Individual differences in the effects of midazolam on anxiety-like behavior, learning, reward, and choice behavior in male mice.

Introduction: The aim of the present study was to investigate the behavioral effects of the benzodiazepine midazolam in male mice, in models of anxiolysis, learning, and abuse-related effects. Methods: In a first set of experiments, male Swiss mice were submitted to the training session of a discriminative avoidance (DA) task on the elevated plus maze to evaluate anxiety-like behavior and learning after vehicle or midazolam (1, 2 or 5 mg/kg, i.g.) administration. The same animals were submitted to a conditioned place preference (CPP) protocol with midazolam (1, 2 or 5 mg/kg, i.g.). In a second experiment, outbred (Swiss) and inbred (C57BL/6) male mice were submitted to a two-bottle choice (TBC) oral midazolam drinking procedure. Animals were exposed to one sucrose bottle and one midazolam (0.008, 0.016 or 0.032 mg/ml) plus sucrose bottle. Results: Midazolam (1 and 2 mg/kg) induced anxiolytic-like effects, and all doses of midazolam prevented animals from learning to avoid the aversive closed arm during the DA training session. Assessment of midazolam reward via the CPP procedure and choice via the TBC procedure showed notable variability. A 2-step cluster analysis for the CPP data showed that midazolam data were well-fitted to 2 separate clusters (preference vs. aversion), albeit with the majority of mice showing preference (75%). Correlational and regression analyses showed no relationship between midazolam reward and anxiolytic-like effects (time spent in the open arms in the DA test) or learning/memory. Two-step cluster analysis of the TBC data also demonstrated that, regardless of strain, mice overall fell into two clusters identified as midazolam-preferring or midazolam-avoiding groups. Both midazolam preference and avoidance were concentration-dependent in a subset of mice. Discussion: Our findings show that midazolam preference is a multifactorial behavior, and is not dependent solely on the emergence of therapeutic (anxiolytic-like) effects, learning impairments, or on genetic factors (inbred vs. outbred animals).

The influence of early exposure to methylphenidate on addiction-related behaviors in mice.

Methylphenidate (MET) has a putative cognitive enhancer effect that has led adolescents and young adults to increase and indiscriminate its use aiming to ameliorate their productivity. However, the impacts of MET on addiction-related behaviors, emotional levels, and cognition are still not fully understood. To investigate the influence of chronic treatment with MET during adolescence on addiction-like behaviors, memory, and anxiety in adult mice. Thirty-day-old female mice received i.p. 10 mg/kg MET or Veh injections for 10 consecutive days. Forty days after the treatment (mice were 70-days-old), animals were submitted to the behavioral evaluation under the effects of MET, which included: MET-induced conditioned place preference (CPP), behavioral sensitization, and plus-maze discriminative avoidance task. Pre-exposure to MET during adolescence promoted an early expression of CPP and also facilitated the development of MET-induced behavioral sensitization during adulthood. These addictive-like behaviors were accompanied by anxiogenic effects of MET but not by any memory-enhancing effect. We demonstrated that exposure to MET during adolescence can increase the vulnerability to addiction-like behaviors and anxiety during adulthood. Our results reinforce the necessity of a more efficient system to control MET indiscriminate use, thus avoiding its potential tardive addictive effects.

Antinociceptive Activity of the Skin Secretion of Phyllomedusa rohdei (Amphibia, Anura).

Pain is a distressful experience that can have a major impact on an individual's quality of life. The need for new and better analgesics has been further intensified in light of the current opioid epidemic. Substances obtained from amphibians have been shown to contain bioactive peptides that exert analgesic effects. The genus Phyllomedusa represents an important source of peptides and bioactive components. The aim of this study was to investigate the antinociceptive effects of the skin secretion of Phyllomedusa rohdei in rodent models of pain. The crude skin extract of P. rohdei was tested in different pain models: acetic acid-induced writhing test (mice), formalin test (rats), Von Frey electronic test for hypernociception induced by PGE2 (rats), and hot plate test (mice). Motor-impairing effects were tested using the rota-rod test. The results showed that the skin extract of P. rohdei exerted antinociceptive effects in all pain models tested. Particularly, the highest dose tested of the skin extract decreased acetic acid-induced writhing by 93%, completely blocked formalin-induced nociception both during the acute and inflammatory phases of the test, PGE2-induced hypernociception by 73% and increased latency to paw withdrawal in the hot plate test by 300%. The effects observed in the hot plate test were reversed by pretreatment with selective µ and κ, but not δ, opioid receptor antagonists, indicating a mechanism of action dependent on µ and κ opioid receptors. The results were not influenced by sedative effects. Further studies remain necessary to reveal the specific compounds involved in the antinociceptive effects of P. rohdei skin extract as a new therapeutic tool in pain management.

Effects of chronic treatment with new strains of Lactobacillus plantarum on cognitive, anxiety- and depressive-like behaviors in male mice.

Psychobiotics correspond to a class of probiotics, mainly of the genus Lactobacillus and Bifidobacterium, capable of producing neuroactive substances, such as γ-aminobutyric acid (GABA) and serotonin, which exert effects on the brain-gut axis. Evidence suggests that psychobiotics can have a beneficial effect on mood, anxiety and cognition. The present study evaluated the effects of chronic administration of two new strains of Lactobacillus plantarum, L. plantarum 286 (Lp 286) and L. plantarum 81 (Lp 81) isolated from the fermentation of cocoa (Theobroma cacao L.) and cupuaçu (Theobroma grandiflorum), respectively, on cognitive, anxiety- and depressive-like behaviors in male Swiss mice. Different groups of animals were administered (oral gavage) solutions of vehicle (0.85% saline plus 15% skim milk), Lp 286 (109/0.1 ml CFU) or Lp 81 (109/0.1 ml CFU) for 30 days, and animals were tested for general locomotor activity, depressive-like behavior in the forced swim test, and learning/memory and anxiety-like behavior in the plus-maze discriminative avoidance task. Treatment with the strains Lp 286 and Lp 81 did not interfere with locomotor activity or learning and memory. The Lp 286 strain exerted anti-depressant- and anxiolytic-like effects under our experimental conditions. Our findings add to the current body of evidence suggesting that probiotics from the genus Lactobacillus may exert psychobiotic potential and introduce a new strain, Lp 286, as a potential candidate in the prevention or as therapeutic adjuvant in the treatment of mental disorders.

Effects of hydroalcoholic extract of Solidago chilensis Meyen on nociception and hypernociception in rodents.

BACKGROUND: Solidago chilensis (syn. microglossa) is a plant from the Asteraceae family widely distributed in South America and used to treat inflammatory diseases. In 2009, it was listed as one of the native medicinal herbal plants used in the Brazilian public health system. In addition to its anti-inflammatory properties, a recent clinical study has shown antinociceptive effects of S. chilensis, introducing a new potential medical use for this plant. The aim of the present study was to investigate the antinociceptive activity of the hydroalcoholic extract of Solidago chilensis (HESc) in rodent models of pain. METHODS: The dried plant extract was obtained from its aerial parts, maintained in ethanol (100 g/l) and filtered. Rats or mice were treated with intraperitoneal injections of HESc (3, 10 or 30 mg/kg) 30 min before being submitted to writhing, 0.2%-formaline or hot-plate tests or prostaglandin E2 (PGE2) administration in the hind paw. Mechanical hypernociception and motor impairment were evaluated by electronic von Frey and rota-rod, respectively. RESULTS: HESc dose-dependently inhibited abdominal contortions in the writhing test and attenuated phases I and II formalin-induced nociceptive behavior. Treatment with HESc also increased thermal threshold and decreased PGE2-induced hypernociception without promoting motor impairment. CONCLUSIONS: Our data suggest that, when systemically administered, HESc decreases nociception without inducing a sedative effect. Importantly, this effect was observed in both inflammatory and non-inflammatory models of pain and nociception, suggesting a specific non-inflammatory mechanism of HESc on pain. Our findings indicate that S. chilensis might be an important adjuvant in pain management.