Intermittent intake of rapid cocaine injections promotes the risk of relapse and increases mesocorticolimbic BDNF levels during abstinence.

Cocaine is thought to be more addictive when it reaches the brain rapidly. We predicted that variation in the speed of cocaine delivery influences the likelihood of addiction in part by determining the risk of relapse after abstinence. Under an intermittent-access schedule, rats pressed a lever for rapid (injected over 5 s) or slower (90 s) intravenous cocaine injections (0.5 mg/kg/injection). Control rats self-administered food pellets. A tone-light cue accompanied each self-administered reward. The 5s- and 90s-rats took a similar average amount of cocaine. One or 45 days after withdrawal from cocaine/forced abstinence, lever-pressing behaviour was extinguished during a 6-h session. Immediately thereafter, cue- or cocaine (10 mg/kg, i.p.)-induced reinstatement was assessed for 1 h. One or 45 days after withdrawal, only 5s-rats showed significant cocaine-induced reinstatement of reward-seeking behaviour. In both cocaine groups, cue-induced reinstatement behaviour was more pronounced after 45 days than after 1 day of withdrawal from cocaine, indicating incubation of conditioned drug craving. However, cue-induced reinstatement after extended abstinence was greatest in the 5s-rats. Brain-derived neurotrophic factor (BDNF) activity in the brain regulates reinstatement behaviour. Thus, 24 h after reinstatement tests, we measured BDNF protein concentrations in mesocorticolimbic regions. Only 5s-rats showed time-dependent increases in BDNF concentrations in the prelimbic cortex, nucleus accumbens core and ventral tegmental area after withdrawal from cocaine (day 45 > day 1). Thus, rapidly rising brain cocaine levels might facilitate addiction by evoking changes in the brain that intensify drug craving after abstinence, and these changes persist long after the last bout of cocaine use.

Unlimited sucrose consumption during adolescence generates a depressive-like phenotype in adulthood.

Depression is highly prevalent worldwide, but its etiology is not fully understood. An overlooked possible contributor to the epidemic of depression is feeding styles, particularly at early age when the brain is intensely changing. We have previously reported that unlimited sucrose consumption during adolescence leads to enduring changes in brain reward function. Here, we tested the hypothesis that sucrose consumption during adolescence would lead to a 'depressive-like' phenotype. Adolescent male rats were given unlimited access to 5% sucrose in their home cages from postnatal day 30 to postnatal day 46 and their emotional behavior was subsequently examined at adulthood. Sucrose consumption during adolescence caused anhedonia, decreased motivation for saccharin, increased immobility in the forced swim test and exacerbated anxiety-like behavior. Additionally, sucrose consumption during adolescence decreased cell proliferation in the hippocampus in adulthood. Chronic treatment with imipramine (10 mg/kg) normalized behavior and restored cell proliferation in the hippocampus of adult rats with a history of sucrose consumption during adolescence. A similar sucrose consumption starting at adulthood only increases immobility in the forced swim test, suggesting that sucrose intake affects also adults' behavior but to a lesser degree. Overall, our findings reveal an unsuspected protracted effect of sucrose consumption on behavior and suggest that unlimited sucrose consumption during critical periods of brain development may play an important role in the etiology of reward-related disorders such as depression.

The CB1 Neutral Antagonist AM4113 Retains the Therapeutic Efficacy of the Inverse Agonist Rimonabant for Nicotine Dependence and Weight Loss with Better Psychiatric Tolerability.

BACKGROUND: Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforcing effects of various substances of abuse. Rimonabant, a CB1 inverse agonist found to be effective for smoking cessation, was associated with an increased risk of anxiety and depression. Here we evaluated the effects of the CB1 neutral antagonist AM4113 on the abuse-related effects of nicotine and its effects on anxiety and depressive-like behavior in rats. METHODS: Rats were trained to self-administer nicotine under a fixed-ratio 5 or progressive-ratio schedules of reinforcement. A control group was trained to self-administer food. The acute/chronic effects of AM4113 pretreatment were evaluated on nicotine taking, motivation for nicotine, and cue-, nicotine priming- and yohimbine-induced reinstatement of nicotine-seeking. The effects of AM4113 in the basal firing and bursting activity of midbrain dopamine neurons were evaluated in a separate group of animals treated with nicotine. Anxiety/depression-like effects of AM4113 and rimonabant were evaluated 24h after chronic (21 days) pretreatment (0, 1, 3, and 10mg/kg, 1/d). RESULTS: AM4113 significantly attenuated nicotine taking, motivation for nicotine, as well as cue-, priming- and stress-induced reinstatement of nicotine-seeking behavior. These effects were accompanied by a decrease of the firing and burst rates in the ventral tegmental area dopamine neurons in response to nicotine. On the other hand, AM4113 pretreatment did not have effects on operant responding for food. Importantly, AM4113 did not have effects on anxiety and showed antidepressant-like effects. CONCLUSION: Our results indicate that AM4113 could be a promising therapeutic option for the prevention of relapse to nicotine-seeking while lacking anxiety/depression-like side effects.

Effects of various cannabinoid ligands on choice behaviour in a rat model of gambling.

It is estimated that 0.6-1% of the population in the USA and Canada fulfil the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) criteria for gambling disorders (GD). To date, there are no approved pharmacological treatments for GD. The rat gambling task (rGT) is a recently developed rodent analogue of the Iowa gambling task in which rats are trained to associate four response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. Similar to healthy human volunteers, most rats adopt the optimal strategies (optimal group). However, a subset of animals show preference for the disadvantageous options (suboptimal group), mimicking the choice pattern of patients with GD. Here, we explored for the first time the effects of various cannabinoid ligands (WIN 55,212-2, AM 4113, AM 630 and URB 597) on the rGT. Administration of the cannabinoid agonist CB1/CB2 WIN 55,212-2 improved choice strategy and increased choice latency in the suboptimal group, but only increased perseverative behaviour, when punished, in the optimal group. Blockade of CB1 or CB2 receptors or inhibition of fatty-acid amide hydrolase did not affect rGT performance. These results suggest that stimulation of cannabinoid receptors could affect gambling choice behaviours differentially in some subgroups of subjects.

Role of the endogenous cannabinoid system in nicotine addiction: novel insights.

Several lines of evidence have shown that the endogenous cannabinoids are implicated in several neuropsychiatric diseases. Notably, preclinical and human clinical studies have shown a pivotal role of the cannabinoid system in nicotine addiction. The CB1 receptor inverse agonist/antagonist rimonabant (also known as SR141716) was effective to decrease nicotine-taking and nicotine-seeking in rodents, as well as the elevation of dopamine induced by nicotine in brain reward area. Rimonabant has been shown to improve the ability of smokers to quit smoking in randomized clinical trials. However, rimonabant was removed from the market due to increased risk of psychiatric side-effects observed in humans. Recently, other components of the endogenous cannabinoid system have been explored. Here, we present the recent advances on the understanding of the role of the different components of the cannabinoid system on nicotine's effects. Those recent findings suggest possible alternative ways of modulating the cannabinoid system that could have implication for nicotine dependence treatment.

Sugar overconsumption during adolescence selectively alters motivation and reward function in adult rats.

BACKGROUND: There has been a dramatic escalation in sugar intake in the last few decades, most strikingly observed in the adolescent population. Sugar overconsumption has been associated with several adverse health consequences, including obesity and diabetes. Very little is known, however, about the impact of sugar overconsumption on mental health in general, and on reward-related behavioral disorders in particular. This study examined in rats the effects of unlimited access to sucrose during adolescence on the motivation for natural and pharmacological rewards in adulthood. METHODOLOGY/PRINCIPAL FINDINGS: Adolescent rats had free access to 5% sucrose or water from postnatal day 30 to 46. The control group had access to water only. In adulthood, rats were tested for self-administration of saccharin (sweet), maltodextrin (non-sweet), and cocaine (a potent drug of abuse) using fixed- and progressive-ratio schedules, and a concentration-response curve for each substance. Adult rats, exposed or not exposed to sucrose, were tested for saccharin self-administration later in life to verify the specificity of adolescence for the sugar effects. Sugar overconsumption during adolescence, but not during adulthood, reduced the subsequent motivation for saccharin and maltodextrin, but not cocaine. This selective decrease in motivation is more likely due to changes in brain reward processing than changes in gustatory perception. CONCLUSIONS/SIGNIFICANCE: Sugar overconsumption induces a developmental stage-specific chronic depression in reward processing that may contribute to an increase in the vulnerability to reward-related psychiatric disorders.