Lais Fernanda Berro

Introduction: Benzodiazepines (GABA _A receptor positive allosteric modulators) have been used for decades as effective and safe anxiolytic medications. However, they also have addiction/dependence liability and side effects that include sedative-motor and memory impairment. Several of these side effects have been associated with activity at GABA _A receptors containing α1 subunits (α1GABA _A receptors), suggesting that compounds with reduced efficacy at this receptor subtype might have an improved therapeutic profile. In the present study, we investigated the behavioral effects of the novel benzodiazepine-like compounds, HZ-166 and KRM-II-81, which show preferential efficacy for α2/3GABA _A receptors, in comparison with the α1GABA _A -selective compound, zolpidem. Methods: Adult male mice were treated with vehicle or one of the compounds (3, 10, or 30 mg/kg, i.p.) and tested in the open-field, the elevated plus maze-discriminative avoidance task, and conditioned place preference (CPP). Results: In the open-field test, HZ-166 and KRM-II-81 showed anxiolytic-like, but not sedative-like effects. In the discriminative avoidance task, only KRM-II-81 showed anxiolytic-like effects, but, unlike HZ-166, also induced memory deficits in mice. HZ-166 and KRM-II-81 did not have rewarding effects in CPP, with KRM-II-81 inducing conditioned place aversion instead. In contrast, zolpidem induced sedation, memory impairment, and rewarding effects, without displaying anxiolytic-like activity. Conclusions: These findings reinforce the role of α1GABA _A receptors in benzodiazepine-induced sedation, cognitive impairment, and addiction potential, and its lack of a role in anxiety-like behaviors. Drugs with selectivity for α2/3GABA _A receptors might have an improved therapeutic profile compared to conventional benzodiazepines.

Introduction: Studies suggest that serotonin (5-HT) plays an important role in alcohol use disorder (AUD). While several receptor subtypes modulate the role of 5-HT in AUD, evidence suggests that 5-HT_2A and 5-HT_2C receptors may be directly involved in alcohol drinking due to their interaction with the mesolimbic dopaminergic system. The aim of the present study was to investigate the effects of 5-HT_2A and 5-HT_2C antagonists, alone or in combination, on the acquisition and expression (i.e., return to alcohol drinking after a period of abstinence/treatment) of voluntary alcohol drinking in male mice.Methods: Animals had intermittent access to alcohol (10% v/v) in a two-bottle choice procedure for 30 days (acquisition), and were then submitted to alcohol re-exposure sessions after periods of abstinence. Vehicle, the 5-HT_2A receptor antagonist M100907 (M100, 1 mg/kg) and/or the 5-HT_2C receptor antagonist SB242084 (SB, 1 mg/kg) were administered either prior to acquisition (Experiment 1) or during the abstinence period preceding re-exposure sessions (Experiment 2). During re-exposure tests, animals were submitted to the same conditions as during acquisition, with no treatments prior to those sessions.Results: Our findings show that combined treatment with 5-HT_2A and 5-HT_2C antagonists, but not treatment with the antagonists separately, reduced alcohol drinking and preference when administered immediately before acquisition (Experiment 1). Combined treatment with 5-HT_2A and 5-HT_2C antagonists after the establishment of voluntary alcohol drinking did not alter the expression of drinking behavior (Experiment 2). On the other hand, while post-acquisition treatment with a 5-HT_2A antagonist alone decreased alcohol intake and preference during re-exposure, co-administration of a 5-HT_2C antagonist blocked these effects.Discussion: Our findings suggest that 5-HT_2A and 5-HT_2C receptors differentially modulate the acquisition and expression of voluntary alcohol drinking in mice.

Ayahuasca has been proposed as a treatment for substance use disorders. However, because of its hallucinogenic properties, studies investigating its abuse potential are needed. The aim of the present study was to investigate voluntary ayahuasca drinking in male mice using a two-bottle choice procedure. Male mice were exposed to two bottles, one of water and one of ayahuasca (0.01, 0.03 or 0.1 mg/ml), for 15 h/day, under 3 protocols (acquisition): (1) every other day access; (2) access every 3 days; (3) access every 5 days. Animals were then submitted to a 14-day drug-free period, followed by 3 re-exposure phases (same conditions as during acquisition), with 7 drug-free days between each. Regardless of the ayahuasca concentration, animals showed a preference for ayahuasca over water when exposed to ayahuasca every other day during the acquisition and re-exposure phases. Extending the period between ayahuasca exposures changed the expression of ayahuasca preference, with the longest break (every 5 days) being associated with preference for water over ayahuasca (i.e., ayahuasca aversion), an effect that was more predominantly observed at higher ayahuasca concentrations. A significant interaction was observed between frequency of exposure to ayahuasca and ayahuasca concentration for total ayahuasca intake during the later re-exposure phase. Our findings show that both the frequency of exposure and the ayahuasca concentration are critical when determining ayahuasca preference in a two-bottle choice model in mice, which can help guide therapeutic/ritualistic ayahuasca use.

Evidence suggests that exercise may promote well-being and decrease anxiety levels. However, the specific relationship between resistance exercise and different domains of anxiety and well-being remains poorly understood. The aim of the present study was to evaluate the relationship between resistance exercise and state-trait anxiety, positive and negative affect, and life satisfaction in adults. The participants consisted of 302 individuals (age range between 18 and 73 years; M = 34.31, SD = 11.55), 112 males and 189 females. The psychometric instruments State-Trait Anxiety Inventory, Subjective Well-Being Scale and Satisfaction With Life Scale were applied at the participants’ training place. The results showed that resistance exercise practice was associated with decreased anxiety and increased subjective well-being. A Structural Equation Model showed that the association between the number of months of exercise practice experience and subjective well-being is mediated by state and trait anxiety, after controlling for sex and age. This study provides further evidence that the practice of resistance exercise is beneficial for mental health.

Editorial: Benzodiazepine addiction: from lab to street