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The inability to maintain drug abstinence is often referred to as relapse and consists of a process by which an abstaining individual slips back into old behavioral patterns and substance use. Animal models of relapse have been developed over the last decades and significantly contributed to shed light on the neurobiological mechanisms underlying vulnerability to relapse. The most common procedure to study drug-seeking and relapse-like behavior in animals is the "extinction-reinstatement model." Originally elaborated by Pavlov and Skinner, the concepts of reinforced operant responding were applied to addiction research not before 1971 (Stretch et al., Can J Physiol Pharmacol 49:581-589, 1971), and the first report of a reinstatement animal model as it is now used worldwide was published only 10 years later (De Wit and Stewart, Psychopharmacology 75:134-143, 1981). According to the proposed model, opioids are typically self-administered intravenously, as humans do, and although rodents are most often employed in these studies, a variety of species including nonhuman primates, dogs, cats, and pigeons can be used. Several operant responses are available, depending on the species studied. For example, a lever press or a nose poke response typically is used for rodents, whereas a panel press response typically is used for nonhuman primates. In this chapter we describe a simple and easily reproducible protocol of heroin-seeking reinstatement in rats, which proved useful to study the neurobiological mechanisms underlying relapse to heroin and vulnerability factors enhancing the resumption of heroin-seeking behavior.

BACKGROUND AND PURPOSE Methoxetamine (MXE) is a novel psychoactive substance that is emerging on the Internet and induces dissociative effects and acute toxicity. Yet, its pharmacological effects are still poorly investigated. EXPERIMENTAL APPROACH We examined a range of behavioural effects induced by acute intraperitoneal administration of MXE (0.5-5 mg/kg) in rats, and whether it causes rapid neuroadaptive molecular changes. KEY RESULTS MXE (0.5-5 mg/kg) significantly affected motor activity in a dose- and time-dependent manner, inducing hypermotility and hypomotility at low and high doses, respectively. At low/intermediate doses (0.5 and 1 mg/kg) MXE induced anxious and/or obsessive-compulsive traits (marble burying test), slightly (but not significantly) increased sociability (social interaction test) but did not induce spatial anxiety (elevated plus maze test). At a high dose (5 mg/kg), MXE induced transient analgesia (tail flick and hot plate test), significantly decreased social interaction time (social interaction test) and significantly reduced immobility time while increasing swimming activity (forced swim test), suggesting an antidepressant effect. Acute MXE administration did not affect self-grooming behaviour at any dose tested. Immunohistochemistry analysis showed that behaviourally active doses of MXE (1 and 5 mg/kg) increased the phosphorylation of ribosomal protein S6 (rpS6) in the medial prefrontal cortex and hippocampus. CONCLUSIONS AND IMPLICATIONS Findings indicate that MXE differentially affects motor activity, behaviour and emotional states in rats depending on the dose tested. As recently reported for ketamine, rpS6 phosphorylation was increased in MXE-treated animals thus providing a ‘molecular snapshot’ of rapid neuroadaptive molecular changes induced by behaviourally active doses of MXE.

Dopamine agonists have been proposed as therapeutic tools for cocaine addiction. We have recently demonstrated that indirect dopamine agonists, including levodopa (L-DOPA), markedly increase cocaine-induced dopamine release in the medial prefrontal cortex (mPFC) of rats leading to the suppression of cocaine-seeking behavior. This study was aimed to understand the behavioral and neurochemical effects of L-DOPA on cocaine-taking and cocaine-seeking in rats. After reaching a stable pattern of intravenous cocaine self-administration under a continuous fixed ratio (FR-1) schedule of reinforcement, male rats were treated with L-DOPA at different steps of the self-administration protocol. We found that L-DOPA reduced cocaine self-administration under FR-1 schedule of reinforcement and decreased the breaking points and the amount of cocaine self-administered under the progressive ratio schedule of reinforcement. Levodopa also decreased cocaine-seeking behavior both in a saline substitution test and in the cue priming-induced reinstatement test, without affecting general motor activity. Importantly, L-DOPA greatly potentiated cocaine-induced dopamine release in the mPFC of self-administering rats while reducing their cocaine intake. In the same brain area, L-DOPA also increased dopamine levels during cue priming-induced reinstatement of cocaine-seeking behavior. The potentiating effect was also evident in the mPFC but not nucleus accumbens core of drug-naive rats passively administered with cocaine. Altogether, these findings demonstrate that L-DOPA efficaciously reduces the reinforcing and motivational effects of cocaine likely potentiating dopamine transmission in the mPFC. Its ability to prevent cue priming-induced reinstatement of cocaine-seeking suggests that it might be effective in reducing the risk to relapse to cocaine in abstinent patients.

Men and women affected by schizophrenia display different age of onset, symptom profile and course of the disease. Similarly, men and women differ in the prevalence and frequency of drug use, pattern and reasons of use, and vulnerability to develop drug addiction. An understanding of the role of sex in modulating brain processes and behavior in patients with substance use disorder and/or schizophrenia-like symptoms has broad implications for gender-tailored treatment approaches. Cognizant of the considerable recent evidence for sex and gender differences in drug addiction and schizophrenia, we focused this review on the sex-dependent differences in drug-induced psychosis and on factors that may contribute to such male–female differences.

Sex differences in inhibition and self-regulation at a behavioral level have been widely described. From an evolutionary point of view, the different selection pressures placed on male and female hominids led them to differ in their behavioral strategies that allowed our species to survive during natural selection processes. These differences reflect changes in neural and structural plasticity that might be the core of sex differences, and of the susceptibility towards one psychiatric condition rather than another. The goal of the present review is to summarize current evidence for such a dichotomy in impulsive and compulsive behavior with a focus on drug addiction. Sex-dependent differences in drug abuse and dependence will be examined in the context of pathophysiological regulation of impulse and motivation by neuromodulators (i.e. gonadal hormones) and neurotransmitters (i.e. dopamine). Advances in the understanding of the sex differences in the capability to control impulses and motivational states is key for the determination of efficacious biologically based intervention and prevention strategies for several neuropsychiatric disorders where loss of impulse control and compulsivity are the core symptoms.

Different tastes elicit integrative functions of the central nervous system that provide a complex sensation generally associated with gustation. Eating a new food is the result of interplay of concurrent factors orchestrated by physiological and environmental elements. Taste novelty is able to regulate learning and to promote the environmental adaptation of different animal species and human beings. A corollary of events spins around taste novelty such as reactivity, neophobia, habituation, and predictivity. Intriguingly, dopamine (DA) transmission regulates many aspects of these events. Several methodological approaches show that salient stimuli affect DA transmission in different terminal areas (e.g., medial prefrontal cortex and nucleus accumbens) concurrently to behavioral adaptations related to general arousal, approach, or avoidance of a taste stimulus. The involvement of DAergic terminal areas in the detection of taste novelty is confirmed by the activation of specific molecular markers. Notably, the DA response to taste novelty is connected with some aspects of psychiatric disorders.

As part of an increasing worldwide use of designer drugs, recent use of compounds containing cathinones and synthetic cannabinoids is especially prevalent. Here, we reviewed current literature on the prevalence, epidemiology, bio-behavioral effects, and detection of these compounds. Gender differences and clinical effects will also be examined. Chronic use of synthetic cathinone compounds can have major effects on the central nervous system and can induce acute psychosis, hypomania, paranoid ideation, and delusions, similar to the effects of other better-known amphetamine-type stimulants. Synthetic cannabinoid products have effects that are somewhat similar to those of natural cannabis but more potent and long-lasting than THC. Some of these compounds are potent and dangerous, having been linked to psychosis, mania, and suicidal ideation. Novel compounds are developed rapidly and new screening techniques are needed to detect them as well as a rigorous regulation and legislation reinforcement to prevent their distribution and use. Given the rapid increase in the use of synthetic cathinones and cannabinoid designer drugs, their potential for dependence and abuse, and harmful medical and psychiatric effects, there is a need for research and education in the areas of prevention and treatment.

Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial “psychedelic effect,” which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy. Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories. We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition. Metaplasticity may be the process in common between cannabinoids and ketamine/ketamine-like substance effects on the mediation and potential manipulation of maladaptive memories.

Previous investigations indicate that the dopamine-β-hydroxylase (DBH) inhibitors disulfiram and nepicastat suppress cocaine-primed reinstatement of cocaine self-administration behaviour. Moreover, both inhibitors increase dopamine release in the rat medial prefrontal cortex (mPFC) and markedly potentiate cocaine-induced dopamine release in this region. This study was aimed to clarify if the suppressant effect of DBH inhibitors on cocaine reinstatement was mediated by the high extracellular dopamine in the rat mPFC leading to a supra-maximal stimulation of D1 receptors in the dorsal division of mPFC, an area critical for reinstatement of cocaine-seeking behaviour. In line with previous microdialysis studies in drug-naive animals, both DBH inhibitors potentiated cocaine-induced dopamine release in the mPFC, in the same animals in which they also suppressed reinstatement of cocaine seeking. Similar to the DBH inhibitors, L-DOPA potentiated cocaine-induced dopamine release in the mPFC and suppressed cocaine-induced reinstatement of cocaine-seeking behaviour. The bilateral microinfusion of the D1 receptor antagonist SCH 23390 into the dorsal mPFC not only prevented cocaine-induced reinstatement of cocaine seeking but also reverted both disulfiram- and L-DOPA-induced suppression of reinstatement. Moreover, the bilateral microinfusion of the D1 receptor agonist chloro-APB (SKF 82958) into the dorsal mPFC markedly attenuated cocaine-induced reinstatement of cocaine seeking. These results suggest that stimulation of D1 receptors in the dorsal mPFC plays a crucial role in cocaine-induced reinstatement of cocaine seeking, whereas the suppressant effect of DBH inhibitors and L-DOPA on drug-induced reinstatement is mediated by a supra-maximal stimulation of D1 receptors leading to their inactivation.

Cannabis is the world's most widely used illicit substance, with an estimated number of 119-224 million users worldwide. In recent years we assisted to an increased effort aimed to individuate the brain circuits underlying cannabis addiction and dependence. Similarly to other drugs of abuse, repeated exposure to cannabinoids causes brain neuroadaptations that persist long after drug effects, contribute to the negative affective states during withdrawal, and ultimately facilitate relapse. Recently, considerable progress has been made in understanding the cellular and molecular consequences of prolonged cannabis use, among which is the identification of specific set of transcriptional regulations that develop differently after chronic cannabinoids and in the abstinent brain.

The Editorial on the Research Topic Exploring Gender and Sex Differences in Behavioral Dyscontrol: From Drug Addiction to Impulse Control Disorders This Research Topic gathers animal and human research articles, reviews, and opinion articles on current research in the field of sex and gender differences in behavioral addictions, which are complex disorders with interacting factors, including environmental factors, comorbidity, and personality traits (1, 2). Research in this field adds to the long-held argument that male and female brains do differ. However, while evidence exists on how male and female brains functionally differ (3–5), conflicting findings suggest that human brains cannot be narrowly classified into sexes/genders (6). Over the past decade, there have been major advances in our understanding of sex and gender differences in behavioral addictions and underlying motivations (7, 8), brain reward processes (9), and impulsive behaviors (10). Potential factors, which could provide a neurobiological basis for sex- and gender-based differences in behavioral addictions, have been identified. Among them, there are organizational and activational effects of gonadal hormones, socio-cultural factors, different impulse-control ability, and responsiveness to stress (11, 12). It is important to note that, although often used as synonymous, the terms “sex” and “gender” are not interchangeable. In fact, the term “sex” is referred to biological attributes and characteristics associated with the adjectives “male” and “female” (i.e., anatomy and physiology inherent male-female differences), while “gender” concerns sociocultural distinctions between males and females (i.e., culture-related dogmas and roles, behaviors embraced by men and women that shape their daily life and activities). In this Research Topic, basic researchers and clinicians that are leading experts in the field provide original findings and overviews on the role of sex and gender in modulating addictive behaviors and developing behavioral addictions. First, sex and gender differences in addiction to cannabis, methamphetamine, cocaine, and alcohol are discussed. Rubino and Parolaro systematically reviewed human and animal studies showing how males and females respond differently to cannabinoid compounds. In particular, dichotomy in the pharmacokinetics of THC observed in males and females may contribute to their dissimilar responses to cannabinoids. The role of sexual dimorphism in the brain endocannabinoid system and its interaction with gonadal hormones may also play a part (13–18). Accordingly, Ruda-Kucerova et al. presented evidence that sex-dependent differences exist in the reinstatement of methamphetamine-seeking behavior in abstinent rats. Notably, females displayed higher vulnerability to relapse to methamphetamine seeking independently of the current estrous cycle phase, thus suggesting that central mechanisms responsible for the enhanced response displayed by females are not affected by circulating ovarian hormones. In humans, sex and gender differences are reported in psychiatric comorbidity and plasma biomarkers in abstinent cocaine addicts and in behavioral impulsivity in heavy alcohol drinkers. Specifically, Pedraz et al. demonstrated that cocaine addicted men and women differ with regard to the levels of plasma biomarkers for cocaine addiction. Notably, while men exhibit a higher incidence of substances use comorbidity (e.g., alcohol), cocaine addicted women display a higher prevalence of comorbid psychiatric disorders (e.g., anxiety). In addition, Weafer et al. demonstrated that heavy alcohol female drinkers show poorer inhibitory control than male drinkers do, although it remains to be determined whether the reported higher behavioral impulsivity in women is the cause or the consequence of heavy drinking. That behavioral control is impacted by sex and gender is further supported by evidence compellingly reviewed by Carroll and Smethells revealing sex- and gender-dependent differences in impulsivity, food, and drug addiction. Importantly, authors discussed pharmacological and behavioral treatments for improving control of impulses in a sex-tailored manner, an approach also suggested for drug and behavioral addictions (19, 20). Among behavioral addictions, sexual addiction (often referred to as compulsive sexual behavior) is discussed by Weinstein et al. who found that men are more likely to use cybersex and experience craving for pornography than women. Importantly, both craving for pornography and frequency of cybersex were associated with difficulty in forming intimate relationship. In another clinical setting, Davis et al. used a moderator-mediation model to perform an elegant analysis of personality risk-factors and sex in moderating the relationship between ADHD symptomatology and addictive behaviors. According to their observations, no sex differences in personality risk for addiction or in the use of addictive behaviors were found in ADHD patients. A positive affective neuroendocrinology (PANE) approach to study the mechanisms of reward motivation and dysregulation is herein proposed by Welker et al., which investigated sources of potential sex differences in the hormonal mechanisms of behavioral dyscontrol. Finally, Mitchell and Potenza highlighted the importance of investigating the relationship between sexual hormones and impulsivity traits to disentangle sex and gender differences in impulse control and behavioral addictions. Equally, Mendrek et al. emphasize the need of considering sex and gender in neuroscience by focusing on psychiatric disorders, such as schizophrenia and drug addiction, where research on such differences is still in its infancy. We wish to thank all the Authors of this Research Topic for presenting and discussing their work and sharing their personal expertise and opinions on this emerging field. Moreover, we express gratitude to all reviewers that found time in their busy schedules to provide us with useful and constructive comments. We feel that research on factors and mechanisms allowing for the pursuit of drug and non-drug rewards is essential to deliver innovative gender-tailored treatments and to develop preventive strategies that may efficiently reduce in men and women the risk of becoming addicted to a substance or an activity. Improving our knowledge on sex and gender differences in drug addiction and reward processing will remarkably have therapeutic implications and help the development of sex-tailored, gender-sensitive treatment interventions. Some evidence has been already provided. In fact, pharmacological treatments differently affect male and female addicts. That is, the long-acting injectable form of naltrexone was found to be efficacious for males but not for females (21). This finding was further supported by the observation that oral naltrexone lacked efficacy relative to placebo in alcoholic women (22). Conversely, a 16-week course of fluoxetine initiated 8 weeks pre-quit cigarette smoking (“sequential” fluoxetine) reduced pre-quit depressive symptoms, withdrawal-relevant negative affect, and craving to smoke during a pre-quit period only in women (23). These and similar studies confirmed the importance of considering gender when examining treatment efficacy, and highlight the timeliness of this Research Topic.

Binge eating disorder (BED) is characterized by uncontrolled consumption of a large amount of food in a brief period of time. A large body of evidence has shown that BED can be a chronic condition associated with elevated psychiatric comorbidity, including depression and anxiety, and compulsive behavior. In this study we used an animal model of BED in which binge eating behavior was induced in female rats by providing limited access to high fat diet (margarine) to investigate the emotional traits of bingeing animals before and after the binge-like consumption of margarine. Using the plus maze test to disclose a potential anxious phenotype, we found that bingeing rats are much more anxious before the access to margarine, and that this condition is significantly reduced after its consumption. Conversely, no difference was detected between bingeing rats in the marble burying test before and after access to margarine. Yet, the number of marbles buried by bingeing rats before margarine consumption was significantly higher than control groups thus suggesting a compulsive-like trait. In the forced swimming test, bingeing rats showed a decrease in depression-like behavior after the consumption of margarine. Altogether, our findings demonstrate the occurrence of an altered emotional state in female rats showing binge eating behavior.

Drug addiction is a compulsive behavioral abnormality. In spite of pharmacological treatments and psychosocial support to reduce or eliminate drug intake, addiction tends to persist over time. Preclinical and human observations have converged on the hypothesis that addiction represents the pathological deterioration of neural processes that normally serve affective and cognitive functioning. The major elements of persistent compulsive drug use are hypothesized to be structural, cellular and molecular that underlie enduring changes in several forebrain circuits that receive input from midbrain dopamine neurons and are involved in affective (e.g. ventral striatum) and cognitive (e.g. prefrontal cortex) mechanisms. Here we review recent progress in identifying crucial elements useful to understand the pathophysiology of the disease and its treatments. Manipulation of neuropeptides brain systems and pharmacological targeting of κ-opioid receptors and/or drug metabolism may hold beneficial effects at affective and cognitive level. Non-pharmacological, highly innovative approaches such as Transcranial Magnetic Stimulation may reveal unsuspected potential and promise to be the first neurobiology-based therapeutics in addiction.

BACKGROUND AND PURPOSE Opioids and cannabinoids interact in drug addiction and relapse. We investigated the effect of the opioid receptor antagonist naloxone and/or the cannabinoid CB1 receptor antagonist rimonabant on cannabinoid-induced reinstatement of heroin seeking and on cannabinoid substitution in heroin-abstinent rats.

Females typically show greater behavioural responses to stimulant drugs than males, including loss of appetite; as seen, for example, in those who use methylphenidate (MP) therapeutically for treatment of attention deficit hyperactivity disorder (ADHD). This is a relevant issue because of the strong link between ADHD and obesity. In a sample (n=132) of normal-weight (BMI25) and obese (BMI30) men and women we assessed appetite, cravings, and snack-food intake in response to MP (0.5 mg/kg) and placebo. Results indicated a significant three-way interaction for the three dependent variables--food-related responding diminishing in all groups from placebo to MP, except in obese males who showed no decreases to the MP challenge. These data show for the first time the existence of gender differences in the appetite response to MP, and are relevant for finding a dopamine pathway to new weight-loss medications, which would be utilized differently in males than in females.

In humans as in animals, males and females are dissimilar in their genetic and hormonally driven behaviour; they process information differently, perceive experience and emotions in different ways, display diverse attitudes, language and social skills, and show sex-related differences in the brain anatomy and organization. Drug addiction is a widespread relapsing illness that affects both men and women. Sex-dependent differences have been frequently observed in the biological and behavioural effects of substances of abuse, including cannabis. Beside sex differences observed in the cannabinoid-induced effects related to cannabis abuse and dependence, cannabinoids have been shown to exert sex-dependent effects also in other physiological and behavioural aspects, such as food intake and energy balance (more evident in males), or anxiety and depression (more evident in females). Research has just begun to identify factors which could provide a neurobiological basis for gender-based differences in cannabinoid effects, among which, gonadal hormones seem to play a crucial role. Yet, cannabinoid pharmacodynamic and pharmacokinetic may also be important, as sex differences in cannabinoid effects might be due, at least in part, to differences in muscle mass and fat tissue distribution between males and females. Here, we will review both clinical and laboratory-based research evidence revealing important sex-related differences in cannabinoid effects, and put forward some suggestions for future studies to fill the gap in our knowledge of gender-specific bias in cannabinoid pharmacology. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x

Background and purpose: Animal and human studies have shown that sex and hormones are key factors in modulating addiction. Previously, we have demonstrated that self-administration of the cannabinoid CB1 receptor agonist WIN55,212-2 (WIN; 12.5 µg·kg−1 per infusion) is dependent on sex, intact female rats being more sensitive than males to the reinforcing properties of cannabinoids, and on the oestrous cycle, ovariectomized (OVX) females being less responsive than intact females. Experimental approach: This follow-up study investigated whether sex and ovarian function also affect reinstatement of cannabinoid-seeking in rats after exposure to drug or cue priming. Key results: After priming with 0.15 or 0.3 mg·kg−1 WIN, intact female rats exhibited stronger reinstatement than males and OVX females. Responses of intact female rats were higher than those of male and OVX rats even after priming with a drug-associated visual (Light) or auditory (Tone) cue, or a WIN + Light combination. However, latency to the first response did not differ between intact and OVX female rats, and males showed the longest latency to initiate lever-pressing activity. Conclusions and implications: Our study provides compelling evidence for a pivotal role of sex and the oestrous cycle in modulating cannabinoid-seeking, with ovariectomy diminishing drug and cue-induced reinstatement. However, it is possible that sex differences during self-administration training are responsible for sex differences in reinstatement. Finding that not only drug primings but also acute exposure to drug-associated cues can reinstate responding in rats could have significant implications for the development of pharmacological and behavioural treatments of abstinent female and male marijuana smokers. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x

Many studies have provided evidence for important sex-dependent differences in the origins, outcomes and treatment of drug abuse and dependence. Preclinical studies typically have employed animal models of addiction, such as oral or intravenous self-administration, to untangle the environmental, neurobiological and genetic factors that contribute to the shift from occasional, recreational use to compulsive, uncontrolled intake of drugs. Craving and relapse of drug seeking in abstinent individuals have also been found to differ between men and women. Identification of the neurobiological basis of craving and drug dependence continues to pose a challenge to addiction research. Significant sex differences are emerging in substance-abuse-related behavior, which has increased the demand for research on how drug consumption may have different causes, progression and consequences in men and women. In keeping with epidemiological data in humans, differences between the two sexes in drug seeking and intake have been well-documented in animal studies, with most recent findings related to abuse of cannabinoids. Clinical and preclinical findings indicate that sex and gonadal hormones may account for individual differences in susceptibility to the reinforcing effects of addictive substances, and that differences in vulnerability to drug abuse may be mediated by the same biological mechanisms. This review focuses on the differences between males and females in relation to drug self-administration and how such behavior may be affected by hormonal status.

The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for, respectively, rapid vs extremely poor acquisition of avoidant behavior in a shuttlebox has produced two phenotypes that differ in temperament traits, in mesocortical/mesolimbic dopamine system function, and in the behavioral and neurochemical responses to the acute and repeated administration of psychostimulants and opiates. The phenotypic traits of the RHA line predict higher susceptibility, compared with RLA rats, to the reinforcing properties of addictive substances like cocaine. The present study was designed to compare the acquisition, maintenance, reinstatement of drug-seeking after long-term extinction, and reacquisition of intravenous cocaine self-administration (SA) behavior in the Roman lines. Compared with RLA rats, the rates of responding during cocaine SA acquisition were higher, extinction from cocaine SA was prolonged, and drug-induced reinstatement of cocaine-seeking behavior was more robust in RHA rats. Moreover, only RHA rats reacquired extinguished lever-pressing activity when a low reinforcing dose of cocaine was available. These findings are consistent with the view that subjects with genetically determined high responsiveness to the acute and chronic (ie, sensitizing) effects of psychostimulants, such as RHA rats, also display a higher propensity to self -administer cocaine. Further comparative studies in the Roman lines, using SA paradigms that distinguish mere drug-taking from the compulsive and uncontrolled drug use that characterizes addiction in humans, may eventually help to characterize the relationships among genotype, temperament traits, and neurobiological mechanisms involved in the individual vulnerability to cocaine addiction.

Background and purpose: We recently demonstrated the existence of strain differences in self-administration of the cannabinoid CB1 receptor agonist WIN55,212-2 (WIN) by Long Evans (LE) and Lister Hooded (LH) but not Sprague-Dawley (SD) male rats. This follow-up study is aimed at verifying whether sex and ovarian hormones might also be critical factors in the initiation, retention and extinction of WIN self-administration. Experimental approach: LE, LH and SD male and female rats, the latter either intact or bilaterally ovariectomized (OVX), were trained to self-administer WIN (12.5 μg kg−1 per infusion) under a FR1 reinforcement schedule, using lever-pressing. Key results: Data showed that contrary to the findings in SD rats, LE and LH rats developed robust cannabinoid intake, with rates of responding for WIN being constantly higher in intact females than in males (+45 and +42% for LE and LH strains, respectively). In comparison with intact females, OVX females of both strains acquired self-administration at lower rates, displaying slower acquisition, lower drug intake (−42 and −52% for LE and LH, respectively) and longer extinction. Conclusions and implications: These findings provide the first evidence of significant sex differences in cannabinoid self-administration, females acquiring stable WIN intake at higher rates and more rapidly than males. Moreover, when compared to intact females, a lower percentage of LE and LH OVX rats acquired and maintained stable drug intake, suggesting that ovarian hormones might represent a critical factor in modulating the reinforcing effect of cannabinoids. British Journal of Pharmacology (2007) 152, 795–804; doi:10.1038/sj.bjp.0707465; published online 24 September 2007

Opiate addiction is a chronic relapsing disorder characterized by high rates of relapse. The gamma-aminobutyric acid GABA(B) receptor agonist baclofen is known to affect the reinforcing effects of several drugs of abuse, including heroin, as well as to decrease cue-maintained responding for heroin, cocaine and nicotine and suppress alcohol deprivation effect in rats. Here we studied the effect of baclofen on the reinstatement of extinguished heroin-seeking behavior triggered by a priming injection of heroin in abstinent rats trained to stably self-administer heroin (30 microg/kg per infusion) under a continuous reinforcement schedule. Following extinction, the effect of non-contingent non-reinforced primings with heroin, baclofen or heroin/baclofen combination on the resumption of responding was evaluated. Results indicate that heroin priming (0.25mg/kg) promptly reinitiated heroin-seeking behavior, an effect dose-dependently reduced by baclofen at doses (0.625 and 1.25mg/kg) not affecting responding per sè. Importantly, baclofen did not affect locomotion either alone or in combination with heroin, dispelling any doubt as to the eliciting of possible non-specific (motor) effects. The present results show that GABA(B) receptor activation may reduce the propensity to resume drug-induced heroin-seeking behavior thus offering a possible approach in maintaining opiate abstinence.

This study examines the effect of intravenous self-administration (SA) of either heroin or the cannabinoid receptor agonist WIN 55,212-2 on levels and functionality of mu-opioid (MOR) and CB1-cannabinoid receptors (CB1R) in reward-related brain areas, such as the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CP), hippocampus (Hippo), amygdala (Amy), hypothalamus (Hypo) and ventral tegmental area (VTA). [3H]DAMGO and [3H]CP-55,940 autoradiography and agonist-stimulated [35S]GTPgammaS binding were performed on brain sections of rats firmly self-administering heroin or WIN 55,212-2. Animals failing to acquire heroin or cannabinoid SA behaviour as well as drug-naïve animals never exposed to experimental apparatus or procedure (home-control group) were used as controls. With respect to control groups, which displayed very similar values, rats SA heroin showed increased MOR binding in the NAc (+174%), CP (+165%), Hippo (+121%), VTA (+175%), an enhanced CB1R density localized in the Amy (+147%) and VTA (+37%), and a widespread increased CB1 receptor functionality in the PFC (+95%), NAc (+313%), CP (+265%), Hippo (+38%), Amy (+221%). In turn, cannabinoid SA differently modulates CB1R binding in the Amy (+47%), Hypo (+94%), Hippo (-23%), VTA (-15%), and increases MOR levels (PFC: +124%; NAc: +68%; CP: +80%; Hippo: +73%; Amy: +99%) and efficiency (Hippo: +518%; Amy: +173%; Hypo: +188%). These findings suggest that voluntary chronic intake of opioids or cannabinoids induces reciprocal but differential regulation of MORs and CB1Rs density and activity in brain structures underlying drug-taking and drug-seeking behaviour, which could represent long-term neuroadaptations contributing to the development of drug addiction and dependence.

Cannabis is the most commonly used illicit drug worldwide, and use is typically initiated during adolescence. The endocannabinoid system has an important role in formation of the nervous system, from very early development through adolescence. Cannabis exposure during this vulnerable period might lead to neurobiological changes that affect adult brain functions and increase the risk of cannabis use disorder. The aim of this study was to investigate whether exposure to Δ(9)-tetrahydrocannabinol (THC) in adolescent rats might enhance reinforcing effects of cannabinoids in adulthood. Male adolescent rats were treated with increasing doses of THC (or its vehicle) twice/day for 11 consecutive days (PND 45-55). When the animals reached adulthood, they were tested by allowing them to intravenously self-administer the cannabinoid CB1-receptor agonist WIN55,212-2. In a separate set of animals given the same THC (or vehicle) treatment regimen, electrophysiological and neurochemical experiments were performed to assess possible modifications of the mesolimbic dopaminergic system, which is critically involved in cannabinoid-induced reward. Behavioral data showed that acquisition of WIN55,212-2 self-administration was enhanced in THC-exposed rats relative to vehicle-exposed controls. Neurophysiological data showed that THC-exposed rats displayed a reduced capacity for WIN55,212-2 to stimulate firing of dopamine neurons in the ventral tegmental area and to increase dopamine levels in the nucleus accumbens shell. These findings-that early, passive exposure to THC can produce lasting alterations of the reward system of the brain and subsequently increase cannabinoid self-administration in adulthood-suggest a mechanism by which adolescent cannabis exposure could increase the risk of subsequent cannabis dependence in humans.

Reward processing is crucial to our health and wellbeing and dysfunctional brain reward signaling is a component of a number of psychiatric disorders, including major depression and drug addiction. Rewarding behaviors like eating, parenting, nursing, social play, and sexual activity are powerfully preserved in evolution and are essential for survival. All of them gratifying, they represent enjoyable experiences with high reward values and activate the same brain circuits that mediate the positive reinforcing effects of drugs of abuse. In line with preclinical findings and clinical observations, recent imaging studies confirmed that natural (sex, food) and non-natural (drugs of abuse) rewards differently activate male and female brains (Haase et al., 2011; Wetherill et al., 2014) and also that men and women differ in the ability to resist reward-related impulses (Diekhof et al., 2012). The study of sexual morphological differences in human brain has provided evidence of critical effects of gender on brain architecture and morphometry (Giedd et al., 2012; Feis et al., 2013). Male-female differences in human brain anatomy have stimulated research on the difference in onset, prevalence, and symptomatology of many neuropsychiatric illnesses between women and men, including drug addiction (Rando et al., 2013; Tanabe et al., 2013; Ide et al., 2014). Following the official recognition by International Institutions and Funding Research Agencies on the importance of taking into account potential differences between men and women in all of the relevant aspects of health-related research, gender is receiving increasing attention by medical and scientific communities. As a consequence, evaluation of sex and gender (i.e., biological characteristics and socio-political-cultural influences associated with the terms “male” and “female,” respectively) differences in reward processing in general, and in drug addiction in particular, is increasingly being studied. Numerous human behaviors are driven by evolved instincts and urges. We have evolved the capacity to experience considerable pleasure and happiness from several behaviors, among which are eating, drinking, mating, creating protective shelter, and reproducing, all activating an anatomical and neurochemically defined brain circuit commonly referred to as the “pleasure circuit” or “brain reward system.” In both animals and humans, males and females display diverse attitudes and expectancies, process information differently, perceive experience and emotions in different ways and are behaviorally determined by different needs and drives. Reward processing may also differ between male and female population with sexual hormones playing an important, although not exclusive, role. When looking at the most common behavioral features known to favor the development of drug dependence, such as poor impulse control, risk-taking behavior, a heightened reactivity to stress and psychiatric comorbidity, all reveal important differences between men and women. Here I will illustrate the most recent evidence showing sex/gender differences in these and other behavioral traits linked to reward processing and enhancing the vulnerability to drug addiction.

Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), produces rewarding effects in animals and humans. Over the past years, the endocannabinoid system has received increasing attention due to the wide spectrum of physiological functions in which it plays a modulating role. Growing evidence is emerging on a possible participation of the endogenous cannabinoid system in the brain reward processes and addictive behaviors. In the present chapter, we will review the most recent findings on the relationship between the endocannabinoid system and drug abuse, addiction, and relapse phenomena. We will first provide a brief overview of the different aspects of the drug addiction cycle, and then summarize what is known about the moderating effects of endocannabinoids in human drug use, abuse, and dependence. For each class of abused drugs, the conspicuous progress made in defining the role of the endocannabinoid system in drug-taking and drug-seeking behaviors will be examined.

In humans as in animals, males and females are dissimilar in their genetic and hormonally driven behaviour; they process information differently, perceive experiences and emotions in different ways, and display diverse attitudes. In the human population, gender differences in the frequency and patterns of cannabis use have been identified in clinical studies and in anecdotal observations, although the nature of these differences is still poorly explored. The motivations for smoking cannabis are also different between sexes, especially in adolescents. A number of potential factors which could provide a neurobiological basis for gender-based differences in cannabinoid addiction have been identified, among which are organizational and activational effects of gonadal hormones, socio-cultural factors, different stress responsiveness and impulse-control ability as well as different cannabinoid pharmacodynamic and pharmacokinetic in males and females. In this chapter we will review both clinical and laboratory-based research evidence revealing important sex-related differences in cannabinoid-induced effects on reward and motivation.

Rats with a previous history of heroin self-administration were studied to assess interactions occurring between cannabinoids and opioids in an animal model of reinstatement of heroin-seeking behaviour. Rats were trained to self-administer heroin and after a long-term extinction were primed with one of the following non-contingent non-reinforced drug administrations: saline (or vehicle), heroin, synthetic cannabinoid CB1 receptor agonists (WIN 55,212-2 or CP 55,940), opioid antagonist (naloxone) or CB1 antagonist (SR 141716A), alone or in combination. After primings, lever-pressing activity was recorded and compared to those observed during previous phases of training and extinction. Results of this study showed that (i) priming injections of heroin (0.1 mg/kg) as well as CB1 agonists WIN 55,212-2 (0.15 or 0.30 mg/kg) and CP 55,940 (0.05 or 0.1 mg/kg) completely restore heroinseeking behaviour; (ii) primings of naloxone (1 mg/kg) and SR 141716A (0.3 mg/kg) had no effect when administered alone; (iii) heroin-induced reinstatement was fully prevented by pre-treatment with either naloxone or SR 141716A; (iv) pre-treatment with SR 141716A significantly reduced WIN 55,212-2 and CP 55,940 priming effects. These results suggest that cannabinoid CB1 receptors play an important role in the mechanisms underlying relapse to heroin-seeking and depict CB1 antagonists as possible therapeutic agents for use in the prevention of relapse to heroin abuse. 2005 Elsevier Ltd. All rights reserved.

We recently provided evidence for a functional link between cannabinoid and opioid endogenous systems in relapse to heroin-seeking behaviour in rats. In the present study, we aimed at investigating whether the previously observed cross-talk between cannabinoids and opioids could be extended to mechanisms underlying relapse to cannabinoid-seeking behaviour after a prolonged period of abstinence. In rats previously trained to intravenously self-administer the synthetic cannabinoid receptor (CB1) agonist WIN 55,212-2 (12.5 microg kg(-1) inf(-1)) under a fixed ratio (FR1) schedule of reinforcement, noncontingent nonreinforced intraperitoneal (i.p.) priming injections of the previously self-administered CB1 agonist (0.25 and 0.5 mg kg(-1)) as well as heroin (0.5 mg kg(-1)), but not cocaine (10 mg kg(-1)), effectively reinstate cannabinoid-seeking behaviour following 3 weeks of extinction. The selective CB1 receptor antagonist SR 141716A (0.3 mg kg(-1) i.p.) does not reinstate responding when given alone, but completely prevents the cannabinoid-seeking behaviour triggered by WIN 55,212-2 or heroin primings. The nonselective opioid antagonist naloxone (1 mg kg(-1) i.p.) has no effect on operant behaviour per se, but significantly blocks cannabinoid- and heroin-induced reinstatement of cannabinoid-seeking behaviour. These results provide the first evidence of drug-induced reinstatement of cannabinoid-seeking behaviour, and further strengthen previous findings on a cross-talk between the endogenous cannabinoid and opioid systems in relapse mechanisms to drug-seeking.

Because opioid and cannabinoid systems have been reported to interact in the modulation of addictive behaviour, this study was aimed at investigating the ability of cannabinoid agents to reinstate or prevent heroin-seeking behaviour after a prolonged period of extinction. In rats previously trained to self-administer heroin intravenously, non-contingent non-reinforced priming administrations of heroin and cannabinoids were presented after long-term extinction, and lever pressing following injections was observed. Results showed that: (i) intravenous priming infusions of heroin (0.1 and 0.2 mg/kg) lead to reinstatement of drug-seeking behaviour; (ii) intraperitoneal priming injections of the central cannabinoid receptor agonists R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazinyl) (1-naphthalenyl)methanonemesylate (WIN 55,212-2, 0.15 and 0.3 mg/kg) and (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940, 0.05 and 0.1 mg/kg), but not delta9-tetrahydrocannabinol (delta9-THC, 0.1-1.0 mg/kg), effectively restored heroin-seeking behaviour; (iii) intraperitoneal priming injection of the central cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)4-methyl-1H-pyrazole-3-carboxamide (SR 141716A, 0.3 mg/kg) did not reinstate responding, but (iv) completely prevented heroin-induced reinstatement of drug-seeking behaviour. Moreover, heroin-seeking behaviour was still present for a few days following cannabinoid primings, indicating a long-lasting effect of cannabinoids on responding for heroin. These findings indicate that relapse to heroin after an extended drug-free period is triggered by cannabinoid agonists and that SR 141716A prevents drug-seeking behaviour, suggesting that the use of the cannabinoid antagonist could have some therapeutic benefits in heroin-induced relapse.

The inability to maintain drug abstinence is often referred to as relapse and consists of a process by which an abstaining individual slips back into old behavioral patterns and substance use. Animal models of relapse have been developed and validated over the last decades, and significantly contributed to shed light on the neurobiological mechanisms underlying vulnerability to relapse. The most common procedure to study drug-seeking and relapse-like behavior in animals is the "reinstatement model." Originally elaborated by Pavlov and Skinner, the concepts of reinforced operant responding and conditioned behavior were applied to addiction research not before 1971 (Stretch et al., Can J Physiol Pharmacol 49:581-589, 1971), and the first report of a reinstatement animal model as it is now used worldwide was published only 10 years later (De Wit and Stewart, Psychopharmacology 75:134-143, 1981). According to the proposed model, opioids are typically self-administered intravenously, as humans do, and although rodents are most often employed in these studies, this model has been used with a variety of species including nonhuman primates, dogs, cats, and pigeons. A variety of operant responses are available, depending on the species studied. For example, a lever press or a nose poke response typically is used for rodents, whereas a panel press response typically is used for nonhuman primates. Here, we describe a simple and easily reproducible protocol of heroin-seeking reinstatement in rats, which proved useful to study the neurobiological mechanisms underlying relapse to heroin and vulnerability factors enhancing the resumption of heroin-seeking behavior.

The rewarding effects of morphine, cocaine, amphetamine and nicotine were evaluated in CB1 receptor knockout mice by means of an intravenous self-administration model. Experiments were carried out on drug-naive animals using a nose-poking response (NPR)-like as operandum. The results of the present study indicate that morphine did not induce intravenous self-administration in mutant CB1 receptor knockout mice, whereas it was significantly self-administered by the corresponding wild type mice. On the contrary, cocaine, amphetamine and nicotine were self-administered to the same extent by both wild type and CB1 receptor knockout mice. These data clearly indicate that the CB1 cannabinoid receptor is essential not only for the expression of cannabinoid reinforcing effects but also for the modulation of morphine rewarding effects. The specificity of such interaction is supported by the finding that contrary to morphine, cocaine, d-amphetamine and nicotine were self-administered by mice at the same extent either in presence or in absence of the CB1 receptor.

Marijuana is one of the most widely used illicit recreational drugs. However, contrary to the majority of drugs abused by humans, there is a general opinion that rewarding effects are not manifested by animals. We studied a synthetic cannabinoid agonist WIN 55,212-2 using an intravenous self-administration model in drug-naive mice. The results of this study show that WIN 55,212-2 was intravenously self-administered by mice in a concentration-dependent manner according to a bell-shaped curve. Thus, self-administration of WIN 55,212-2 significantly increased, with respect to the vehicle self-administration control group, at concentrations of 0.5 and 0.1 mg/kg per injection. However, at WIN 55,212-2 concentration of 0.5 mg/kg per injection, self-administration significantly decreased. The results obtained show how WIN 55,212-2 is able to elicit both rewarding and aversive effects depending on the concentration used. Pretreatment of mice with the cannabinoid CB1 receptor antagonist SR 141716A (0.25 mg/kg, i.p.) completely prevented WIN 55,212-2 (0.1 mg/kg per injection) self-administration, indicating that WIN 55,212-2 rewarding effects are specifically mediated by cannabinoid CB1 receptors.

Gamma-hydroxybutyric acid (GHB) is an endogenous compound present in mammalian brain suggested as a putative neurotransmitter, which has been shown to affect several aspects of dependence from various classes of drugs of abuse. In the present study, two sets of experiments were performed to investigate the effects of acute pretreatment with GHB on intravenous cocaine self-administration in rats. In the first experiment GHB was administered intragastrically at the doses of 175, 350, and 700 mg/kg to Long–Evans rats trained to self-administer cocaine using nose-poke as operandum. In the second experiment, GHB was administered intraperitoneally at the doses of 100, 200, and 400 mg/kg to Wistar rats trained to self-administer cocaine intravenously using lever-pressing as operandum. In both experiments acute pretreatment with GHB significantly and dose dependently reduced cocaine self-administration. The effectiveness of GHB was similar in both experiments, indicating that the effect of GHB on cocaine self-administration is independent of animal strain, route of administration, and type of operant response required. These results indicate that GHB reduces cocaine-seeking behavior in rats, modulating the acute reinforcing effect of cocaine. The clinical effectiveness of GHB in dependence from various classes of abused drugs warrants further studies to evaluate the possibility that GHB might represent a useful therapeutic agent for cocaine addiction in humans.

Gamma-hydroxybutyric acid (GHB), a putative neurotransmitter or neuromodulator found in the mammalian brain, has been successfully used in clinical practice to alleviate both alcohol and opiate withdrawal symptoms. In the present study we used a conditioned place preference (CPP) paradigm to investigate whether GHB possesses rewarding properties in rats. In order to exclude possible artifacts due to experimental design, we evaluated the possibility of a shift in preference when rats are conditioned either on their non-preferred side or on a randomly assigned side of conditioning. In both experiments GHB was seen to induce CPP. Although to date the physiological role of this compound still remains unclear, there is no doubt that GHB, further to its proven effect on alcohol and opiates, possesses rewarding properties of its own. The abuse liability afforded by this drug suggests the use of particular caution in handling GHB as a clinically useful drug.

Gender-dependent differences in the rate of initiation and frequency of misuse of addicting drugs have been widely described. Yet, men and women also differ in their propensity to become addicted to other rewarding stimuli (e.g., sex, food) or activities (e.g., gambling, exercising). The goal of the present review is to summarize current evidence for gender differences not only in drug addiction, but also in other forms of addictive behaviours. Thus, we first reviewed studies showing gender-dependent differences in drug addiction, food addiction, compulsive sexual activity, pathological gambling, Internet addiction and physical exercise addiction. Potential risk factors and underlying brain mechanisms are also examined, with particular emphasis given to the role of sex hormones in modulating addictive behaviours. Investigations on factors allowing the pursuit of non-drug rewards to become pathological in men and women are crucial for designing gender-appropriate treatments of both substance and non-substance addictions.

Addiction as a psychiatric disorder involves interaction of inherited predispositions and environmental factors. Similarly to humans, laboratory animals self-administer addictive drugs, whose appetitive properties result from activation and suppression of brain reward and aversive pathways, respectively. The ventral tegmental area (VTA) where dopamine (DA) cells are located is a key component of brain reward circuitry, whereas the rostromedial tegmental nucleus (RMTg) critically regulates aversive behaviors. Reduced responses to either aversive intrinsic components of addictive drugs or to negative consequences of compulsive drug taking might contribute to vulnerability to addiction. In this regard, female Lister Hooded (LH) rats are more vulnerable than male counterparts to cannabinoid self-administration. We, therefore, took advantage of sex differences displayed by LH rats, and studied VTA DA neuronal properties to unveil functional differences. Electrophysiological properties of DA cells were examined performing either single cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. In vivo, DA cell spontaneous activity was similar, though sex differences were observed in RMTg-induced inhibition of DA neurons. In vitro, DA cells showed similar intrinsic and synaptic properties. However, females displayed larger depolarization-induced suppression of inhibition (DSI) than male LH rats. DSI, an endocannabinoid-mediated form of short term plasticity, was mediated by 2-arachidonoylglycerol (2-AG) activating type 1-cannabinoid (CB1) receptors. We found that sex-dependent differences in DSI magnitude were not ascribed to CB1 number and/or function, but rather to a tonic 2-AG signaling. We suggest that sex specific tonic 2-AG signaling might contribute to regulate responses to aversive intrinsic properties to cannabinoids, thus resulting in faster acquisition/initiation of cannabinoid taking and, eventually, in progression to addiction.

The contribution of dopamine and cannabinoid neurotransmission in emotional brain circuits regulating motivational and emotional neural processing has been well acknowledged by both animal and clinical studies (LeDoux, 2000; Laviolette and Grace, 2006). The endocannabinoid system has arisen as part of the complex circuitry that regulates stress and as a crucial mediator of emotional learning (for a comprehensive review see Viveros et al., 2005). The idea that this system is involved in the control of emotions is rooted in the fact that Cannabis sativa is used recreationally, mainly for its euphoric effects. The dopamine (DA) neurotransmitter system is significantly crucial for the neural processing of motivational and emotionally salient information (Wise, 2004). Yet, less is known about the functional interaction between cannabinoid and dopaminergic receptors in the control of emotional behavior. Much of our understanding has been improved only recently by studies using knockout (KO) animals (Micale et al., 2009; Ortega-Alvaro et al., 2011; Thanos et al., 2011), behavioral approaches (Ramiro-Fuentes and Fernandez-Espejo, 2011; Zarrindast et al., 2011), or neuroanatomical and electrophysiological techniques (Chiu et al., 2010). In an intriguing article of the Special Issue “The endocannabinoid system: a key modulator of emotions and cognition” published in Frontiers in Behavioral Neuroscience, Terzian and colleagues provide the first evidence for a physiological cross-talk between the cannabinoid CB1 receptors (CB1Rs) and the dopamine D1 receptors (D1Rs) in the modulation of depression-like behavior, social skills, and fear conditioning. Specifically, these authors examined the responses of conditional CB1 mutant mice genetically selected for the absence of CB1Rs exclusively in neurons containing D1Rs receptors (D1–CB1 KO mice), in a battery of behavioral tests, and reported the following interesting results. First, when compared to their WT counterparts, D1–CB1 KO mice displayed similar performance in the social novelty, the elevated plus maze, and the light/dark test (all paradigms evaluating different aspects of unconditioned anxiety), but spent more time on grooming activity and showed less social interaction when tested under low aversive conditions. By measuring the anxiety-like profile of these animals using different tests, authors thus disentangled different components of the anxiety state, bringing to light the specific role of CB1–D1 receptors in modulating emotional states under conditions of stress-induced conflict/frustration (grooming behavior) or inescapable situations (social interactions). Secondly, D1–CB1 KO mice showed lower sucrose consumption than WT mice, a behavior reminiscent of a mild anhedonia-like state (commonly associated with depression). However, the finding that such a difference disappears on the second day of testing does not support a depressive-like behavioral phenotype, as also suggested by the observation that KO mice performed as WTs in the forced swim test (commonly used to evaluate animals’ behavioral despair). Finally, in the fear conditioning task (a fear-related memory test involving a strong mnemonic component), D1–CB1 KO mice showed significantly increased auditory-cued and contextual fear responses, which is not surprising when considering the important role of DA receptors in fear adaptation processes (El-Ghundi et al., 2001; de la Mora et al., 2010) and that of CB1 receptors in fear alleviation (Marsicano et al., 2002; Kamprath et al., 2006). The main outcome of this study is the demonstration that CB1Rs and D1Rs cooperate for the control of a negative affect. This implies that D1R and CB1R signaling systems may mediate overlapping pharmacological responses in clinically important brain areas that mediate diseases, such as Parkinson and epilepsy, in which these two classes of receptors have been reported to strictly interact (Ferrer et al., 2003; Gangarossa et al., 2011). Although limited by potential compensatory mechanisms that may take place during development, these conditional animals represent a precious tool for investigating whether CB1 and D1 receptors also interact in modulating other brain circuits (motivation, reward) and behavioral traits (impulsivity/compulsivity), which may contribute to the development of several disorders (i.e., binge eating disorder). The involvement of the two receptor systems in motivational and emotional neural processing phenomena also suggests that their interaction might be implicated in other neuropathologies such as schizophrenia and addiction (Grace, 1995, 2000; Zavitsanou et al., 2004; Semple et al., 2005). Perhaps the most robust effect demonstrated by Terzian and colleagues involves the enhancement of conditioned fear and the possible attenuation of extinction learning. This is an important step in advancing our knowledge on the functional interaction between D1Rs and CB1Rs in emotional neural processing and specifically fear adaptation. However, further studies are required to clarify the mechanisms underlying cannabinoids modulation of the DAergic system. For example, it needs to be determined what are the specific neuronal circuits mediating the effects on fear retrieval and fear adaptation in the D1–CB1 KO mice. Another issue to focus on is short- and long-term extinction in these mutant mice. The ability to extinguish emotional responses in the face of a no-longer relevant conditioned cue is an essential part of a healthy emotional memory system (Charney et al., 1993) and deficits in fear extinction are thought to contribute to anxiety disorders such as post-traumatic stress disorder (PTSD). It has been consistently demonstrated that CB1R-deficient mice and CB1R antagonists block fear extinction. The results by Terzian et al. (2011) suggest that this may also be the case with the D1–CB1 KO mice. This should be carefully examined as it is a clinically relevant issue to ask whether or not a stimulation of D1R–CB1R signaling might accelerate extinction of fear and hence, might be therapeutically effective in the treatment of anxiety disorders, particularly PTSD. In conclusion, findings here reported by Terzian and colleagues represent an appealing topic of investigation from both pharmacological and pharmaceutical points of view in that it provides a rationale of developing in the future chemical compounds that, by manipulating simultaneously both the D1Rs and CB1Rs, may ameliorate negative and aversive emotional states.

Rewarding behaviours such as sexual activity, eating, nursing, parenting, social interactions, and play activity are conserved strongly in evolution, and they are essential for development and survival. All of these behaviours are enjoyable and represent pleasant experiences with a high reward value. Remarkably, rewarding behaviours activate the same brain circuits that mediate the positive reinforcing effects of drugs of abuse and of other forms of addiction, such as gambling and food addiction. Given the involvement of the endocannabinoid system in a variety of physiological functions of the nervous system, it is not surprising that it takes part in the complex machinery that regulates gratification and perception of pleasure. In this review, we focus first on the role of the endocannabinoid system in the modulation of neural activity and synaptic functions in brain regions that are involved in natural and nonnatural rewards (namely, the ventral tegmental area, striatum, amygdala, and prefrontal cortex). Then, we examine the role of the endocannabinoid system in modulating behaviours that directly or indirectly activate these brain reward pathways. More specifically, current knowledge of the effects of the pharmacological manipulation of the endocannabinoid system on natural (eating, sexual behaviour, parenting, and social play) and pathological (gambling) rewarding behaviours is summarised and discussed.

The γ-aminobutyric acid(GABA)-B receptor agonist baclofen is known to reduce drug intake in both animals and humans and to prevent reinstatement of cocaine-, opioid-, and alcohol-seeking in rats after a period of extinction, but its effect on nicotine reinstatement is unknown. This study investigated the effect of baclofen on nicotine-seeking reinstatement both using the extinction/reinstatement model of nicotine self-administration and conditioned place preference (CPP). Results showed that in rats previously trained to intravenously self-administer nicotine (30 µg/kg/inf) under a FR-1 schedule of reinforcement, acute nicotine (0.15 mg/kg) priming effectively reinstates nicotine-seeking behaviour following extinction. At doses used in this study (up to 2.5 mg/kg) baclofen alone did not affect locomotor activity and did not reinstate responding. However, baclofen dose-dependently attenuated drug-induced reinstatement of nicotine-seeking in rats. Moreover, baclofen (1.25 mg/kg) completely blocked nicotine-induced reinstatement of extinguished nicotine (0.3 mg/kg) CPP in mice. Altogether, our results showed that baclofen is able to antagonise reinstatement of nicotine-seeking and CPP triggered by nicotine primings, suggesting its potential clinical utility as an anti-relapse agent.

The endocannabinoid system is implicated in the regulation of a variety of physiological processes, among which conditioning, motivation, habit forming, memory, learning, and cognition play pivotal roles in drug reinforcement and reward. In this article we will give a synopsis of last developments in research on cannabinoid actions on brain reward circuits coming from behavioral, neurochemical and electrophysiological studies. Central cannabinoid-induced effects as measured by animal models of addiction, in vivo cerebral microdialysis, in vitro and in vivo electrophysiological recording techniques, will be reviewed. Brain sites that have been implicated in the mediation of addictive cannabinoid properties include primarily the ventral tegmental area, the nucleus accumbens, and the medial prefrontal cortex, although the amygdala, the substantia nigra, the globus pallidus, and the hippocampus have also been shown to be critical structures mediating motivational and reinforcing effects of cannabinoids. Putative neurobiological mechanisms underlying these effects will be delineated.

Detoxification from drug abuse is strongly threatened by the occurrence of renewed episodes of drug intake. In human addicts, relapse to drug seeking may take place even after a considerably long period from the last drug consumption. Over the last decade, the endocannabinoid system has received remarkable attention due to its unique features, including its rewarding properties closely resembling those of the most commonly abused substances and its multiple therapeutic implications. Although limited at present, evidence is now emerging on a possible participation of the endogenous cannabinoid system in the regulation of relapsing phenomena. Both stimulation and blockade of the central cannabinoid CB-sub1 receptor have proved to play an important role in drug- as well as in cue-induced reinstatement of drug seeking behavior. Indeed, while CB-sub1 receptor stimulation may elicit relapse not only to cannabinoid seeking but also to cocaine, heroin, alcohol and methamphetamine, this effect is significantly attenuated, when not fully prevented, by pretreatment with the CB-sub1 receptor antagonist rimonabant. However, corroborating data on the involvement of the cannabinoid system in stress-induced reinstatement are still rather scarce. The present review attempts to collect data obtained from different laboratories using diverse experimental approaches, to provide a comprehensive picture of the recent evidence of a relationship between the cannabinoid system and the neurobiological mechanisms leading to relapse. For each class of abused drugs, the conspicuous progress made in delineating the role of the endocannabinoid system in relapse to drug seeking has been examined by placing particular emphasis on the findings obtained from behavioral studies. After summarizing findings and implications emerging from the reviewed studies, we conclude by briefly discussing what information is still missing and how missing information might be obtained.

Cannabinoids produce a variety of pharmacological effects very similar to those elicited by opioids. Direct and indirect interactions with opioid system have been proposed to explain some cannabinoid effects such as analgesia and attenuation of opioid-withdrawal syndrome, and evidence has been provided in support to the notion that rewarding properties of cannabinoids and opioids might be functionally linked. In particular, a growing body of studies points to an important role of the endogenous cannabinoid system in the modulation of opioid rewarding and addictive effects. The current review examines progresses in the past few years in the elucidation of cannabinoid-opioid interactions in drug abuse and dependence, focusing on recent findings from behavioural studies using different animal models of addiction. Specifically, here we review data on the behavioural aspects (i.e., drug abuse, dependence, tolerance, sensitization, relapse and drug vulnerability) of the specific, often reciprocal, cross-talk between cannabinoids and opioids with particular reference to the role of the endocannabinoid system in opioid addiction. The potential biochemical mechanisms involved in these pharmacological interactions are discussed together with possible therapeutic implications in the pharmacotherapy of opioid dependence. However, individuation of the precise anatomical substrates and molecular mechanisms of such interaction still remains a complex and challenging field for future research.

gamma-Hydroxybutyric acid (GHB) is a widely used recreational drug known to exert positive reinforcing effects in animals and humans. The GABA(B) receptor agonist baclofen has been proved to possess antimotivational effect and to inhibit alcohol, cocaine, heroin and nicotine intake. In the present study we evaluated the effect of baclofen on i.v. self-administration of GHB in drug-naive mice under a fixed-ratio (FR-1) schedule of reinforcement and nose-poking-like response as operandum. Results show that baclofen was able to completely prevent GHB seeking behaviour, decreasing the rate of responding to basal values, without showing any reinforcing properties when made contingent on nose-poking response. Our findings demonstrate that baclofen antagonises GHB i.v. self-administration, supporting an important role for the GABA(B) receptor in reward-related mechanisms underlying addictive behaviour.

Gamma-hydroxybutyric acid, an endogenous compound present in mammalian brain and supposed to be a neurotransmitter or neuromodulator, has been shown to affect several aspects of dependence from some drugs of abuse. It has been successfully used in clinical practice to alleviate both alcohol and opiate withdrawal symptoms. The aim of this study was to investigate whether gamma-hydroxybutyric acid possesses rewarding properties by means of conditioned place preference and intravenous self-administration paradigms. In the present study, gamma-hydroxybutyric acid induced conditioned place preference in rats, was intravenously self-administered by drug-naive mice, and altered cocaine intravenous self-administration in rats. Although to date the physiological role of this compound still remains unclear, there is no doubt that gamma-hydroxybutyric acid, in addition to its proved effect on alcohol and opiate dependence, possesses reinforcing properties of its own and may interfere with the neurochemical events in the rewarding effects produced by psychostimulant drugs. Our investigation points out the abuse liability of this drug, suggesting the use of particular precaution in handling gamma-hydroxybutyric acid as a clinically useful drug.