Social stress under binge-like alcohol withdrawal in adolescence: evidence of cannabidiol effect on maladaptive plasticity in rats.

BACKGROUND: Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses. METHODS: As socially stressful events pose particular challenges at developmental stages, this research applied the resident-intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms. RESULTS: Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intruder rats, at the expenses of freezing time, and in control rats, which received less aggressive attacks from the resident; (2) reduce corticosterone levels independently on alcohol previous exposure; (3) restore DA transmission and (4) facilitate excitatory postsynaptic strength and remodelling. CONCLUSIONS: Overall, the maladaptive behavioural and synaptic plasticity promoted by the intersection between binge-like alcohol withdrawal and exposure to adverse social stress can be rescued by a CBD détente effect that results in a successful defensive strategy, supported by a functional endocrine and synaptic plasticity. The current data highlight CBD's relevant therapeutic potential in alcohol- and stress-related harms, and prompt further investigation on its molecular targets.

Cannabidiol tempers alcohol intake and neuroendocrine and behavioural correlates in alcohol binge drinking adolescent rats. Focus on calcitonin gene-related peptide's brain levels.

Alcohol binge drinking is common among adolescents and may challenge the signalling systems that process affective stimuli, including calcitonin gene-related peptide (CGRP) signalling. Here, we employed a rat model of adolescent binge drinking to evaluate reward-, social- and aversion-related behaviour, glucocorticoid output and CGRP levels in affect-related brain regions. As a potential rescue, the effect of the phytocannabinoid cannabidiol was explored. Adolescent male rats underwent the intermittent 20% alcohol two-bottle choice paradigm; at the binge day (BD) and the 24 h withdrawal day (WD), we assessed CGRP expression in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, hypothalamus and brainstem; in addition, we evaluated sucrose preference, social motivation and drive, nociceptive response, and serum corticosterone levels. Cannabidiol (40 mg/kg, i.p.) was administered before each drinking session, and its effect was measured on the above-mentioned readouts. At BD and WD, rats displayed decreased CGRP expression in mPFC, NAc and amygdala; increased CGRP levels in the brainstem; increased response to rewarding- and nociceptive stimuli and decreased social drive; reduced serum corticosterone levels. Cannabidiol reduced alcohol consumption and preference; normalised the abnormal corticolimbic CGRP expression, and the reward and aversion-related hyper-responsivity, as well as glucocorticoid levels in alcohol binge-like drinking rats. Overall, CGRP can represent both a mediator and a target of alcohol binge-like drinking and provides a further piece in the intricate puzzle of alcohol-induced behavioural and neuroendocrine sequelae. CBD shows promising effects in limiting adolescent alcohol binge drinking and rebalancing the bio-behavioural abnormalities.

Phosphodiesterase-10A Inverse Changes in Striatopallidal and Striatoentopeduncular Pathways of a Transgenic Mouse Model of DYT1 Dystonia.

We report that changes of phosphodiesterase-10A (PDE10A) can map widespread functional imbalance of basal ganglia circuits in a mouse model of DYT1 dystonia overexpressing mutant torsinA. PDE10A is a key enzyme in the catabolism of second messenger cAMP and cGMP, whose synthesis is stimulated by D1 receptors and inhibited by D2 receptors preferentially expressed in striatoentopeducuncular/substantia nigra or striatopallidal pathways, respectively. PDE10A was studied in control mice (NT) and in mice carrying human wild-type torsinA (hWT) or mutant torsinA (hMT). Quantitative analysis of PDE10A expression was assessed in different brain areas by rabbit anti-PDE10A antibody immunohistochemistry and Western blotting. PDE10A-dependent cAMP hydrolyzing activity and PDE10A mRNA were also assessed. Striatopallidal neurons were identified by rabbit anti-enkephalin antibody.In NT mice, PDE10A is equally expressed in medium spiny striatal neurons and in their projections to entopeduncular nucleus/substantia nigra and to external globus pallidus. In hMT mice, PDE10A content selectively increases in enkephalin-positive striatal neuronal bodies; moreover, PDE10A expression and activity in hMT mice, compared with NT mice, significantly increase in globus pallidus but decrease in entopeduncular nucleus/substantia nigra. Similar changes of PDE10A occur in hWT mice, but such changes are not always significant. However, PDE10A mRNA expression appears comparable among NT, hWT, and hMT mice.In DYT1 transgenic mice, the inverse changes of PDE10A in striatoentopeduncular and striatopallidal projections might result over time in an imbalance between direct and indirect pathways for properly focusing movement. The decrease of PDE10A in the striatoentopeduncular/nigral projections might lead to increased intensity and duration of D1-stimulated cAMP/cGMP signaling; conversely, the increase of PDE10A in the striatopallidal projections might lead to increased intensity and duration of D2-inhibited cAMP/cGMP signaling.SIGNIFICANCE STATEMENT In DYT1 transgenic mouse model of dystonia, PDE10A, a key enzyme in cAMP and cGMP catabolism, is downregulated in striatal projections to entopeduncular nucleus/substantia nigra, preferentially expressing D1 receptors that stimulate cAMP/cGMP synthesis. Conversely, in DYT1 mice, PDE10A is upregulated in striatal projections to globus pallidus, preferentially expressing D2 receptors that inhibit cAMP/cGMP synthesis. The inverse changes to PDE10A in striatoentopeduncular/substantia nigra and striatopallidal pathways might tightly interact downstream to dopamine receptors, likely resulting over time to increased intensity and duration respectively of D1-stimulated and D2-inhibited cAMP/cGMP signals. Therefore, PDE10A changes in the DYT1 model of dystonia can upset the functional balance of basal ganglia circuits, affecting direct and indirect pathways simultaneously.

Rifabutin Triple Therapy is Effective in Patients With Multidrug-resistant Strains of Helicobacter pylori.

INTRODUCTION: Eradicating Helicobacter pylori continues to be a challenge, and no treatment regimen is uniformly successful in all treated patients. Triple therapy with rifabutin and amoxicillin is a successful rescue therapy after consecutive treatment failures. We designed this study to test the efficacy of 12-day rifabutin-based triple therapy in patients infected with multidrug-resistant strains. METHODS: Consecutive patients with dyspeptic symptoms after at least 1 antibiotic therapy course for H. pylori infection harboring triple-resistant (clarithromycin, metronidazole, levofloxacin) strains were enrolled. They received triple therapy with esomeprazole 40 mg bid, amoxicillin 1 g bid, and rifabutin 150 mg od for 12 days. Patients who failed rifabutin therapy were treated empirically on the basis of the judgment of the treating physician. RESULTS: A total of 254 out of 756 tested patients were found to be infected with a triple-resistant H. pylori strains after at least 1 antibiotic therapy course. Overall, the infection was eradicated in 213 patients, corresponding to a cure rate of 82.9% (95% CI, 78.3-87.5) by intention-to-treat analysis and 88.7% (95% CI, 84.7-92.7) at per-protocol analysis. In multivariate analysis, no factor was identified as an independent predictor of bacterial eradication. CONCLUSIONS: There is no current standard for the growing population of patients with multidrug-resistant strains of H. pylori. The 12-day low-dose rifabutin/high-dose proton pump inhibitor regimen is a safe and reliable option for patients infected with triple-resistant strains.

The endocannabinoid-alcohol crosstalk: Recent advances on a bi-faceted target.

Increasing evidence has focusesed on the endocannabinoid system as a relevant player in the induction of aberrant synaptic plasticity and related addictive phenotype following chronic excessive alcohol drinking. In addition, the endocannabinoid system is implicated in the pathogenesis of alcoholic liver disease. Interestingly, whereas the involvement of CB1 receptors in alcohol rewarding properties is established, the central and peripheral action of CB2 signalling is still to be elucidated. This review aims at giving the input to deepen knowledge on the role of the endocannabinoid system, highlighting the advancing evidence that suggests that CB1 and CB2 receptors may play opposite roles in the regulation of both the reinforcing properties of alcohol in the brain and the mechanisms responsible for cell injury and inflammation in the hepatic tissue. The manipulation of the endocannabinoid system could represent a bi-faceted strategy to counteract alcohol-related dysfunction in central transmission and liver structural and functional disarrangement.

Culture-based selection therapy for patients who did not respond to previous treatment for Helicobacter pylori infection.

BACKGROUND & AIMS: Eradication of Helicobacter pylori using empiric therapy has become difficult as a result of increasing resistance to antibiotics. We evaluated the efficacy of specific treatments, selected based on response of bacterial samples to culture with clarithromycin, levofloxacin, and metronidazole, for patients infected with resistant strains of H pylori. METHODS: We performed a prospective study at a single center of 236 consecutive patients with persistent H pylori infection, despite 1 or more treatment attempts, and documented resistance to at least 1 antimicrobial agent (based on bacterial culture tests). Biopsy samples were collected by endoscopy and cultured in selective media. Patients received either 10 days of levofloxacin (250 mg twice daily for 131 patients with susceptible infections) or 12 days of rifabutin (150 mg once daily for 105 patients resistant to levofloxacin) in combination with amoxicillin (1 g twice daily) and esomeprazole (40 mg twice daily). Efficacy of eradication was determined by the (13)C-urea breath test, 6 to 8 weeks after therapy. Compliance and side effects were determined via personal interviews at the end of therapy. Rifabutin toxicity was monitored by analysis of blood samples. RESULTS: H pylori infection was cured in 118 of the patients who received levofloxacin triple therapy (90%; 95% confidence interval, 85%-95%) and 93 of the patients who received rifabutin triple therapy (88.6%; 95% confidence interval, 82%-95%). In each group, the cure rate did not differ significantly between patients infected with H pylori strains resistant to single or multiple antibiotics. Mild side effects occurred in 15.5% and 14.9% of patients resistant to single or multiple antibiotics, respectively, and self-limiting neutropenia was observed in 1 (0.7%) case. CONCLUSIONS: Selection of triple therapy with either levofloxacin or rifabutin, based on results from bacterial culture tests, cures H pylori infection in about 90% who did not previously respond to antibiotics.

Adolescent binge-like alcohol exposure dysregulates NPY and CGRP in rats: Behavioural and immunochemical evidence.

Alcohol binge drinking during adolescence impacts affective behaviour, possibly impinging on developing neural substrates processing affective states, including calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY). Here, we modelled binge-like alcohol exposure in adolescence, by administering 3.5 g/kg alcohol per os, within 1 h, to male adolescent rats every other day, from postnatal day 35 to 54. The effects on positive and negative affective behaviour during abstinence were explored including: consummatory behaviour and weight gain; social behaviour in the modified social interaction test; thermal nociception in the tail-flick test; psychosocial stress coping in the resident-intruder paradigm. Moreover, CGRP and NPY levels were evaluated in functionally relevant brain regions. Our data shows that binge-like intermittent alcohol administration during adolescence decreased weight gain, social preference and motivation, nociception, and active psychosocial stress coping during abstinence. In addition, intermittent alcohol-exposed rats displayed increased expression of CGRP and NPY in the prefrontal cortex and nucleus accumbens; decreased NPY levels in the amygdala; opposite changes in CGRP levels in the hypothalamus and brainstem. Overall, our data shows that adolescent binge-like alcohol exposure, through the allostatic load of alternate intoxication and withdrawal, produces long-term consequences in sensory and affective processes and dysregulated complementary neuropeptidergic systems. Thus, neuropeptide-targeted interventions hold promising potential for addressing negative affect during prolonged withdrawal in young subjects.

Prenatal Exposure to Δ9-Tetrahydrocannabinol Affects Hippocampus-Related Cognitive Functions in the Adolescent Rat Offspring: Focus on Specific Markers of Neuroplasticity.

Previous evidence suggests that prenatal exposure to THC (pTHC) derails the neurodevelopmental trajectories towards a vulnerable phenotype for impaired emotional regulation and limbic memory. Here we aimed to investigate pTHC effect on hippocampus-related cognitive functions and markers of neuroplasticity in adolescent male offspring. Wistar rats were exposed to THC (2 mg/kg) from gestational day 5 to 20 and tested for spatial memory, object recognition memory and reversal learning in the reinforce-motivated Can test and in the aversion-driven Barnes maze test; locomotor activity and exploration, anxiety-like behaviour, and response to natural reward were assessed in the open field, elevated plus maze, and sucrose preference tests, respectively. The gene expression levels of NMDA NR1-2A subunits, mGluR5, and their respective scaffold proteins PSD95 and Homer1, as well as CB1R and the neuromodulatory protein HINT1, were measured in the hippocampus. pTHC offspring exhibited deficits in spatial and object recognition memory and reversal learning, increased locomotor activity, increased NR1-, decreased NR2A- and PSD95-, increased mGluR5- and Homer1-, and augmented CB1R- and HINT1-hippocampal mRNA levels. Our data shows that pTHC is associated with specific impairment in spatial cognitive processing and effectors of hippocampal neuroplasticity and suggests novel targets for future pharmacological challenges.

CBD enhances the cognitive score of adolescent rats prenatally exposed to THC and fine-tunes relevant effectors of hippocampal plasticity.

Introduction: An altered neurodevelopmental trajectory associated with prenatal exposure to ∆-9-tetrahydrocannabinol (THC) leads to aberrant cognitive processing through a perturbation in the effectors of hippocampal plasticity in the juvenile offspring. As adolescence presents a unique window of opportunity for "brain reprogramming", we aimed at assessing the role of the non-psychoactive phytocannabinoid cannabidiol (CBD) as a rescue strategy to temper prenatal THC-induced harm. Methods: To this aim, Wistar rats prenatally exposed to THC (2 mg/kg s.c.) or vehicle (gestational days 5-20) were tested for specific indexes of spatial and configural memory in the reinforcement-motivated Can test and in the aversion-driven Barnes maze test during adolescence. Markers of hippocampal excitatory plasticity and endocannabinoid signaling-NMDAR subunits NR1 and 2A-, mGluR5-, and their respective scaffold proteins PSD95- and Homer 1-; CB1R- and the neuromodulatory protein HINT1 mRNA levels were evaluated. CBD (40 mg/kg i.p.) was administered to the adolescent offspring before the cognitive tasks. Results: The present results show that prenatal THC impairs hippocampal memory functions and the underlying synaptic plasticity; CBD is able to mitigate cognitive impairment in both reinforcement- and aversion-related tasks and the neuroadaptation of hippocampal excitatory synapses and CB1R-related signaling. Discussion: While this research shows CBD potential in dampening prenatal THC-induced consequences, we point out the urgency to curb cannabis use during pregnancy in order to avoid detrimental bio-behavioral outcomes in the offspring.

Alcohol binge drinking in adolescence and psychological profile: Can the preclinical model crack the chicken-or-egg question?

During adolescence, internal and external factors contribute to engaging with alcohol binge drinking (ABD), putting at risk the neurodevelopment of brain regions crucial for emotional control and stress coping. This research assessed the prevalence of ABD in late adolescent students of Southern Italy and characterized their psychological profile and drinking motives. Translational effects of alcohol binge drinking in the animal model were also studied. Seven hundred and fifty-nine high school students of both sexes (aged 18-20) were recruited. Alcohol Use Disorder Identification Test-Consumption (AUDIT-C), Drinking Motives Questionnaire-Revised Short Form, Millon Clinical Multiaxial Inventory-Third Ed., State-Trait Anxiety Inventory, Connor-Davidson Resilience Scale, and Basic Self-Esteem Scale identified alcohol habits, drinking motives, and psychopathological profile. Eighty-five percentage of the students drank alcohol and 28% of them engaged in ABD; AUDIT-C correlated with enhancement, coping, and conformity motives. ABD was related to a greater likelihood of presenting clinical syndromes and personality disorders, as well as low resilience and self-esteem. Thereafter, in the pre-clinical model, adolescent male rats were exposed to alcohol (3.5 g/kg) in an intermittent binge-like paradigm and tested during prolonged abstinence. Rats were evaluated for anxiety-like behavior, motivated behaviors, resilience, and stress response following a psychosocial challenge. Binge-like alcohol-exposed adolescent rats displayed high integrated z-score for social- and novelty-induced anxiety, altered motivation-driven output, decreased resilience, and a blunted HPA axis response to psychosocial stress, with respect to respective controls. Our data confirm that ABD is the chosen pattern of drinking in a significant percentage of high school students in Southern Italy, and highlights AUDIT-C score as a relevant parameter able to predict the occurrence of affective disturbances. The evidence from the preclinical model shows that ABD produces detrimental consequences in the adolescent rat brain, resulting in negative affect, emotional dysregulation, and aberrant stress response, pointing to decreasing excessive alcohol drinking as a primary goal for the global act for brain health.

Alcohol and Nicotine Use among Adolescents: An Observational Study in a Sicilian Cohort of High School Students.

In recent years, the mode of alcoholic intake known as binge drinking (BD) has become a common practice, especially among adolescents who, due to socio-environmental motives, tend to reach a rapid state of drunkenness. This drunkeness leads to alterations in brain areas responsible for executive functions and cognitive processes, as well as to the genesis of factors that predispose to lasting addiction. Likewise, nicotine leads to a comparable degree of addiction. On this basis, the aim of this research was to evaluate, on a cohort of 349 high school students (15−17 years old) in the province of Palermo, the following: (I) the drinking model of alcoholic beverages; (II) the use of nicotine and the degree of dependence; (III) the correlation between the consumption of alcoholic beverages and the use of nicotine. We employed the AUDIT-C test and the Fagerström test, two valid and standard instruments, in order to assess alcohol and nicotine use, respectively. Statistical analysis of the data showed that male and female students consumed alcohol prominently in a BD mode (77.2%, audit score (AS) 3.497, confidence interval (CI) 3.206−3.788; 69.6%, AS 2.793, CI 2.412−3.274) and nicotine (41.5%, Fagerström score (FS) 3.882, CI 3.519−4.245; 28%, FS 3.286, CI 2.547−4.024). Furthermore, a positive correlation between alcohol consumption and nicotine use was found for male (r = 0.6798, p < 0.0001) and female (r = 0.6572, p < 0.0001) students. This study provided further insights into the use of legal substances of abuse in adolescents, evidencing the obvious need for the promotion of specific school educational programs aimed at the wellbeing of youth populations.

Alcohol Abuse and Insomnia Disorder: Focus on a Group of Night and Day Workers.

The sleep-wake cycle plays a fundamental role in maintaining the physiological balance of our body. Its alteration favours the genesis of several organic alterations and diseases including sleep disorders and the consumption of several substances of abuse. It has been reported that the work activity, especially that carried out during the night, is able to influence the sleep-wake cycle, promoting the development of insomnia, which, in turn, would subject the worker to a stressful condition such as to encourage adverse behaviour such as the use/abuse of psychotropic substances. Based on the above premises, the aim of our research was to evaluate, in night workers: (i) the pattern of consumption of alcoholic beverages; (ii) the presence of insomnia; and (iii) the possible correlation between alcohol consumption and insomnia disorder. We used the AUDIT-C test (the abbreviated version of the Alcohol Use Disorders Identification Test) and the Insomnia Severity Index to assess alcohol consumption and insomnia disorder, respectively. All questionnaires were completed by workers of both sexes belonging to different types of work activities, exclusively day or night. The results of our research show a higher propensity of night workers to consume alcoholic beverages than those who work during daytime hours, often in binge-drinking mode. In addition, an increase in the amount of alcohol consumed was found to be related to insomnia disorder, especially in night workers. This study provides further awareness of the importance of the negative impact of alcohol consumption on sleep quality in night workers.

Binge-like Alcohol Exposure in Adolescence: Behavioural, Neuroendocrine and Molecular Evidence of Abnormal Neuroplasticity and Return.

Binge alcohol consumption among adolescents affects the developing neural networks underpinning reward and stress processing in the nucleus accumbens (NAc). This study explores in rats the long-lasting effects of early intermittent exposure to intoxicating alcohol levels at adolescence, on: (1) the response to natural positive stimuli and inescapable stress; (2) stress-axis functionality; and (3) dopaminergic and glutamatergic neuroadaptation in the NAc. We also assess the potential effects of the non-intoxicating phytocannabinoid cannabidiol, to counteract (or reverse) the development of detrimental consequences of binge-like alcohol exposure. Our results show that adolescent binge-like alcohol exposure alters the sensitivity to positive stimuli, exerts social and novelty-triggered anxiety-like behaviour, and passive stress-coping during early and prolonged withdrawal. In addition, serum corticosterone and hypothalamic and NAc corticotropin-releasing hormone levels progressively increase during withdrawal. Besides, NAc tyrosine hydroxylase levels increase at late withdrawal, while the expression of dopamine transporter, D1 and D2 receptors is dynamically altered during binge and withdrawal. Furthermore, the expression of markers of excitatory postsynaptic signaling-PSD95; Homer-1 and -2 and the activity-regulated spine-morphing proteins Arc, LIM Kinase 1 and FOXP1-increase at late withdrawal. Notably, subchronic cannabidiol, during withdrawal, attenuates social- and novelty-induced aversion and passive stress-coping and rectifies the hyper-responsive stress axis and NAc dopamine and glutamate-related neuroplasticity. Overall, the exposure to binge-like alcohol levels in adolescent rats makes the NAc, during withdrawal, a locus minoris resistentiae as a result of perturbations in neuroplasticity and in stress-axis homeostasis. Cannabidiol holds a promising potential for increasing behavioural, neuroendocrine and molecular resilience against binge-like alcohol harmful effects.

Environmental Enrichment During Adolescence Mitigates Cognitive Deficits and Alcohol Vulnerability due to Continuous and Intermittent Perinatal Alcohol Exposure in Adult Rats.

Perinatal alcohol exposure affects ontogenic neurodevelopment, causing physical and functional long-term abnormalities with limited treatment options. This study investigated long-term consequences of continuous and intermittent maternal alcohol drinking on behavioral readouts of cognitive function and alcohol vulnerability in the offspring. The effects of environmental enrichment (EE) during adolescence were also evaluated. Female rats underwent continuous alcohol drinking (CAD)-or intermittent alcohol drinking paradigm (IAD), along pregestation, gestation, and lactation periods-equivalent to the whole gestational period in humans. Male offspring were reared in standard conditions or EE until adulthood and were then assessed for declarative memory in the novel object recognition test; spatial learning, cognitive flexibility, and reference memory in the Morris water maze (MWM); alcohol consumption and relapse by a two-bottle choice paradigm. Our data show that perinatal CAD decreased locomotor activity, exploratory behavior, and declarative memory with respect to controls, whereas perinatal IAD displayed impaired declarative memory and spatial learning and memory. Moreover, both perinatal alcohol-exposed offspring showed higher vulnerability to alcohol consummatory behavior than controls, albeit perinatal IAD rats showed a greater alcohol consumption and relapse behavior with respect to perinatal-CAD progeny. EE ameliorated declarative memory in perinatal CAD, while it mitigated spatial learning and reference memory impairment in perinatal-IAD progeny. In addition, EE decreased vulnerability to alcohol in both control and perinatal alcohol-exposed rats. Maternal alcohol consumption produces drinking pattern-related long-term consequences on cognition and vulnerability to alcohol in the offspring. However, increased positive environmental stimuli during adolescence may curtail the detrimental effects of developmental alcohol exposure.

Targeting the Stress System During Gestation: Is Early Handling a Protective Strategy for the Offspring?

The perinatal window is a critical developmental time when abnormal gestational stimuli may alter the development of the stress system that, in turn, influences behavioral and physiological responses in the newborns. Individual differences in stress reactivity are also determined by variations in maternal care, resulting from environmental manipulations. Despite glucocorticoids are the primary programming factor for the offspring's stress response, therapeutic corticosteroids are commonly used during late gestation to prevent preterm negative outcomes, exposing the offspring to potentially aberrant stress reactivity later in life. Thus, in this study, we investigated the consequences of one daily s.c. injection of corticosterone (25 mg/kg), from gestational day (GD) 14-16, and its interaction with offspring early handling, consisting in a brief 15-min maternal separation until weaning, on: (i) maternal behavior; and (ii) behavioral reactivity, emotional state and depressive-like behavior in the adolescent offspring. Corticosterone plasma levels, under non-shock- and shock-induced conditions, were also assessed. Our results show that gestational exposure to corticosterone was associated with diminished maternal care, impaired behavioral reactivity, increased emotional state and depressive-like behavior in the offspring, associated with an aberrant corticosterone response. The early handling procedure, which resulted in increased maternal care, was able to counteract the detrimental effects induced by gestational corticosterone exposure both in the behavioral- and neurochemical parameters examined. These findings highlight the potentially detrimental consequences of targeting the stress system during pregnancy as a vulnerability factor for the occurrence of emotional and affective distress in the adolescent offspring. Maternal extra-care proves to be a protective strategy that confers resiliency and restores homeostasis.

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

BACKGROUND: Cannabinoid consumption during pregnancy has been increasing on the wave of the broad-based legalisation of cannabis in Western countries, raising concern about the putative detrimental outcomes on foetal neurodevelopment. Indeed, since the endocannabinoid system regulates synaptic plasticity, emotional and cognitive processes from early stages of life interfering with it and other excitability endogenous modulators, such as neuropeptide Y (NPY), might contribute to the occurrence of a vulnerable phenotype later in life. AIMS: This research investigated whether in utero exposure to Δ9-tetrahydrocannabinol (THC) may induce deficits in emotional/cognitive processes and alcohol vulnerability in adolescent offspring. NPY and excitatory postsynaptic density (PSD) machinery were measured as markers of neurobiological vulnerability. METHODS: Following in utero THC exposure (2 mg/kg delivered subcutaneously), preadolescent male rat offspring were assessed for: behavioural reactivity in the open field test, neutral declarative memory and aversive limbic memory in the Novel Object and Emotional Object Recognition tests, immunofluorescence for NPY neurons and the PSD proteins Homer-1, 1b/c and 2 in the prefrontal cortex, amygdala and nucleus accumbens at adolescence (cohort 1); and instrumental learning, alcohol taking, relapse and conflict behaviour in the operant chamber throughout adolescence until early adulthood (cohort 2). RESULTS: In utero THC-exposed adolescent rats showed: (a) increased locomotor activity; (b) no alteration in neutral declarative memory; (c) impaired aversive limbic memory; (d) decreased NPY-positive neurons in limbic regions; (e) region-specific variations in Homer-1, 1b/c and 2 immunoreactivity; (f) decreased instrumental learning and increased alcohol drinking, relapse and conflict behaviour in the operant chamber. CONCLUSION: Gestational THC impaired the formation of memory traces when integration between environmental encoding and emotional/motivational processing was required and promoted the development of alcohol-addictive behaviours. The abnormalities in NPY signalling and PSD make-up may represent the common neurobiological background, suggesting new targets for future research.

Pre-conceptional and Peri-Gestational Maternal Binge Alcohol Drinking Produces Inheritance of Mood Disturbances and Alcohol Vulnerability in the Adolescent Offspring.

Although binge drinking is on the rise in women of reproductive age and during pregnancy, the consequences in the offspring, in particular the inheritance of alcohol-related mood disturbances and alcohol abuse vulnerability, are still poorly investigated. In this study, we modeled both Habitual- and Binge Alcohol Drinking (HAD and BAD) in female rats by employing a two-bottle choice paradigm, with 20% alcohol and water. The exposure started 12 weeks before pregnancy and continued during gestation and lactation. The consequences induced by the two alcohol drinking patterns in female rats were assessed before conception in terms of behavioral reactivity, anxiety- and depressive-like behavior. Afterwards, from adolescence to young-adulthood, male offspring was assessed for behavioral phenotype and alcohol abuse vulnerability. At pre-conceptional time BAD female rats showed higher mean alcohol intake and preference than HAD group; differences in drinking trajectories were attenuated during pregnancy and lactation. Pre-conceptional BAD induced a prevalent depressive/anhedonic-like behavior in female rats, rather than an increase in anxiety-like behavior, as observed in HAD rats. In the adolescent offspring, peri-gestational BAD did not affect behavioral reactivity in the open field and anxiety-like behavior in the elevated plus maze. Rather, BAD dams offspring displayed higher despair-behavior and lower social interaction with respect to control- and HAD dams progeny. Notably, only binge drinking exposure increased offspring vulnerability to alcohol abuse and relapse following forced abstinence. This is the first report showing that binge-like alcohol consumption from pre-conceptional until weaning induces relevant consequences in the affective phenotype of both the mothers and the offspring, and that such effects include heightened alcohol abuse vulnerability in the offspring. These findings highlight the need for more incisive public education campaigns about detrimental consequences of peri-gestational alcohol exposure.

Homer2 and Alcohol: A Mutual Interaction.

The past two decades of data derived from addicted individuals and preclinical animal models of addiction implicate a role for the excitatory glutamatergic transmission within the mesolimbic structures in alcoholism. The cellular localization of the glutamatergic receptor subtypes, as well as their signaling efficiency and function, are highly dependent upon discrete functional constituents of the postsynaptic density, including the Homer family of scaffolding proteins. The consequences of repeated alcohol administration on the expression of the Homer family proteins demonstrate a crucial and active role, particularly for the expression of Homer2 isoform, in regulating alcohol-induced behavioral and cellular neuroplasticity. The interaction between Homer2 and alcohol can be defined as a mutual relation: alcohol consumption enhances the expression of Homer2 protein isoform within the nucleus accumbens and the extended amygdala, cerebral areas where, in turn, Homer2 is able to mediate the development of the "pro-alcoholic" behavioral phenotype, as a consequence of the morpho-functional synaptic adaptations. Such findings are relevant for the detection of the strategic molecular components that prompt alcohol-induced functional and behavioral disarrangement as targets for future innovative treatment options.

Tablet and oral liquid L-thyroxine formulation in the treatment of naïve hypothyroid patients with Helicobacter pylori infection.

To compare the clinical efficacy of tablet and oral liquid L-thyroxine (LT4) formulation in naïve hypothyroid subjects with Helicobacter pylori infection. Forty-seven adult naïve hypothyroid subjects with dyspeptic symptoms were investigated with upper endoscopy and divided into: 28 patients with Helicobacter pylori infection (Group A); 15 patients without gastric alterations (group B); 4 patients with autoimmune gastritis were excluded from the study. Subjects were randomly treated with a same dose of LT4 tablet (TAB) or oral liquid formulation (SOL), for 9 months on group A and 6 months on group B. Helicobacter pylori infection was eradicated after 3 months of LT4 treatment. On group A, after 3 months (before Helicobacter pylori eradication), subjects treated with SOL showed a greater thyroid-stimulating hormone reduction (ΔTSH3-0: TAB = -4.1 ± 4.6 mU/L; SOL = -7.7 ± 2.5 mU/L; p = 0.029) and a greater homogeneity in the thyroid-stimulating hormone values (TSH3mo: TAB = 5.7 ± 4.9 mU/L; SOL = 4.1 ± 2.0 mU/L; p = 0.025), compared to LT4 tablet. At 9 months (after 6 months of Helicobacter pylori eradication) mean thyroid-stimulating hormone values were lower in subjects treated with LT4 tablet (TSH9mo: TAB = 1.8 ± 1.2 mU/L; SOL = 3.2 ± 1.7 mU/L; p = 0.006). On group B no difference were observed, at each time point, in the mean thyroid-stimulating hormone values and thyroid-stimulating hormone variations between two LT4 formulations. LT4 liquid formulation may produce a better clinical response compared to the tablet formulation in hypothyroid subjects with Helicobacter pylori infection.

Power of screening tests for colorectal cancer enhanced by high levels of M2-PK in addition to FOBT.

Colorectal cancer (CRC) is a multistep process that involves adenoma-carcinoma sequence. CRC can be prevented by routine screening, which can detect precancerous lesions. The aim of this study is to clarify whether faecal occult blood test (i-FOBT), tumor M2 pyruvate kinase (t-M2-PK), and endocannabinoid system molecules (cannabinoid receptors type 1-CB1, type 2-CB2, and fatty acid amide hydrolase-FAAH) might represent better diagnostic tools, alone or in combination, for an early diagnosis of CRC. An immunochemical FOB test (i-FOBT) and quantitative ELISA stool test for t-M2-PK were performed in 127 consecutive patients during a 12 month period. Endocannabinoid system molecules and t-M2-PK expression were detected by immunostaining in healthy tissues and normal mucosa surrounding adenomatous and cancerous colon lesions. i-FOBT and t-M2-PK combination leads to a better diagnostic accuracy for pre-neoplastic and neoplastic colon lesions. T-M2-PK quantification in stool samples and in biopsy samples (immunostaining) correlates with tumourigenesis stages. CB1 and CB2 are well expressed in healthy tissues, and their expression decreases in the presence of advanced stages of carcinogenesis and disappears in CRC. FAAH signal is well expressed in normal mucosa and low-risk adenoma, and increased in high-risk adenoma and carcinoma adjacent tissues. This study shows that high levels of t-M2-PK in addition to FOBT enhance the power of a CRC screening test. Endocannabinoid system molecule expression correlates with colon carcinogenesis stages. Developing future faecal tests for their quantification must be undertaken to obtain a more accurate early non-invasive diagnosis for CRC.