Potential Benefits of N-Acetylcysteine in Preventing Pregabalin-Induced Seeking-Like Behavior

Substance-use disorder is globally prevalent and responsible for numerous social and medical problems. Pregabalin (Lyrica), typically used to treat diabetic neuropathy, has recently emerged as a drug of abuse. Drug abuse is associated with several neuronal changes, including the downregulation of glutamate transporters such as glutamate transporter 1 and cystine/glutamate antiporter. We investigated the effects of N-acetylcysteine, a glutamate transporter 1 and xCT upregulator, on pregabalin addiction using a conditioned place preference paradigm. Pregabalin (60 mg/kg) was found to induce conditioned place preference when compared to a vehicle. A 100 mg/kg dose of N-acetylcysteine was found to block pregabalin-seeking behaviors. These results support previous findings showing that glutamate transporters play an important role in pregabalin-induced seeking behaviors. N-acetylcysteine may represent a beneficial agent in preventing the abuse potential of pregabalin.

Oral Monosodium Glutamate Differentially Affects Open-Field Behaviours, Behavioural Despair and Place Preference in Male and Female Mice

Background: Monosodium glutamate (MSG) is a flavour enhancer which induces behavioural changes in animals. However the influence of sex on the behavioural response to MSG has not been investigated. Objective: The sex-differential effects of MSG on open-field behaviours, anxiety-related behaviour, behavioural despair, place-preference, and plasma/brain glutamate levels in adult mice were assessed. Methods: Mice were assigned to three groups (1-3), based on the models used to assess behaviours. Animals in group 1 were for the elevated-plus maze and tail-suspension paradigms, group 2 for the open-field and forced-swim paradigms, while mice in group 3 were for observation in the conditioned place preference paradigm. Mice in all groups were further assigned into five subgroups (10 males and 10 females), and administered vehicle (distilled water at 10 ml/kg) or one of four doses of MSG (20, 40, 80 and 160 mg/kg) daily for 6 weeks, following which they were exposed to the behavioural paradigms. At the end of the behavioural tests, the animals were sacrificed, and blood was taken for estimation of glutamate levels. The brains were also homogenised for estimation of glutamate levels. Results: MSG was associated with a reduction in locomotion in males and females (except at 160 mg/kg, male), an anxiolytic response in females, an anxiogenic response in males, and decreased behavioural despair in both sexes (females more responsive). Postconditioning MSG-associated place-preference was significantly higher in females. Plasma/ brain glutamate was not significantly different between sexes. Conclusion: Repeated MSG administration alters a range of behaviours in a sex-dependent manner in mice.

Link between personality and response to THC exposure

ABSTRACTThe effects of cannabis reported by users range from experiences of euphoria and anxiolytic effects to paranoia, anxiety, and increased risk of depression. Attempts to reconcile the apparent contradictions in user response have not been conclusive. Here, we utilized selectively-bred stress-resilient socially dominant (Dom) and stress-sensitive socially submissive (Sub) mice to elucidate this contradiction. Following short-term, repeated treatment with delta-9-tetrahydrocannabinol (THC) at two different doses (1.5 mg/kg and 15 mg/kg), Sub mice presented significant place-aversion in a Conditioned Place Preference paradigm at a high dose, whereas Dom mice displayed no place preference or aversion. Forced Swim test conducted after 6-week of washout period, revealed differential impact of the two THC doses depending upon behavioral pattern. Specifically, the low dose alleviated depressive-like behavior in Sub mice, while the high dose produced the opposite effect in Dom mice. Interestingly, corticosterone concentration in serum was elevated at the high dose regardless of the mice-population tested. We conclude here that differences in dominance behavior and stress vulnerability are involved in the regulation of cannabis response among users and should be considered when prescribing THC-containing medications to patients.

Fluoxetine exposure in adolescent and adult female mice decreases cocaine and sucrose preference later in life

Background: Preclinical evidence from male subjects indicates that exposure to psychotropic medications, during early development, results in long-lasting altered responses to reward-related stimuli. However, it is not known if exposure to the antidepressant fluoxetine, in female subjects specifically, changes sensitivity to natural and drug rewards, later in life. Aims: The aim of this work was to investigate if exposure to fluoxetine mediates enduring changes in sensitivity to the rewarding properties of cocaine and sucrose, using female mice as a model system. Methods: We exposed C57BL/6 female mice to fluoxetine (250 mg/L in their drinking water) for 15 consecutive days, either during adolescence (postnatal day 35–49) or adulthood (postnatal day 70–84). Twenty-one days later, mice were examined on their behavioral reactivity to cocaine (0, 2.5, 5, 7.5 mg/kg) using the conditioned place preference paradigm, or assessed on the two-bottle sucrose (1%) test. Results: We found that regardless of age of antidepressant exposure, female mice pre-exposed to fluoxetine displayed reliable conditioning to the cocaine-paired compartment. However, when compared to respective age-matched controls, antidepressant pre-exposure decreased the magnitude of conditioning at the 5 and 7.5 mg/kg cocaine doses. Furthermore, fluoxetine pre-exposure reduced sucrose preference without altering total liquid intake. Conclusions: The data suggest that pre-exposure to fluoxetine, during adolescence or adulthood, results in a prolonged decrease in sensitivity to the rewarding properties of both natural and drug rewards in female C57BL/6 mice.

Effects of Cannabidiol on Morphine Conditioned Place Preference in Mice

This study sought to determine whether the cannabis constituent cannabidiol attenuates the development of morphine reward in the conditioned place preference paradigm. Separate groups of mice received either saline or morphine in combination with one of four doses of cannabidiol using three sets of drug/no-drug conditioning trials. After drug-place conditioning, morphine mice displayed robust place preference that was attenuated by 10 mg/kg cannabidiol. Further, when administered alone, this dose of cannabidiol was void of rewarding and aversive properties. The finding that cannabidiol blocks opioid reward suggests that this compound may be useful in addiction treatment settings.