Caucasian subjects. Interestingly, this CNR1 polymorphism increases the risk of intravenous drug use in this population, with strongest correlation observed in cocaine, amphetamine, and marijuana dependence (236). Similarly, a study from Ballon and colleagues shows that detection of this CNR1 polymorphism in a sample of 142 African-Caribbean individuals predisposed them to cocaine addiction (237). Unfortunately, while single sequence repetitions can alter transcriptional rates and thereby induced gene overexpression or silencing (238), the functional nature of the microsatellite polymorphism triplet repetition (AAT)n in modulating CNR1 gene expression remains blurred (239). It has been hypothesized that the presence of long alleles with high numbers of AAT triplets alter CNR1 transcriptional gene expression, ultimately leading to low levels of CNR1 protein synthesis (240). A recent meta-analysis of 11 studies aimed at investigating the contribution of three CNR1 polymorphisms (rs1049353, rs806379, and the AAT triplet repetitions) to drug dependence vulnerability confirmed the presence of (AAT)n repeats, but only in the Caucasian population [reviewed in Ref. (239)]. Unfortunately, the effect of the three CNR1 polymorphisms appeared to be insignificant and showed high heterogeneity. Important caveats have to be considered when looking at these studies. First, the ethnicity of the different subjects may prove important, as some studies included several ethnic groups in their samples, and in some cases, these groups were not even mentioned (241, 242). Some reports also examined CNR1 gene polymorphisms in connection with a different phenotype or stage of drug addiction such as craving, drug consumption, dependence, or drug withdrawal (243). Furthermore, a detailed description of the repercussions of CNR1 polymorphisms on CB1 function from a neurobiological standpoint is lacking from the reviewed studies.\nTable 1 ECBS and factors contributing to vulnerability to psychostimulants in humans. Polymorphisms in the gene coding for the endocannabinoid-inactivating enzyme FAAH may constitute another risk factor for problematic drug use, as described by initial reports identifying C385A, a mis-sense single nucleotide polymorphism (SNP) causing reduced FAAH enzymatic activity (245, 246). Indeed, a study from Sipe et al. reveals significant association between C385A SNP and street drug abuse in a sample of 1737 Caucasian subjects with addictive disorders. Neuroimaging studies combined with genetic analysis reveal that low FAAH activity enhances AEA protein expression levels which, in turn, modulate brain regions implicated in drug addiction and reward circuitry such as the OFC, AC gyrus, and NAc (242). Additional neuroimaging studies show that C385A carriers exhibit increased ventral striatal reactivity – a correlate for heightened impulsivity and reward sensitivity. C385A carriers display low threat-related amygdala reactivity – a pattern observed in individuals with high familial risk of alcoholism. Moreover, C385A polymorphism-reduced FAAH functional activity increases risk-taking behavior associated with addiction through abnormal impulsivity and threat perception [reviewed in Ref. (224, 243)]. Contribution of SNPs that modulate FAAH functions to stimulant addiction remain to be explored as the aforementioned data were not obtained in individuals specifically addicted to stimulants.\n\nEffect of exogenous cannabinoids on psychostimulant reward\nAs mentioned previously (see The Endocannabinoid System), an intriguing characteristic of psychostimulants abuse is the concurrent consumption of cannabis. Parallel to studies on the long-term effects of cannabis exposure on subsequent psychostimulant use, researchers also examined the acute rewarding effects of cannabis use on concurrent psychostimulant addiction (91, 222). However, studies aimed at investigating such interactions are sparse. Conflicting results from Foltin et al. and Lukas et al. provide evidence that cannabinoids modulate cocaine-mediated euphoric actions. First, data from Foltin and colleagues show that human volunteers who smoked cannabis prior to intravenous cocaine experience a prolongation of the “high” sensation (248). Second, a study from Lukas and colleagues reveals that smoking Δ9-THC, 30 min prior to intranasal cocaine decreases the latency to onset of cocaine-induced euphoria significantly, from 1.87 to 0.53 min, as well as the duration of cocaine-induced dysphoria, from 2.1 to 0.5 min (249). Interestingly, when both drugs are administered concomitantly, no changes are observed in cocaine- and Δ9-THC-induced positive subjective properties. Furthermore, Δ9-THC increases the peak plasma levels and bioavailability of cocaine considerably. This increase might be the result of Δ9-THC-induced vasodilation of the nasal mucosa which, in turn, reduces cocaine-induced vasoconstriction, thereby increasing cocaine’s absorption. In addition, the discrepancies between these two studies might be also due to pharmacodynamic mechanisms including differences in cocaine absorption or in the ratio of CBD/Δ9-THC levels found in the type of cannabis used for each study.\nUsing fMRI technology combined with script-guided imagery paradigm in which subjects imagined being in a real-life stressful situation, Rajita Sinha’s group found that cannabis abuse contributed to stress-induced blood-oxygen-level-dependent (BOLD) contrast in a group of cocaine-dependent individuals. More specifically, cannabis consumption decreases emotional stress cue-induced frontal and cingulate activation in cocaine-dependent individuals (247). These findings suggest an abnormal cognitive control mechanism during affective processing in association with heavy cannabis use. An important caveat to consider in the latter study is that cocaine-dependent individuals were abstinent for several weeks prior to the neuroimagery session and were not current users of cannabis. Thus the study did not allow to examine the acute effect of cannabis on neural and behavioral responses. However, the fact that this cannabis-induced alteration in stress-response can be translated to cocaine craving and relapse vulnerability has definitely piqued further interest, and initial data on this matter already exists. Indeed, the effects of cannabis consumption on abstinence and relapse to cocaine use have been provided in a study from Labigalini and colleagues, in which 25 cocaine-crack dependent individuals reported to smoke cannabis in order to get relief from abstinence mediated-cocaine-withdrawal symptoms. From this sample, 68% of addicts achieved crack-cocaine cessation while using cannabis during the 9 months duration of the study (90). However, the self-reported nature of this study and its limited duration suggest cautiousness in interpreting its outcome. In a more recent study, Aharonovich et al. drew opposite conclusions on the consequences of smoking cannabis on cocaine relapse. In this study, researchers investigated whether cannabis use after the discharge of 144 drug-addicts from inpatient treatment program could help them to maintain abstinence and thereby preventing relapse to cocaine use. Results from this study suggest that smoking cannabis reduced the achievement of sustained remission and increased relapse to cocaine use (91) (see Table 1). Surprisingly, a study from Jutras-Aswad et al. supports the assumption that irregular cannabis use increases risky behaviors (syringe sharing) of cocaine and opioid users, as opposed to regular cannabis use, suggesting a complex dose-effect relationship between cannabis and addictive behaviors (22). The possibility that cannabis use by recently abstinent cocaine-dependent individuals influences relapse to drug and other related behaviors remains poorly documented.\n\nAnimal studies\nOver the last decades, development of animal models have allowed a better understanding of psychostimulant effects and addiction-related behaviors. These studies would not be available through clinical studies for ethical and practical reasons. Notably, invasive measures such as catheter installation for drug administration and surgical brain procedures for assessment of drug-induced neurobiological changes, as well as strictly controlled conditioning protocols involving restrictive environments, have extended the knowledge of psychostimulants effect on neurotransmission. These methods have also allowed observations of specific behavioral aspects of psychostimulant addiction. Thus, studies on animal models of psychostimulants abuse have provided tremendous insights on the role of ECBS in various aspects of psychostimulant addiction, spanning from drug reward, acquisition, and relapse.\n\nInfluence of ECBS on psychostimulants-induced behavioral and reinforcing effects\nAs mentioned above (see Neurobiology of Psychostimulants), substantial evidence indicates that behavioral and addictive properties of psychostimulants come from the interactions of psychostimulants with brain monoamines. Specifically, increase of extracellular levels of DA through promotion of DA release by amphetamine and MDMA, as well as inhibition of DA reuptake by cocaine, represent the primary mechanisms involved in rewarding effects mediated by psychostimulants (224). In animal models of intracranial self-stimulation (ICSS), the rewarding properties of drugs of abuse typically translate into lowering of the so-called reward threshold established after operant training [see Ref. (250) for description]. Initial experiments showed no effect of CB1 antagonist SR141716A on cocaine’s ability to lower ICSS threshold in rats (251), although careful data analysis suggests a tendency toward attenuation. However, different results were obtained when using a more potent antagonist – AM251. This antagonist proves CB1 blockade’s effectiveness in inhibiting cocaine’s action on brain stimulation reward (250). Paradoxically, the non-selective cannabinoid agonist – WIN55, 212-2 – and the endocannabinoid transmission enhancer – AM404 – are also able to abolish cocaine’s reinforcing effects as assessed by ICSS (252). Whether these apparently contradictory findings may indicate an inverse U-shape effect of CB1 stimulation function on rewarding properties of stimulants is not entirely clear. However, these results clearly indicate that cannabinoids might interfere with brain systems responsible for psychostimulants rewarding effects, and the mechanism underlying this phenomenon should be further explored.\nLi and colleagues recently found significant reductions in DA levels in striatum of mice lacking the CNR1 gene, when compared to their wildtype counterparts following acute cocaine administration and during the basal state (253). This observation shows consistency with above-cited ICSS studies and with a previous report on the inhibition of cocaine-induced DA release in rats by CB1 antagonist SR141716A (254). In contrast, initial findings suggested that neither basal levels nor cocaine-induced increases in extracellular NAc DA of CB1 knockout mice differed from that of normal mice (255), and that CB1 inactivation by antagonists AM251 and SR141716A failed to alter the increase in extracellular NAc DA responsible for cocaine-mediated rewarding effects in rats (256, 257). Differences in experimental methods used to measure DA levels (voltammetry vs. in vivo microdialysis) and in the genetic background of the knockout animals (C57BL/6J vs. CD1) could account for such discrepancies. Notably, compensatory neurobiological changes due to lack of CB1 receptors could explain the subnormal basal DA levels observed in Li et al. study. This subnormal basal DA levels could also have contributed to apparent attenuation of DA levels enhancement produced by cocaine. Overall, the extent to which ECBS interaction with psychostimulants-mediated reward effects depends on DA transmission seems limited, especially when CB1 is targeted. It remains a controversial issue, with subsequent reports of attenuation of cocaine-enhanced extracellular NAc DA activity by CB2 agonists JWH133 and GW405833 in mice (258), but not by the pharmacological FAAH inhibitor URB597 in rats (259) adding to the complexity of the matter (see Table 2).\nTable 2 Pharmacological inhibition of FAAH inhibition and properties of psychostimulants. The increase of DA neurotransmission in the NAc and other striatal regions responsible for psychostimulant-induced rewarding parallels the stimulation of locomotor activity following acute drug administration. Sensitization to hyperlocomotor responses produced by psychostimulants occurs after chronic treatment, reflecting adaptive changes in DA transmission and potentially correlating with drug-seeking and reinstatement behavior (254, 262). In various studies, neither genetic deletion (262–264) nor pharmacological inhibition of CB1 receptors by SR141716A (265, 266) altered cocaine’s ability to induce acute motor effects or behavioral sensitization in rats and mice. However, a comparable number of reports described contradictory results, showing attenuation of both of these outcomes in CB1 knockout mice (253, 267) (see Table 3) as well as impairment of sensitization in animals pretreated with SR141716A (254, 268) or AM251 (267). Interestingly, although chronic cocaine use still induced sensitization in mice with invalidated CB1 receptors, sensitized response appeared somewhat changed when compared to control animals. Corbille et al. also found that AM251, unlike SR141716A (269), only impaired sensitization to cocaine after a single exposure, but not upon repeated administration. Similar experiments with cannabinoid agonists showed mixed results, as non-selective WIN 55,212-2 reduced cocaine’s motor effects, probably in a non-CB1 mediated fashion (252, 270). Likewise, CB2 agonists JWH133 and GW405833 decreased both acute hyperlocomotion and sensitization in rats (258), which parallels findings observed in mice genetically overexpressing CB2 (271). Δ9-THC failed to alter cocaine’s motor effects in rats (268, 272). Similarly, cannabinoid-amphetamine interactions studies demonstrate that acute cannabinoid exposure antagonizes amphetamine’s locomotion effects in a dose-dependent manner in rats. On the other hand, chronic exposure to Δ9-THC induces sensitization to the psychomotor effects mediated by amphetamine in rats (273). Taken together, these experiments suggest that the acute motor stimulant effects of psychostimulant and the induction of cocaine sensitization may not depend on endocannabinoid tone, even though CB1 receptors could play a minor modulating role in this regard [reviewed in Ref. (274)].\nTable 3 Effects of CB1 cannabinoid receptor deletion and properties of psychostimulants; CB1 receptor antagonists and properties of psychostimulants. Overall, while some evidence of ECBS involvement in the neurobiological and behavioral correlates of psychostimulant reinforcing properties exists, influence of ECBS on acute psychostimulant reward is modest and probably involves a combination of mechanisms which may not directly involve DA activity in the NAc or CB1 receptors.\n\nInfluence of ECBS on acquisition and maintenance of psychostimulant-induced seeking behaviors\nModels of conditioning such as the SA paradigm and the conditioned place-preference (CPP) procedure illustrate the reinforcing properties of drugs of abuse and demonstrate their ability to induce and maintain drug-seeking behaviors. Consistent with findings showing the limited involvement of the ECBS in the reinforcing properties of psychostimulants (see Influence of ECBS on Psychostimulants-Induced Behavioral and Reinforcing Effects), modulation of the ECBS appears to have a modest influence on acquisition and maintenance of psychostimulant-taking behavior in animals. In CPP experiments, while CB1 receptor deletion did not affect psychostimulant-induced place conditioning in mice, SR141716A impaired cocaine-, methamphetamine-, and MDMA-induced place conditioning in both rats and mice (262–265, 281, 286, 287). Difference in species, compensatory changes in the knockout animals due to the lack of CB1 receptors, as well as use of more intense conditioning and higher doses of drugs in the genetic deletion studies may have contributed to this discrepancy. This suggests that intensity of conditioning could overcome the effects of blocking ECBS signaling [reviewed in Ref. (274)]. It is important to note that the weaker cannabinoid antagonist CBD did not affect establishment of amphetamine-induced CPP in rats (290) and that the genetic overexpression of cannabinoid receptor CB2 impaired acquisition of both cocaine-induced CPP and SA (271). Thus the CPP model indicates that, although not directly interfering with the rewarding properties of psychostimulant drugs, ECBS could play a role in the perception and memory of psychostimulant reward, depending on environment-related factors.\nIn general, CB1 receptor invalidation does not seem to affect SA of psychostimulants. Experiments with genetic deletion of CB1 show conflicting results, as both knockout and SR141716A-treated mice still acquired amphetamine- and cocaine-taking behavior in restrained mobility conditions (266, 275), whereas knockout mice showed impaired SA behavior in other protocols (255, 258). Overall, results suggest that learning SA behavior might not require extensive ECBS involvement. Maintenance of such behavior may not depend on CB1 either, as drug-taking responses under a fixed-ratio schedule in animals that had already acquired cocaine SA remained unaffected after CB1 blockade by SR141716A in mice (266, 283), monkeys (280), and rats (250, 256, 269, 283) and by AM251 in rats (250, 277). Only one contradicting report exists in which AM251 decreased methamphetamine SA in conditioned rats (278). Cannabinoid signaling enhancement by the pharmacological FAAH inhibitors – URB597 and PMSF – also failed to affect maintenance of fixed-ratio drug-taking behavior in rats (261) and monkeys (260). On the other hand, cannabinoid stimulation by CB1 agonists had significant effects in several studies. Indeed, WIN 55,212-2 increased acquisition of MDMA SA in mice (286) and exposure to CP55,940 enhances development of cocaine SA in female rats (291). THC failed to alter acquisition of cocaine SA and amphetamine SA in monkeys (272) and rats (290), respectively. In regard to maintenance of drug intake in animals with SA behavior, cannabinoid agonists decreased drug-taking responses in rats – CP55,940 diminished MDMA intake (288) and WIN55,212-2 decreased cocaine administration (292) – and in monkeys – Δ9-THC also decreased cocaine intake (272). Fattore et al. first interpreted the shift in psychostimulant intake produced by CB1 agonists as indicative of a synergistic action of CB1 stimulation on reinforcing properties of the drugs, which, incidentally, could account for the frequent use of cannabis among human psychostimulants users (292). Complementary experiments using progressive-ratio schedules also reveal interaction of CB1 receptors with psychostimulant-induced reinforcing properties. In PR schedules, both genetic deletion and antagonist treatment of CB1 receptors produce a decrease in the maximal effort mice provided to self-administer cocaine, as made apparent by decreases in breaking point measures induced by SR141716A (255, 277, 284) and by AM251 (250) (SR141716A producing no effect in this specific report). This adds to the evidence that the CB1 receptors, while not indispensable for acquisition or maintenance of cocaine-seeking behavior, may exert a specific modulation on motivation and reward salience in psychostimulant addiction.\n\nRole of ECBS in extinction and reinstatement of drug-taking behaviors\nAlthough the mechanism used by endocannabinoid signaling to modulate psychostimulant reward and acquisition or maintenance is still the subject of debate, some form of consensus exists in the literature about the pivotal role of the ECBS in extinction and reinstatement in animal behavioral models of psychostimulant addiction [reviewed in Refs. (89) and (274)]. In conditioning procedures, extinction refers to the learning phase that follows the removal of the reinforcer (i.e., psychostimulant drugs), during which rates of conditioned responses (i.e., SA or CPP) progressively decline back to pre-conditioning levels. After drug-seeking behavior becomes extinct, several behavioral phenomena can reinstate drug-seeking behavior. These include not only re-exposure to the abused drug itself, but also exposure to contextual cues associated with previous drug administration and to environmental stressors (274, 293).\nIn a recent study from Ward et al. mice treated with SR141716 after removal of cocaine in a SA paradigm altered the burst in cocaine-seeking observed in the initial phase of extinction learning, while decreasing the time required to achieve complete extinction of cocaine-seeking behavior when compared to vehicle-treated mice (282). CB1 blockade by SR141716A also significantly decreases cue-induced reinstatement of cocaine SA behavior following extinction, supporting similar reports of attenuation of cue-induced reinstatement of cocaine-seeking by CB1 antagonism in rats (269, 277, 283). Evaluation of reinstatement of SA behavior induced by drug-priming produced similar results: SR141716A blocks cocaine-induced reinstatement (269, 283), and both AM251 (257, 277) and SR141716A inhibit methamphetamine-induced reinstatement (289). It is worth noting that CB2 antagonism also has an anti-reinstatement effect in cocaine-primed, but not in cue-exposed rats (277). In CPP models, CB1 blockade by SR141716A, but not by AM251 (276), impaired drug-induced reinstatement in cocaine-conditioned mice (281). SR141716A also impaired methamphetamine-induced reinstatement of CPP (281). Few studies focused on stress-induced reinstatement of psychostimulant-seeking. Vaughn et al. recently found that AM251 reverses stress-induced CPP (276). De Vries et al. could not find an impact of SR141716A on stress-induced SA reinstatement (283).\nStimulation of CB1 receptors produced opposite results to those obtained in pharmacological blockade experiments (see Table 4). WIN55,212-2 increases time for extinction of CPP and enhances drug-induced reinstatement in MDMA-conditioned mice (285, 286). Similarly, Δ9-THC increases cue-induced reinstatement of methamphetamine SA in rats (289). However, studies from Parker et al. and Adamczyk et al. complexify the interpretation of these results (290). Indeed, Adamczyk’s group showed that FAAH inhibition impairs cue- and drug-induced reinstatement of cocaine SA. Using the place-preference conditioning paradigm, Parker et al. have assessed the potential of both exogenous cannabinoids – Δ9-THC and CBD – to potentiate the extinction of cocaine- and amphetamine-induced CPP (290). After the establishment of cocaine-induced and amphetamine-induced place preference, rats were given an extinction trial, 30 min prior to which they were injected with a low dose of Δ9-THC, CBD, or vehicle. During conditioning trials, researchers also injected rats with cannabinoids, or vehicle, prior to an amphetamine injection, to determine the effects of Δ9-THC or CBD on the establishment and expression of a place preference. Results indicate that Δ9-THC and CBD potentiate the extinction of stimulant-CPP learning, which is not mediated by an alteration of learning or retrieval. CBD does not have a reinforcing or hedonic property on its own, suggesting that it does not have the addictive potential of Δ9-THC, a significant advantage in terms of therapeutic use. The non-reinforcing aspect of CBD has been replicated in studies looking at the co-administration of CBD and Δ9-THC (212, 294). These discrepancies probably result from the lack of receptor selectivity in the methods used to enhanced cannabinoid signaling. Nonetheless, these experiments support a significant involvement of ECBS in the extinction and reinstatement of behaviors related to psychostimulant addiction. Overall, the positive results of CB1 antagonists on extinction and prevention of reinstatement of psychostimulant SA, combined with their lack of reinforcing properties, suggest a therapeutic potential for CB1 modulation in treatment of psychostimulant addiction.\nTable 4 CB1 receptor agonists and properties of psychostimulants.\n\nCon"}

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of the eCBS with Biological and Behavioral Correlates of Psychostimulants Addiction\n\nHuman studies\nHuman studies aimed at understanding the interaction of the ECBS with biological and behavioral correlates of addiction to psychostimulants have mostly focused on ECBS-related risk factors leading to drug dependence. Interestingly, cannabis use is strongly associated with the abuse and/or dependence of several class of drugs including psychostimulants such as cocaine (222). Moreover, exogenous cannabinoids have been shown to modulate the acute rewarding effects of cocaine. These lines of evidence may suggest an association between ECBS and liability to psychostimulant by pointing toward a possible involvement of the ECBS in the motivational effects mediated by psychostimulants (223) [reviewed in Ref. (224)]. Based on these observations, scientific efforts have been devoted to investigate the influence of various genetic (e.g., ECBS-related genes) and environmental characteristics (e.g., previous or current exposure to cannabinoid agonists) in individual progression from occasional use to psychostimulant addiction.\n\n“The gateway theory” and addiction to psychostimulants\nAssociation of prior or concomitant cannabis consumption with other illicit drugs including psychostimulants such as methamphetamine and cocaine, forms the basis of a well-known hypothesis – “ the gateway theory,” which suggests a causal role for cannabis in the development of subsequent drug use and addiction (225). While data indicate that smoking cannabis is positively associated with cocaine consumption, it would be inappropriate to assume that cannabis per se leads to cocaine use. A study from Lynskey et al. in human twins reveals that early cannabis use in life increases the odds of subsequent cocaine use, supporting the causative model of the “gateway theory.” However, results of this study have been refuted by Kandel et al. (226) which argues that several additional genetic, social, and environmental factors, such as life experiences, might link cannabis use with subsequent cocaine consumption (227, 228). Actual neurobiological causal mechanisms underlying this “gateway theory” remain mostly unidentified. Interestingly, Tomasiewicz and colleagues show that Δ9-THC exposure induces epigenetic dysregulation of the endogenous opioid proenkephalin in adolescents; these findings indicate that cannabis exposure, in and of itself, can be considered as a risk factor that acts “above the genome” and can “write” on the existing epigenetic background of adolescent neurodevelopment. Thus, in adolescents, Δ9-THC exposure-mediated epigenetic effects may act in concert with other environmental or social factors to augment future behavioral responses to drugs of abuse via stable and long-term regulation of genes at the transcriptional level. However, while these data establish a direct link between Δ9-THC-induced changes in proenkephalin expression and susceptibility to opiate drugs, no studies have confirmed that this mechanism can be applied to psychostimulants (229).\n\nGenetic determinants of the ECBS and psychostimulant addiction\nIt is worth mentioning that not every subject who experiences the pleasurable effects of psychostimulants will become a chronic user. Indeed it is more likely that additional factors such as: (1) genetic variabilities (e.g., polymorphisms in the catechol O-methyltransferase gene (Val158met) and in the serotonin transporter gene (5-HTTLPR) (230, 231); (2) monoamine receptors deficiency – either genetically or as a result of their drug excesses – also contribute to the psychostimulants addiction process (232–235) (see Table 1). In the ECBS, different genetic variants of the CB1 receptors – CNR1 – and FAAH genes have been associated with increased susceptibility to drug addiction. Indeed, genetic analyses demonstrate that the CNR1 gene exhibits elevated numbers of (AAT)n triplet repetition in a sample of 192 non-Hispanic Caucasian subjects. Interestingly, this CNR1 polymorphism increases the risk of intravenous drug use in this population, with strongest correlation observed in cocaine, amphetamine, and marijuana dependence (236). Similarly, a study from Ballon and colleagues shows that detection of this CNR1 polymorphism in a sample of 142 African-Caribbean individuals predisposed them to cocaine addiction (237). Unfortunately, while single sequence repetitions can alter transcriptional rates and thereby induced gene overexpression or silencing (238), the functional nature of the microsatellite polymorphism triplet repetition (AAT)n in modulating CNR1 gene expression remains blurred (239). It has been hypothesized that the presence of long alleles with high numbers of AAT triplets alter CNR1 transcriptional gene expression, ultimately leading to low levels of CNR1 protein synthesis (240). A recent meta-analysis of 11 studies aimed at investigating the contribution of three CNR1 polymorphisms (rs1049353, rs806379, and the AAT triplet repetitions) to drug dependence vulnerability confirmed the presence of (AAT)n repeats, but only in the Caucasian population [reviewed in Ref. (239)]. Unfortunately, the effect of the three CNR1 polymorphisms appeared to be insignificant and showed high heterogeneity. Important caveats have to be considered when looking at these studies. First, the ethnicity of the different subjects may prove important, as some studies included several ethnic groups in their samples, and in some cases, these groups were not even mentioned (241, 242). Some reports also examined CNR1 gene polymorphisms in connection with a different phenotype or stage of drug addiction such as craving, drug consumption, dependence, or drug withdrawal (243). Furthermore, a detailed description of the repercussions of CNR1 polymorphisms on CB1 function from a neurobiological standpoint is lacking from the reviewed studies.\nTable 1 ECBS and factors contributing to vulnerability to psychostimulants in humans. Polymorphisms in the gene coding for the endocannabinoid-inactivating enzyme FAAH may constitute another risk factor for problematic drug use, as described by initial reports identifying C385A, a mis-sense single nucleotide polymorphism (SNP) causing reduced FAAH enzymatic activity (245, 246). Indeed, a study from Sipe et al. reveals significant association between C385A SNP and street drug abuse in a sample of 1737 Caucasian subjects with addictive disorders. Neuroimaging studies combined with genetic analysis reveal that low FAAH activity enhances AEA protein expression levels which, in turn, modulate brain regions implicated in drug addiction and reward circuitry such as the OFC, AC gyrus, and NAc (242). Additional neuroimaging studies show that C385A carriers exhibit increased ventral striatal reactivity – a correlate for heightened impulsivity and reward sensitivity. C385A carriers display low threat-related amygdala reactivity – a pattern observed in individuals with high familial risk of alcoholism. Moreover, C385A polymorphism-reduced FAAH functional activity increases risk-taking behavior associated with addiction through abnormal impulsivity and threat perception [reviewed in Ref. (224, 243)]. Contribution of SNPs that modulate FAAH functions to stimulant addiction remain to be explored as the aforementioned data were not obtained in individuals specifically addicted to stimulants.\n\nEffect of exogenous cannabinoids on psychostimulant reward\nAs mentioned previously (see The Endocannabinoid System), an intriguing characteristic of psychostimulants abuse is the concurrent consumption of cannabis. Parallel to studies on the long-term effects of cannabis exposure on subsequent psychostimulant use, researchers also examined the acute rewarding effects of cannabis use on concurrent psychostimulant addiction (91, 222). However, studies aimed at investigating such interactions are sparse. Conflicting results from Foltin et al. and Lukas et al. provide evidence that cannabinoids modulate cocaine-mediated euphoric actions. First, data from Foltin and colleagues show that human volunteers who smoked cannabis prior to intravenous cocaine experience a prolongation of the “high” sensation (248). Second, a study from Lukas and colleagues reveals that smoking Δ9-THC, 30 min prior to intranasal cocaine decreases the latency to onset of cocaine-induced euphoria significantly, from 1.87 to 0.53 min, as well as the duration of cocaine-induced dysphoria, from 2.1 to 0.5 min (249). Interestingly, when both drugs are administered concomitantly, no changes are observed in cocaine- and Δ9-THC-induced positive subjective properties. Furthermore, Δ9-THC increases the peak plasma levels and bioavailability of cocaine considerably. This increase might be the result of Δ9-THC-induced vasodilation of the nasal mucosa which, in turn, reduces cocaine-induced vasoconstriction, thereby increasing cocaine’s absorption. In addition, the discrepancies between these two studies might be also due to pharmacodynamic mechanisms including differences in cocaine absorption or in the ratio of CBD/Δ9-THC levels found in the type of cannabis used for each study.\nUsing fMRI technology combined with script-guided imagery paradigm in which subjects imagined being in a real-life stressful situation, Rajita Sinha’s group found that cannabis abuse contributed to stress-induced blood-oxygen-level-dependent (BOLD) contrast in a group of cocaine-dependent individuals. More specifically, cannabis consumption decreases emotional stress cue-induced frontal and cingulate activation in cocaine-dependent individuals (247). These findings suggest an abnormal cognitive control mechanism during affective processing in association with heavy cannabis use. An important caveat to consider in the latter study is that cocaine-dependent individuals were abstinent for several weeks prior to the neuroimagery session and were not current users of cannabis. Thus the study did not allow to examine the acute effect of cannabis on neural and behavioral responses. However, the fact that this cannabis-induced alteration in stress-response can be translated to cocaine craving and relapse vulnerability has definitely piqued further interest, and initial data on this matter already exists. Indeed, the effects of cannabis consumption on abstinence and relapse to cocaine use have been provided in a study from Labigalini and colleagues, in which 25 cocaine-crack dependent individuals reported to smoke cannabis in order to get relief from abstinence mediated-cocaine-withdrawal symptoms. From this sample, 68% of addicts achieved crack-cocaine cessation while using cannabis during the 9 months duration of the study (90). However, the self-reported nature of this study and its limited duration suggest cautiousness in interpreting its outcome. In a more recent study, Aharonovich et al. drew opposite conclusions on the consequences of smoking cannabis on cocaine relapse. In this study, researchers investigated whether cannabis use after the discharge of 144 drug-addicts from inpatient treatment program could help them to maintain abstinence and thereby preventing relapse to cocaine use. Results from this study suggest that smoking cannabis reduced the achievement of sustained remission and increased relapse to cocaine use (91) (see Table 1). Surprisingly, a study from Jutras-Aswad et al. supports the assumption that irregular cannabis use increases risky behaviors (syringe sharing) of cocaine and opioid users, as opposed to regular cannabis use, suggesting a complex dose-effect relationship between cannabis and addictive behaviors (22). The possibility that cannabis use by recently abstinent cocaine-dependent individuals influences relapse to drug and other related behaviors remains poorly documented.\n\nAnimal studies\nOver the last decades, development of animal models have allowed a better understanding of psychostimulant effects and addiction-related behaviors. These studies would not be available through clinical studies for ethical and practical reasons. Notably, invasive measures such as catheter installation for drug administration and surgical brain procedures for assessment of drug-induced neurobiological changes, as well as strictly controlled conditioning protocols involving restrictive environments, have extended the knowledge of psychostimulants effect on neurotransmission. These methods have also allowed observations of specific behavioral aspects of psychostimulant addiction. Thus, studies on animal models of psychostimulants abuse have provided tremendous insights on the role of ECBS in various aspects of psychostimulant addiction, spanning from drug reward, acquisition, and relapse.\n\nInfluence of ECBS on psychostimulants-induced behavioral and reinforcing effects\nAs mentioned above (see Neurobiology of Psychostimulants), substantial evidence indicates that behavioral and addictive properties of psychostimulants come from the interactions of psychostimulants with brain monoamines. Specifically, increase of extracellular levels of DA through promotion of DA release by amphetamine and MDMA, as well as inhibition of DA reuptake by cocaine, represent the primary mechanisms involved in rewarding effects mediated by psychostimulants (224). In animal models of intracranial self-stimulation (ICSS), the rewarding properties of drugs of abuse typically translate into lowering of the so-called reward threshold established after operant training [see Ref. (250) for description]. Initial experiments showed no effect of CB1 antagonist SR141716A on cocaine’s ability to lower ICSS threshold in rats (251), although careful data analysis suggests a tendency toward attenuation. However, different results were obtained when using a more potent antagonist – AM251. This antagonist proves CB1 blockade’s effectiveness in inhibiting cocaine’s action on brain stimulation reward (250). Paradoxically, the non-selective cannabinoid agonist – WIN55, 212-2 – and the endocannabinoid transmission enhancer – AM404 – are also able to abolish cocaine’s reinforcing effects as assessed by ICSS (252). Whether these apparently contradictory findings may indicate an inverse U-shape effect of CB1 stimulation function on rewarding properties of stimulants is not entirely clear. However, these results clearly indicate that cannabinoids might interfere with brain systems responsible for psychostimulants rewarding effects, and the mechanism underlying this phenomenon should be further explored.\nLi and colleagues recently found significant reductions in DA levels in striatum of mice lacking the CNR1 gene, when compared to their wildtype counterparts following acute cocaine administration and during the basal state (253). This observation shows consistency with above-cited ICSS studies and with a previous report on the inhibition of cocaine-induced DA release in rats by CB1 antagonist SR141716A (254). In contrast, initial findings suggested that neither basal levels nor cocaine-induced increases in extracellular NAc DA of CB1 knockout mice differed from that of normal mice (255), and that CB1 inactivation by antagonists AM251 and SR141716A failed to alter the increase in extracellular NAc DA responsible for cocaine-mediated rewarding effects in rats (256, 257). Differences in experimental methods used to measure DA levels (voltammetry vs. in vivo microdialysis) and in the genetic background of the knockout animals (C57BL/6J vs. CD1) could account for such discrepancies. Notably, compensatory neurobiological changes due to lack of CB1 receptors could explain the subnormal basal DA levels observed in Li et al. study. This subnormal basal DA levels could also have contributed to apparent attenuation of DA levels enhancement produced by cocaine. Overall, the extent to which ECBS interaction with psychostimulants-mediated reward effects depends on DA transmission seems limited, especially when CB1 is targeted. It remains a controversial issue, with subsequent reports of attenuation of cocaine-enhanced extracellular NAc DA activity by CB2 agonists JWH133 and GW405833 in mice (258), but not by the pharmacological FAAH inhibitor URB597 in rats (259) adding to the complexity of the matter (see Table 2).\nTable 2 Pharmacological inhibition of FAAH inhibition and properties of psychostimulants. The increase of DA neurotransmission in the NAc and other striatal regions responsible for psychostimulant-induced rewarding parallels the stimulation of locomotor activity following acute drug administration. Sensitization to hyperlocomotor responses produced by psychostimulants occurs after chronic treatment, reflecting adaptive changes in DA transmission and potentially correlating with drug-seeking and reinstatement behavior (254, 262). In various studies, neither genetic deletion (262–264) nor pharmacological inhibition of CB1 receptors by SR141716A (265, 266) altered cocaine’s ability to induce acute motor effects or behavioral sensitization in rats and mice. However, a comparable number of reports described contradictory results, showing attenuation of both of these outcomes in CB1 knockout mice (253, 267) (see Table 3) as well as impairment of sensitization in animals pretreated with SR141716A (254, 268) or AM251 (267). Interestingly, although chronic cocaine use still induced sensitization in mice with invalidated CB1 receptors, sensitized response appeared somewhat changed when compared to control animals. Corbille et al. also found that AM251, unlike SR141716A (269), only impaired sensitization to cocaine after a single exposure, but not upon repeated administration. Similar experiments with cannabinoid agonists showed mixed results, as non-selective WIN 55,212-2 reduced cocaine’s motor effects, probably in a non-CB1 mediated fashion (252, 270). Likewise, CB2 agonists JWH133 and GW405833 decreased both acute hyperlocomotion and sensitization in rats (258), which parallels findings observed in mice genetically overexpressing CB2 (271). Δ9-THC failed to alter cocaine’s motor effects in rats (268, 272). Similarly, cannabinoid-amphetamine interactions studies demonstrate that acute cannabinoid exposure antagonizes amphetamine’s locomotion effects in a dose-dependent manner in rats. On the other hand, chronic exposure to Δ9-THC induces sensitization to the psychomotor effects mediated by amphetamine in rats (273). Taken together, these experiments suggest that the acute motor stimulant effects of psychostimulant and the induction of cocaine sensitization may not depend on endocannabinoid tone, even though CB1 receptors could play a minor modulating role in this regard [reviewed in Ref. (274)].\nTable 3 Effects of CB1 cannabinoid receptor deletion and properties of psychostimulants; CB1 receptor antagonists and properties of psychostimulants. Overall, while some evidence of ECBS involvement in the neurobiological and behavioral correlates of psychostimulant reinforcing properties exists, influence of ECBS on acute psychostimulant reward is modest and probably involves a combination of mechanisms which may not directly involve DA activity in the NAc or CB1 receptors.\n\nInfluence of ECBS on acquisition and maintenance of psychostimulant-induced seeking behaviors\nModels of conditioning such as the SA paradigm and the conditioned place-preference (CPP) procedure illustrate the reinforcing properties of drugs of abuse and demonstrate their ability to induce and maintain drug-seeking behaviors. Consistent with findings showing the limited involvement of the ECBS in the reinforcing properties of psychostimulants (see Influence of ECBS on Psychostimulants-Induced Behavioral and Reinforcing Effects), modulation of the ECBS appears to have a modest influence on acquisition and maintenance of psychostimulant-taking behavior in animals. In CPP experiments, while CB1 receptor deletion did not affect psychostimulant-induced place conditioning in mice, SR141716A impaired cocaine-, methamphetamine-, and MDMA-induced place conditioning in both rats and mice (262–265, 281, 286, 287). Difference in species, compensatory changes in the knockout animals due to the lack of CB1 receptors, as well as use of more intense conditioning and higher doses of drugs in the genetic deletion studies may have contributed to this discrepancy. This suggests that intensity of conditioning could overcome the effects of blocking ECBS signaling [reviewed in Ref. (274)]. It is important to note that the weaker cannabinoid antagonist CBD did not affect establishment of amphetamine-induced CPP in rats (290) and that the genetic overexpression of cannabinoid receptor CB2 impaired acquisition of both cocaine-induced CPP and SA (271). Thus the CPP model indicates that, although not directly interfering with the rewarding properties of psychostimulant drugs, ECBS could play a role in the perception and memory of psychostimulant reward, depending on environment-related factors.\nIn general, CB1 receptor invalidation does not seem to affect SA of psychostimulants. Experiments with genetic deletion of CB1 show conflicting results, as both knockout and SR141716A-treated mice still acquired amphetamine- and cocaine-taking behavior in restrained mobility conditions (266, 275), whereas knockout mice showed impaired SA behavior in other protocols (255, 258). Overall, results suggest that learning SA behavior might not require extensive ECBS involvement. Maintenance of such behavior may not depend on CB1 either, as drug-taking responses under a fixed-ratio schedule in animals that had already acquired cocaine SA remained unaffected after CB1 blockade by SR141716A in mice (266, 283), monkeys (280), and rats (250, 256, 269, 283) and by AM251 in rats (250, 277). Only one contradicting report exists in which AM251 decreased methamphetamine SA in conditioned rats (278). Cannabinoid signaling enhancement by the pharmacological FAAH inhibitors – URB597 and PMSF – also failed to affect maintenance of fixed-ratio drug-taking behavior in rats (261) and monkeys (260). On the other hand, cannabinoid stimulation by CB1 agonists had significant effects in several studies. Indeed, WIN 55,212-2 increased acquisition of MDMA SA in mice (286) and exposure to CP55,940 enhances development of cocaine SA in female rats (291). THC failed to alter acquisition of cocaine SA and amphetamine SA in monkeys (272) and rats (290), respectively. In regard to maintenance of drug intake in animals with SA behavior, cannabinoid agonists decreased drug-taking responses in rats – CP55,940 diminished MDMA intake (288) and WIN55,212-2 decreased cocaine administration (292) – and in monkeys – Δ9-THC also decreased cocaine intake (272). Fattore et al. first interpreted the shift in psychostimulant intake produced by CB1 agonists as indicative of a synergistic action of CB1 stimulation on reinforcing properties of the drugs, which, incidentally, could account for the frequent use of cannabis among human psychostimulants users (292). Complementary experiments using progressive-ratio schedules also reveal interaction of CB1 receptors with psychostimulant-induced reinforcing properties. In PR schedules, both genetic deletion and antagonist treatment of CB1 receptors produce a decrease in the maximal effort mice provided to self-administer cocaine, as made apparent by decreases in breaking point measures induced by SR141716A (255, 277, 284) and by AM251 (250) (SR141716A producing no effect in this specific report). This adds to the evidence that the CB1 receptors, while not indispensable for acquisition or maintenance of cocaine-seeking behavior, may exert a specific modulation on motivation and reward salience in psychostimulant addiction.\n\nRole of ECBS in extinction and reinstatement of drug-taking behaviors\nAlthough the mechanism used by endocannabinoid signaling to modulate psychostimulant reward and acquisition or maintenance is still the subject of debate, some form of consensus exists in the literature about the pivotal role of the ECBS in extinction and reinstatement in animal behavioral models of psychostimulant addiction [reviewed in Refs. (89) and (274)]. In conditioning procedures, extinction refers to the learning phase that follows the removal of the reinforcer (i.e., psychostimulant drugs), during which rates of conditioned responses (i.e., SA or CPP) progressively decline back to pre-conditioning levels. After drug-seeking behavior becomes extinct, several behavioral phenomena can reinstate drug-seeking behavior. These include not only re-exposure to the abused drug itself, but also exposure to contextual cues associated with previous drug administration and to environmental stressors (274, 293).\nIn a recent study from Ward et al. mice treated with SR141716 after removal of cocaine in a SA paradigm altered the burst in cocaine-seeking observed in the initial phase of extinction learning, while decreasing the time required to achieve complete extinction of cocaine-seeking behavior when compared to vehicle-treated mice (282). CB1 blockade by SR141716A also significantly decreases cue-induced reinstatement of cocaine SA behavior following extinction, supporting similar reports of attenuation of cue-induced reinstatement of cocaine-seeking by CB1 antagonism in rats (269, 277, 283). Evaluation of reinstatement of SA behavior induced by drug-priming produced similar results: SR141716A blocks cocaine-induced reinstatement (269, 283), and both AM251 (257, 277) and SR141716A inhibit methamphetamine-induced reinstatement (289). It is worth noting that CB2 antagonism also has an anti-reinstatement effect in cocaine-primed, but not in cue-exposed rats (277). In CPP models, CB1 blockade by SR141716A, but not by AM251 (276), impaired drug-induced reinstatement in cocaine-conditioned mice (281). SR141716A also impaired methamphetamine-induced reinstatement of CPP (281). Few studies focused on stress-induced reinstatement of psychostimulant-seeking. Vaughn et al. recently found that AM251 reverses stress-induced CPP (276). De Vries et al. could not find an impact of SR141716A on stress-induced SA reinstatement (283).\nStimulation of CB1 receptors produced opposite results to those obtained in pharmacological blockade experiments (see Table 4). WIN55,212-2 increases time for extinction of CPP and enhances drug-induced reinstatement in MDMA-conditioned mice (285, 286). Similarly, Δ9-THC increases cue-induced reinstatement of methamphetamine SA in rats (289). However, studies from Parker et al. and Adamczyk et al. complexify the interpretation of these results (290). Indeed, Adamczyk’s group showed that FAAH inhibition impairs cue- and drug-induced reinstatement of cocaine SA. Using the place-preference conditioning paradigm, Parker et al. have assessed the potential of both exogenous cannabinoids – Δ9-THC and CBD – to potentiate the extinction of cocaine- and amphetamine-induced CPP (290). After the establishment of cocaine-induced and amphetamine-induced place preference, rats were given an extinction trial, 30 min prior to which they were injected with a low dose of Δ9-THC, CBD, or vehicle. During conditioning trials, researchers also injected rats with cannabinoids, or vehicle, prior to an amphetamine injection, to determine the effects of Δ9-THC or CBD on the establishment and expression of a place preference. Results indicate that Δ9-THC and CBD potentiate the extinction of stimulant-CPP learning, which is not mediated by an alteration of learning or retrieval. CBD does not have a reinforcing or hedonic property on its own, suggesting that it does not have the addictive potential of Δ9-THC, a significant advantage in terms of therapeutic use. The non-reinforcing aspect of CBD has been replicated in studies looking at the co-administration of CBD and Δ9-THC (212, 294). These discrepancies probably result from the lack of receptor selectivity in the methods used to enhanced cannabinoid signaling. Nonetheless, these experiments support a significant involvement of ECBS in the extinction and reinstatement of behaviors related to psychostimulant addiction. Overall, the positive results of CB1 antagonists on extinction and prevention of reinstatement of psychostimulant SA, combined with their lack of reinforcing properties, suggest a therapeutic potential for CB1 modulation in treatment of psychostimulant addiction.\nTable 4 CB1 receptor agonists and properties of psychostimulants.\n\nCon"}