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.

Histopathologic characteristics of scleromyxedema: A study of a series of 34 cases.

BACKGROUND: Few histologic studies describe the histopathologic aspects of scleromyxedema. OBJECTIVE: We sought to describe the histopathologic and immunohistochemical features of scleromyxedema in a large series of patients. METHODS: We studied all the cases with scleromyxedema diagnosed between 2000 and 2014 at participating centers. Sections with hematoxylin-eosin and special stains were examined. Immunohistochemistry for CD3, CD4, CD8, CD20, CD68, and factor XIIIa was performed in 10 cases. RESULTS: A total of 44 skin biopsy specimens from 34 patients were reviewed. Two different histopathologic patterns were observed: the classic microscopic triad (dermal mucin deposition, fibroblast proliferation, fibrosis) was identified in 34 specimens, whereas an interstitial granuloma annulare-like pattern was found in 10 specimens. A superficial perivascular infiltrate with T lymphocytes was found in all specimens whereas an interstitial proliferation of CD68(+) epithelioid cells was identified in the 10 specimens with an interstitial granuloma annulare-like pattern. Elastic fibers were largely lost, explaining the redundant folds of the disease. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Scleromyxedema shows 2 histopathologic patterns, including the classic type with the microscopic triad of mucin, fibroblast proliferation and fibrosis, and an interstitial granuloma annulare-like pattern. Recognition of these histologic presentations expands the spectrum of scleromyxedema and highlights the difficulty in diagnosing this disabling condition in the absence of a clinicopathological correlation.

Sézary syndrome without erythroderma.

BACKGROUND: Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involvement. OBJECTIVE: We sought to define the clinical, biologic, and histopathologic features of Sézary syndrome without erythroderma. METHODS: Features of patients with Sézary syndrome and normal-appearing skin or stage-T1 patches, fulfilling Sézary syndrome hematologic criteria and with histologically documented disease in normal-appearing skin were collected. Expression of Sézary syndrome molecular biomarkers in peripheral blood and skin lymphocytes were studied. RESULTS: Five women and 1 man (median age: 71 years) were all referred for generalized pruritus. Four had no specific lesions; 2 had T1-stage patches. Histologic examination of normal-appearing skin from all patients showed lesions compatible with Sézary syndrome. Peripheral blood lymphocytes from 3 of 4 patients tested strongly expressed PLS3, Twist-1, and KIR3DL2. All normal-appearing skin biopsy specimens expressed programmed death-1. Median follow-up was 9 years. Although no patient developed erythroderma, tumors, or abnormal lymph nodes, specific skin lesions appeared in all patients during follow-up. Only 1 death, unrelated to Sézary syndrome, occurred. LIMITATIONS: Retrospective design and small sample size are limitations. CONCLUSION: Sézary syndrome without erythroderma is a rare entity that may have a better prognosis than classic Sézary syndrome.

Selective action of an atypical neuroleptic on the mechanisms related to the development of cocaine addiction: a pre-clinical behavioural study.

An increased function in the mesolimbic dopaminergic system has been extensively associated with the rewarding effects of both natural stimuli and drugs of abuse. Thus, dopamine receptor blockers, such as neuroleptic drugs, can be proposed as candidates for potential therapeutic approaches to treat drug dependence. Notwithstanding, this therapeutic potential of neuroleptics critically depends on a selective action on the specific mechanisms related to the development of addiction. We compared the effects of different doses of haloperidol, ziprasidone and aripiprazole (first-, second- and third-generation neuroleptics, respectively) on spontaneous locomotor activity of mice in a novel environment, hyperlocomotion induced by acute cocaine administration and cocaine-induced locomotor sensitization by a two-injection protocol. Whereas high doses of haloperidol abolished the three behavioural paradigms without selectivity, low doses of ziprasidone selectively abolished the development of the behavioural sensitization phenomenon. Finally, low doses of aripiprazole inhibited acute cocaine-induced hyperlocomotion and behavioural sensitization without modifying spontaneous locomotor activity. Thus, aripiprazole at lower doses was the most selective antipsychotic drug concerning the inhibition of the development of behavioural sensitization to cocaine. Because locomotor sensitization in rodents has been proposed to share plastic mechanisms with drug addiction in humans, our data provide relevant suggestions to the clinical practice.

Scleromyxedema: a multicenter study of characteristics, comorbidities, course, and therapy in 30 patients.

BACKGROUND: Scleromyxedema is associated with a monoclonal gammopathy and other comorbidities. Its prognostic and therapeutic features are poorly documented because most reports deal with single cases or small series. OBJECTIVE: We sought to describe the characteristics of patients with scleromyxedema regarding demographics, clinical characteristics, comorbidities, therapeutic interventions, and course. METHODS: We conducted a retrospective and prospective multicenter study. RESULTS: We identified 30 patients with scleromyxedema (17 men and 13 women). The mean age at diagnosis was 59 years. The mean delay between disease onset and diagnosis was 9 months. Monoclonal gammopathy was detected in 27 patients. Extracutaneous manifestations were present in 19 patients including neurologic (30%), rheumatologic (23.3%), and cardiac (20%) manifestations. Two patients developed hematologic malignancies. The most common therapies included oral steroids and intravenous immunoglobulins. Although corticosteroids were ineffective, intravenous immunoglobulins (alone or in combination with other drugs) induced complete remission in 4 and partial remission in 9 patients with a mean treatment duration of 2 years. In all, 21 patients were followed up for a mean period of 33.5 months, at which time 16 patients were alive, 12 with and 4 without skin disease. Five patients died: 2 with dermatoneuro syndrome and 1 each with myeloid leukemia, Hodgkin lymphoma, and myocardial insufficiency. LIMITATIONS: This is mainly a retrospective study. CONCLUSIONS: Our study confirms that scleromyxedema is a chronic and unpredictable disease with severe systemic manifestations leading to a guarded prognosis. There is no specific definitive treatment. Our data support the contention that intravenous immunoglobulin is a relatively effective and safe treatment. The response is not permanent and maintenance infusions are required.

Distinctive Neuroanatomic Regions Involved in Cocaine-Induced Behavioral Sensitization in Mice.

The present study aimed to characterize the phenomenon of behavioral sensitization to cocaine and to identify neuroanatomical structures involved in the induction and expression phases of this phenomenon. For this, in experiment 1 (induction phase), mice were treated with saline or cocaine every second day for 15 days (conditioning period), in the open-field or in their home-cages. In experiment 2 (expression phase), the same protocol was followed, except that after the conditioning period the animals were not manipulated for 10 days, and after this interval, animals were challenged with cocaine. Neuroanatomical structures involved in the induction and expression phases were identified by stereological quantification of c-Fos staining in the dorsomedial prefrontal cortex (dmPFC), nucleus accumbens core (NAc core and shell (NAc shell), basolateral amygdala (BLA), and ventral tegmental area (VTA). Neuroanatomical analysis indicated that in the induction phase, cocaine-conditioned animals had higher expression of c-Fos in the dmPFC, NAc core, BLA, and VTA, whereas in the expression phase, almost all areas had higher expression except for the VTA. Therefore, environmental context plays a major role in the induction and expression of behavioral sensitization, although not all structures that compose the mesolimbic system contribute to this phenomenon.

Context-dependent effects of the CB1 receptor antagonist rimonabant on morphine-induced behavioral sensitization in female mice.

Introduction: The endocannabinoid system has been implicated in the neurobiology of opioid use disorder. While the CB1 receptor antagonist rimonabant has been shown to block some of the behavioral effects of opioids, studies suggest that the treatment environment (i.e., receiving treatment in the drug-associated environment, and/or novelty) can influence its effects. In the present study, we investigated the role of the treatment environment in the effects of rimonabant on the expression of morphine-induced behavioral sensitization. Methods: Adult female Swiss mice were submitted to a behavioral sensitization protocol, during which they received morphine (20 mg/kg, i.p.) in the open-field apparatus, and were subsequently treated with vehicle or rimonabant (1 or 10 mg/kg, i.p.) either in the open-field, in the home-cage or in an activity box (novel environment). The expression of conditioned locomotion (increased locomotor activity in the open-field apparatus in the absence of morphine) and of morphine-induced behavioral sensitization (increased locomotor activity in animals sensitized to morphine) was evaluated during asubsequent saline and morphine challenge, respectively. Results: Animals treated with morphine expressed behavioral sensitization, showing a significant increase in locomotor activity over time. Animals sensitized to morphine and treated with vehicle in the home-cage expressed conditioned locomotion, an effect that was blocked by home-cage treatment with rimonabant. During a saline challenge, only animals sensitized to morphine and treated with saline in the home-cage expressed morphine-induced conditioned locomotion. All morphine-treated animals that received saline during the treatment phase (control groups) expressed behavioral sensitization during the morphine challenge. Treatment with rimonabant in the open-field and in the activity box, but not in the home-cage, blocked the expression of morphine-induced behavioral sensitization. Discussion: Our findings suggest that CB1 receptor antagonism can modulate conditioned responses to morphine even when administered in the home-cage. However, exposure to the drug-associated environment or to a novel environment is necessary for the expression of rimonabant's effects on morphine-induced behavioral sensitization during a morphine challenge.

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).

Distinct merkel cell polyomavirus molecular features in tumour and non tumour specimens from patients with merkel cell carcinoma.

Merkel Cell Polyomavirus (MCPyV) is associated with Merkel Cell carcinoma (MCC), a rare, aggressive skin cancer with neuroendocrine features. The causal role of MCPyV is highly suggested by monoclonal integration of its genome and expression of the viral large T (LT) antigen in MCC cells. We investigated and characterized MCPyV molecular features in MCC, respiratory, urine and blood samples from 33 patients by quantitative PCR, sequencing and detection of integrated viral DNA. We examined associations between either MCPyV viral load in primary MCC or MCPyV DNAemia and survival. Results were interpreted with respect to the viral molecular signature in each compartment. Patients with MCC containing more than 1 viral genome copy per cell had a longer period in complete remission than patients with less than 1 copy per cell (34 vs 10 months, P = 0.037). Peripheral blood mononuclear cells (PBMC) contained MCPyV more frequently in patients sampled with disease than in patients in complete remission (60% vs 11%, P = 0.00083). Moreover, the detection of MCPyV in at least one PBMC sample during follow-up was associated with a shorter overall survival (P = 0.003). Sequencing of viral DNA from MCC and non MCC samples characterized common single nucleotide polymorphisms defining 8 patient specific strains. However, specific molecular signatures truncating MCPyV LT were observed in 8/12 MCC cases but not in respiratory and urinary samples from 15 patients. New integration sites were identified in 4 MCC cases. Finally, mutated-integrated forms of MCPyV were detected in PBMC of two patients with disseminated MCC disease, indicating circulation of metastatic cells. We conclude that MCPyV molecular features in primary MCC tumour and PBMC may help to predict the course of the disease.

Role of 5-HT2A receptors in the effects of ayahuasca on ethanol self-administration using a two-bottle choice paradigm in male mice.

RATIONALE: Ayahuasca has been proposed as a potential treatment of alcohol (ethanol) use disorder (AUD). The serotonin 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT) is the main psychoactive component of ayahuasca, suggesting that its therapeutic effects may be mediated by 5-HT2A receptors. OBJECTIVES: The aim of the present study was to investigate the effects of ayahuasca on the expression of ethanol self-administration using a two-bottle choice procedure and the role of 5-HT2A receptors in those effects. METHODS: Male mice had intermittent access to ethanol (10% v/v) in a two-bottle choice procedure for 30 days. Animals were then submitted to 3 treatment phases, each followed by ethanol re-exposure tests. During the treatment phase, every 3 days, animals received i.p. injections of either vehicle or the 5-HT2A receptor antagonist M100907 (M100, 1 mg/kg) followed by an i.g. (gavage) administration of vehicle or ayahuasca (100 mg/kg) and were exposed to the self-administration apparatus with no ethanol availability. During re-exposure tests, animals were submitted to the same conditions as during acquisition, with no treatments prior to those sessions. RESULTS: Treatment with ayahuasca blocked the expression of ethanol self-administration, decreasing ethanol intake and preference during re-exposure tests. Pretreatment with M100 blocked the effects of ayahuasca on ethanol drinking without significantly attenuating ethanol self-administration. CONCLUSIONS: Treatment with ayahuasca during alcohol abstinence blocked the expression of alcohol self-administration in mice, and 5-HT2A receptor activation is critical for those effects to emerge. Our findings support a potential for ayahuasca and other 5-HT2A receptor agonists as adjunctive pharmacotherapies for the treatment of AUD.

Circadian rhythms and substance use disorders: A bidirectional relationship.

The circadian system organizes circadian rhythms (biological cycles that occur around 24 h) that couple environmental cues (zeitgebers) with internal functions of the organism. The misalignment between circadian rhythms and external cues is known as chronodisruption and contributes to the development of mental, metabolic and other disorders, including cancer, cardiovascular diseases and addictive disorders. Drug addiction represents a global public health concern and affects the health and well-being of individuals, families and communities. In this manuscript, we reviewed evidence indicating a bidirectional relationship between the circadian system and the development of addictive disorders. We provide information on the interaction between the circadian system and drug addiction for each drug or drug class (alcohol, cannabis, hallucinogens, psychostimulants and opioids). We also describe evidence showing that drug use follows a circadian pattern, which changes with the progression of addiction. Furthermore, clock gene expression is also altered during the development of drug addiction in many brain areas related to drug reward, drug seeking and relapse. The regulation of the glutamatergic and dopaminergic neurocircuitry by clock genes is postulated to be the main circadian mechanism underlying the escalation of drug addiction. The bidirectional interaction between the circadian system and drug addiction seems to be mediated by the effects caused by each drug or class of drugs of abuse. These studies provide new insights on the development of successful strategies aimed at restoring/stabilizing circadian rhythms to reduce the risk for addiction development and relapse.

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.

Aripiprazole and topiramate, alone or in combination, block the expression of ethanol-induced conditioned place preference in mice.

BACKGROUND: Ethanol is the most largely consumed drug in the world. Because of its complex mechanisms of action, studies suggest that the combination of drugs with distinct pharmacological effects may be a promising alternative for treating ethanol use disorder. In the present study, we aimed to investigate the effects of topiramate, alone and in combination with aripiprazole, on ethanol-induced conditioned place preference (CPP). METHODS: Adult male mice were conditioned with ethanol (1.8 g/kg, i.p.) in the conditioned place preference (CPP) apparatus. Animals were then treated with vehicle, topiramate (2.5, 5 or 10 mg/kg, i.p.), aripiprazole (0.025, 0.05, 0.075 or 0.1 mg/kg, i.p.) or a combination of subthreshold doses of topiramate and aripiprazole (5 and 0.075 mg/kg, respectively) in the ethanol-paired compartment for 8 consecutive days. The expression of ethanol-induced CPP was then evaluated during a drug-free test performed 24 h after a re-exposure to ethanol in the ethanol-paired compartment. RESULTS: Treatment with 10 mg/kg topiramate or 0.1 mg/kg aripiprazole blocked the expression of ethanol-induced CPP. Combined treatment with 5 mg/kg topiramate and 0.075 mg/kg aripiprazole, doses that alone were not effective, also blocked the expression of CPP to ethanol. CONCLUSIONS: Topiramate and aripiprazole, alone or in combination, blocked the expression of ethanol-induced CPP. By showing that a combination of lower, subthreshold doses or topiramate and aripiprazole was effective in blocking the conditioned reinforcing properties of the ethanol-paired environment in mice, our current findings provide important insights into the therapeutic use of these drugs in ethanol use disorder.

Ibogaine Blocks Cue- and Drug-Induced Reinstatement of Conditioned Place Preference to Ethanol in Male Mice.

Ibogaine is a psychedelic extracted from the plant Tabernanthe iboga Baill. (Apocynaceae), natural from Africa, and has been proposed as a potential treatment for substance use disorders. In animal models, ibogaine reduces ethanol self-administration. However, no study to date has investigated the effects of ibogaine on ethanol-induced conditioned place preference (CPP). The present study aimed to investigate the effects of repeated treatment with ibogaine on the reinstatement of CPP to ethanol in male mice. The rewarding effects of ethanol (1.8 g/kg, i. p.) or ibogaine (10 or 30 mg/kg, p. o.) were investigated using the CPP model. Furthermore, we evaluated the effects of repeated treatment with ibogaine (10 or 30 mg/kg, p. o.) on the reinstatement of ethanol-induced CPP. Reinstatement was evaluated under two conditions: 1) during a priming injection re-exposure test in which animals received a priming injection of ethanol and had free access to the CPP apparatus; 2) during a drug-free test conducted 24 h after a context-paired re-exposure, in which subjects received an injection of ethanol and were confined to the compartment previously conditioned to ethanol. Our results show that ethanol, but not ibogaine, induced CPP in mice. Treatment with ibogaine after conditioning with ethanol blocked the reinstatement of ethanol-induced CPP, both during a drug priming reinstatement test and during a drug-free test conducted after re-exposure to ethanol in the ethanol-paired compartment. Our findings add to the literature suggesting that psychedelics, in particular ibogaine, may have therapeutic properties for the treatment of alcohol use disorder at doses that do not have rewarding effects per se.

Sex differences in the development of conditioned place preference induced by intragastric alcohol administration in mice.

BACKGROUND: The present study aimed to identify for the first time sex differences in the development of CPP induced by intragastric alcohol administration in mice. METHODS: Male and female adult Swiss mice were submitted to 16 days of conditioning with alcohol (0.5-3.0 g/kg, N = 8/dose/sex), with 2 post-conditioning tests (after 8 and 16 sessions) during the protocol. RESULTS: 8 days of conditioning (4 alcohol sessions, 4 saline sessions) with intragastric alcohol administration were sufficient to induce CPP in male mice at the doses of 1.0, 1.5 and 2.0 g/kg. However, only higher doses (2.0, 2.5 and 3.0 g/kg) induced CPP in female mice using an 8-day conditioning protocol, while a 16-day conditioning protocol was necessary for the development of intragastric alcohol-induced CPP at the doses of 1.0 and 1.5 g/kg. Regardless of the conditioning protocol, higher doses or alcohol that had rewarding effects in females (2.5 and 3.0 g/kg) did not induce CPP in males, with a significant difference between males and females at those doses. Analysis of the potency (EC50) and efficacy (Emax) of alcohol in inducing CPP when administered intragastrically in male and female mice showed significant sex differences with 8 conditioning sessions. CONCLUSIONS: Our data show a clear protocol (8 vs 16 days) and dose difference between male and female Swiss mice regarding the development of CPP induced by intragastric alcohol administration. Intragastric alcohol administration is closer to human drinking, and our protocol provides a more translational approach to studying the rewarding effects of alcohol in mice.

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.

Ayahuasca blocks the reinstatement of methylphenidate-induced conditioned place preference in mice: behavioral and brain Fos expression evaluations.

RATIONALE: Accumulating evidence suggests that ayahuasca, a hallucinogenic beverage used in traditional Amazonian communities for ritualistic and curative purposes, has been associated with reduced rates of substance use disorders. However, the brain mechanisms underlying the therapeutic effects of ayahuasca have not yet been fully elucidated. OBJECTIVES: The aim of the present study was to investigate the effects of treatment with ayahuasca on the rewarding properties of the psychostimulant methylphenidate. METHODS: The rewarding properties of ayahuasca (100 mg/kg, orally) and methylphenidate (10 mg/kg, i.p.) were investigated using the conditioned place preference (CPP) model. Furthermore, we evaluated the effects of repeated treatment with ayahuasca on the reinstatement of methylphenidate-induced CPP. Fos expression was evaluated in different limbic structures (cingulate cortex-area 1, prelimbic cortex, infralimbic cortex, orbitofrontal cortex-lateral orbital area, nucleus accumbens core and shell, ventral tegmental area, dorsal striatum, and basolateral amygdala) upon each experimental phase. RESULTS: Both ayahuasca and methylphenidate induced CPP in mice. However, ayahuasca had limited effects on Fos expression, while methylphenidate altered Fos expression in several brain regions associated with the behavioral effects of drugs of abuse. Treatment with ayahuasca after conditioning with methylphenidate blocked the reinstatement of methylphenidate-induced CPP. Those behavioral effects were accompanied by changes in Fos expression patterns, with ayahuasca generally blocking the changes in Fos expression induced by conditioning with methylphenidate and/or reexposure to methylphenidate. CONCLUSIONS: Our findings suggest that ayahuasca restored normal brain function in areas associated with the long-term expression of drug wanting/seeking in animals conditioned to methylphenidate.