Symptomatic remission and recovery in major psychosis: Is there a role for BDNF? A secondary analysis of the LABSP cohort data.

Remission, relapse prevention, and clinical recovery are crucial areas of interest in schizophrenia (SCZ) research. Although SCZ is a chronic disorder with poor overall outcomes, years of research demonstrated that recovery is possible. There are considerable data linking brain-derived neurotrophic factor (BDNF) to SCZ, however, evidence on the role of BDNF in remission in SCZ is scarce. This secondary analysis of the Longitudinal Assessment of BDNF in Sardinian patients (LABSP) data aimed to investigate the relationship between serum BDNF levels and symptomatic remission, simultaneous clinical and functional remission, and recovery in patients with SCZ. A total of 105 patients with SCZ or schizoaffective disorder were recruited for a longitudinal assessment of BDNF levels over 24 months. Longitudinal data were analyzed using mixed-effects linear regression models. The study found significant associations between use of long acting injectables (χ2 = 7.075, df = 1, p = 0.008), baseline serum BDNF levels (U = 701, z = -2.543, p = 0.011), and "childhood" (U = 475, z = -2.124, p = 0.034) and "general" (U = 55, z = -2.014, p = 0.044) subscales of the Premorbid Adjustment Scale (PAS) with patients maintaining remission and recovery. The diagnosis of SCZ was significantly associated with lower BDNF levels for patients with simultaneous clinical and functional remission (Z = 2.035, p = 0.0419) and recovery (Z = 2.009, p = 0.0445) compared to those without. There were no significant associations between remission in the entire sample and longitudinal serum BDNF levels or genetic variants within the BDNF gene. These findings provide further insight into the complex relationship between BDNF and SCZ.

Induction of Activity-Regulated Cytoskeleton-Associated Protein and c-Fos Expression in an Animal Model of Anorexia Nervosa.

Anorexia nervosa (AN) is a complex eating disorder characterized by reduced caloric intake to achieve body-weight loss. Furthermore, over-exercise is commonly reported. In recent years, animal models of AN have provided evidence for neuroplasticity changes in specific brain areas of the mesocorticolimbic circuit, which controls a multitude of functions including reward, emotion, motivation, and cognition. The activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates several forms of synaptic plasticity and has been linked to neuropsychiatric illness. Since the role of Arc in AN has never been investigated, in this study we evaluated whether the anorexic-like phenotype reproduced by the activity-based anorexia (ABA) model may impact its expression in selected brain regions that belong to the mesocorticolimbic circuit (i.e., prefrontal cortex, nucleus accumbens, and hippocampus). The marker of neuronal activation c-Fos was also assessed. We found that the expression of both markers increased in all the analyzed brain areas of ABA rats in comparison to the control groups. Moreover, a negative correlation between the density of Arc-positive cells and body-weight loss was found. Together, our findings suggest the importance of Arc and neuroplasticity changes within the brain circuits involved in dysfunctional behaviors associated with AN.

Anaplastic Lymphoma Kinase Receptor: Possible Involvement in Anorexia Nervosa.

The pathophysiology of Anorexia Nervosa (AN) has not been fully elucidated. Anaplastic lymphoma kinase (ALK) receptor is a protein-tyrosine kinase mainly known as a key oncogenic driver. Recently, a genetic deletion of ALK in mice has been found to increase energy expenditure and confers resistance to obesity in these animals, suggesting its role in the regulation of thinness. Here, we investigated the expression of ALK and the downstream intracellular pathways in female rats subjected to the activity-based anorexia (ABA) model, which reproduces important features of human AN. In the hypothalamic lysates of ABA rats, we found a reduction in ALK receptor expression, a downregulation of Akt phosphorylation, and no change in the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation. After the recovery from body weight loss, ALK receptor expression returned to the control baseline values, while it was again suppressed during a second cycle of ABA induction. Overall, this evidence suggests a possible involvement of the ALK receptor in the pathophysiology of AN, that may be implicated in its stabilization, resistance, and/or its exacerbation.

Food restriction and hyperactivity induce changes in corticolimbic brain dopamine and serotonin levels in female rats.

Compelling data support altered dopamine (DA) and serotonin (5-HT) signaling in anorexia nervosa (AN). However, their exact role in the etiopathogenesis of AN has yet to be elucidated. Here, we evaluated the corticolimbic brain levels of DA and 5-HT in the induction and recovery phases of the activity-based anorexia (ABA) model of AN. We exposed female rats to the ABA paradigm and measured the levels of DA, 5-HT, the metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and the dopaminergic type 2 (D2) receptors density in feeding- and reward-implicated brain regions (i.e., cerebral cortex, Cx; prefrontal cortex, PFC; caudate putamen, CPu; nucleus accumbens, NAcc; amygdala, Amy; hypothalamus, Hyp; hippocampus, Hipp). DA levels were significantly increased in the Cx, PFC and NAcc, while 5-HT was significantly enhanced in the NAcc and Hipp of ABA rats. Following recovery, DA was still elevated in the NAcc, while 5-HT was increased in the Hyp of recovered ABA rats. DA and 5-HT turnover were impaired at both ABA induction and recovery. D2 receptors density was increased in the NAcc shell. These results provide further proof of the impairment of the dopaminergic and serotoninergic systems in the brain of ABA rats and support the knowledge of the involvement of these two important neurotransmitter systems in the development and progression of AN. Thus, providing new insights on the corticolimbic regions involved in the monoamine dysregulations in the ABA model of AN.

Converging Evidence Points to BDNF as Biomarker of Depressive Symptoms in Schizophrenia-Spectrum Disorders.

Brain-derived neurotrophic factor (BDNF) is a key modulator of neuroplasticity and has an important role in determining the susceptibility to severe psychiatric disorder with a significant neurodevelopmental component such as major psychoses. Indeed, a potential association between BDNF serum levels and schizophrenia (SCZ) and schizoaffective disorder (SAD) has been tested in diverse studies and a considerable amount of them found reduced BDNF levels in these disorders. Here, we aimed at testing the association of BDNF serum levels with several demographic, clinical, and psychometric measures in 105 patients with SCZ and SAD, assessing the moderating effect of genetic variants within the BDNF gene. We also verified whether peripheral BDNF levels differed between patients with SCZ and SAD. Our findings revealed that BDNF serum levels are significantly lower in patients affected by SCZ and SAD presenting more severe depressive symptomatology. This finding awaits replication in future independent studies and points to BDNF as a possible prognostic indicator in major psychoses.

Exploring the association between brain-derived neurotrophic factor levels and longitudinal psychopathological and cognitive changes in Sardinian psychotic patients.

BACKGROUND AND HYPOTHESIS: Schizophrenia spectrum disorders are among the most debilitating mental disorders and has complex pathophysiological underpinnings. There is growing evidence that brain-derived neurotrophic factor (BDNF) can play a role in its pathogenesis. The present study investigated the longitudinal variation of serum BDNF levels in a 24-month observational prospective cohort study of Sardinian psychotic patients and its relationship with psychopathological and cognitive changes. Furthermore, we examined whether genetic variation within the BDNF gene could moderate these relationships. STUDY DESIGN: Every 6 months, 105 patients were assessed for their BDNF serum levels, as well as for a series of psychopathological, cognitive, and social measures. We performed a targeted analysis of four tag single nucleotide polymorphisms within the BDNF gene that were selected and analyzed using polymerase chain reaction. Longitudinal data were analyzed using mixed-effects linear regression models. STUDY RESULTS: We observed a declining longitudinal trajectory of BDNF levels in psychotic patients in general, and in relation to the severity of depressive and negative symptoms. BDNF serum levels also declined in patients scoring lower in cognitive measures such as attention and speed of information processing and verbal fluency. The rs7934165 polymorphism moderated the significant association between verbal fluency and BDNF levels. CONCLUSIONS: These findings in patients from real-world settings suggest a plausible role of peripheral BDNF levels as a marker of illness burden in schizophrenia spectrum disorders.

K18- and CAG-hACE2 Transgenic Mouse Models and SARS-CoV-2: Implications for Neurodegeneration Research.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that might lead to very serious consequences. Notably, mental status change, brain confusion, and smell and taste disorders along with neurological complaints have been reported in patients infected with SARS-CoV-2. Furthermore, human brain tissue autopsies from COVID-19 patients show the presence of SARS-CoV-2 neuroinvasion, which correlates with the manifestation of meningitis, encephalitis, leukocyte infiltration, and neuronal damage. The olfactory mucosa has been suggested as a way of entry into the brain. SARS-CoV-2 infection is also known to provoke a hyper-inflammatory reaction with an exponential increase in the production of pro-inflammatory cytokines leading to systemic responses, even in the absence of direct infection of brain cells. Angiotensin-converting enzyme 2 (ACE2), the entry receptor of SARS-CoV-2, has been extensively demonstrated to be present in the periphery, neurons, and glial cells in different brain regions. To dissect the details of neurological complications and develop therapies helping COVID-19 survivors regain pre-infection quality of life, the development of robust clinical models is highly warranted. Several human angiotensin-converting enzyme 2 (hACE2) transgenic mouse models have been developed and used for antiviral drug screening and vaccine development, as well as for better understanding of the molecular pathogenetic mechanisms of SARS-CoV-2 infection. In this review, we summarize recent results from the studies involving two such mouse models, namely K18- and CAG-hACE2 transgenics, to evaluate the direct and indirect impact of SARS-CoV-2 infection on the central nervous system.

Synaptoproteomic Analysis of the Prefrontal Cortex Reveals Spatio-Temporal Changes in SYNGAP1 Following Cannabinoid Exposure in Rat Adolescence.

The regular use of cannabis during adolescence has been associated with a number of negative life outcomes, including psychopathology and cognitive impairments. However, the exact molecular mechanisms that underlie these outcomes are just beginning to be understood. Moreover, very little is known about the spatio-temporal molecular changes that occur following cannabinoid exposure in adolescence. To understand these changes, we exposed mid-adolescent male rats to a synthetic cannabinoid (WIN 55,212-2 mesylate; WIN) and, following drug abstinence through late adolescence, we subjected the synaptosomal fractions of the prefrontal cortex (PFC) to proteomic analyses. A total of N = 487 differentially expressed proteins were found in WIN-exposed animals compared to controls. Gene ontology analyses revealed enrichment of terms related to the gamma-aminobutyric acid (GABA)-ergic neurotransmitter system. Among the top differentially expressed proteins was the synaptic Ras GTPase-activating protein 1 (SYNGAP1). Using Western blotting experiments, we found that the WIN-induced upregulation of SYNGAP1 was spatio-temporal in nature, arising only in the synaptosomal fractions (not in the cytosol) and only following prolonged drug abstinence (not on abstinence day 1). Moreover, the SYNGAP1 changes were found to be specific to WIN-exposure in adolescence and not adulthood. Adolescent animals exposed to a natural cannabinoid (Δ9-tetrahydrocannabinol; THC) were also found to have increased levels of SYNGAP1 in the PFC. THC exposure also led to a pronounced upregulation of SYNGAP1 in the amygdala, but without any changes in the dorsal striatum, hippocampus, or nucleus accumbens. To our knowledge, this is the first study to uncover a link between cannabinoid exposure and changes in SYNGAP1 that are spatio-temporal and developmental in nature. Future studies are needed to investigate the putative role of SYNGAP1 in the negative behavioral consequences of cannabis use in adolescence.

Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research.

Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD's therapeutic outcomes.

Conditioned Place Preference (CPP) in Rats: From Conditioning to Reinstatement Test.

Opioid addiction in humans is a chronically relapsing disorder characterized by discontinuous periods of drug use and abstinence resulting in dependence. With time, the probability of falling into renewed drug consumption becomes particularly high and constitutes a considerable problem in the management of opioid addicts. Opioid addiction represents an important health concern and animal models have been crucial in understanding the neurobiology and pathophysiology of this complex disease. Although animal models of addiction do not fully reproduce the human condition, they do permit investigation of specific elements of the process as well as identification of potential therapeutic targets. In this chapter, we provide a step-by-step description of the morphine-conditioned place preference (CPP) model that represents a useful preclinical animal model extensively used to study the rewarding/aversive effect of drugs.

Analysis of Opioid-Seeking Behavior Through the Intravenous Self-Administration Reinstatement Model in Rats.

The inability to maintain drug abstinence is often referred to as relapse and consists of a process by which an abstaining individual slips back into old behavioral patterns and substance use. Animal models of relapse have been developed over the last decades and significantly contributed to shed light on the neurobiological mechanisms underlying vulnerability to relapse. The most common procedure to study drug-seeking and relapse-like behavior in animals is the "extinction-reinstatement model." Originally elaborated by Pavlov and Skinner, the concepts of reinforced operant responding were applied to addiction research not before 1971 (Stretch et al., Can J Physiol Pharmacol 49:581-589, 1971), and the first report of a reinstatement animal model as it is now used worldwide was published only 10 years later (De Wit and Stewart, Psychopharmacology 75:134-143, 1981). According to the proposed model, opioids are typically self-administered intravenously, as humans do, and although rodents are most often employed in these studies, a variety of species including nonhuman primates, dogs, cats, and pigeons can be used. Several operant responses are available, depending on the species studied. For example, a lever press or a nose poke response typically is used for rodents, whereas a panel press response typically is used for nonhuman primates. In this chapter we describe a simple and easily reproducible protocol of heroin-seeking reinstatement in rats, which proved useful to study the neurobiological mechanisms underlying relapse to heroin and vulnerability factors enhancing the resumption of heroin-seeking behavior.

Cannabinoids and their therapeutic applications in mental disorders
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Mental disorders represent a significant public health burden worldwide due to their high prevalence, chronically disabling nature, and substantial impact on quality of life. Despite growing knowledge of the pathological mechanisms that underlie the development of these disorders, a high percentage of patients do not respond to first-line clinical treatments; thus, there is a strong need for alternative therapeutic approaches. During the past half-century, after the identification of the endocannabinoid system and its role in multiple physiological processes, both natural and synthetic cannabinoids have attracted considerable interest as putative medications in pathological conditions such as, but not exclusive to, mental disorders. Here, we provide a summary of cannabinoid effects in support of possible therapeutic applications for major depression, bipolar disorder, anxiety, posttraumatic stress disorder, and schizophrenia. Considering this evidence, highlighted benefits and risks of cannabinoid use in the management of these illnesses require further experimental study.
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Los trastornos mentales representan una carga importante para la salud pública en todo el mundo debido a su alta prevalencia, su naturaleza crónica con discapacidad y su impacto significativo en la calidad de vida. A pesar del creciente conocimiento de los mecanismos patológicos que subyacen al desarrollo de estos trastornos, un alto porcentaje de pacientes no responde a los tratamientos clínicos de primera línea; por lo que existe una gran necesidad de enfoques terapéuticos alternativos. Durante los últimos cincuenta años, después de la identificación del sistema endocannabinoide y su papel en múltiples procesos fisiológicos, tanto los cannabinoides naturales como los sintéticos han concentrado un alto interés como posibles fármacos para trastornos mentales y otras patologías. En este artículo se resumen los efectos de los cannabinoides en apoyo de posibles aplicaciones terapéuticas para la depresión mayor, el trastorno bipolar, la ansiedad, el trastorno por estrés postraumático y la esquizofrenia. Teniendo en cuenta esta evidencia, el destacar tanto los riesgos como los beneficios del empleo de los cannabinoides en el tratamiento de estas enfermedades requiere de más trabajo experimental.

La prévalence élevée des troubles mentaux, leur chronicité et leur impact important sur la qualité de vie pèsent significativement sur la santé publique mondiale. La connaissance des mécanismes pathologiques qui sous-tendent ces troubles a progressé mais, un pourcentage élevé de patients ne répondant pas aux traitements de première ligne, d'autres approches thérapeutiques sont indispensables. L'étude du système endocannabinoïde et la mise en évidence de son rôle dans de multiples processus physiologiques au cours des cinquante dernières années, ont fortement attiré l'attention sur les cannabinoïdes naturels et synthétiques en tant que médicaments potentiels dans certaines pathologies comme, entre autres, les troubles mentaux. Nous résumons dans cet article les effets cannabinoϊdes qui pourraient s'inscrire dans le traitement de la dépression majeure, des troubles bipolaires, de l'anxiété, de l'état de stress post-traumatique et de la schizophrénie. Ces arguments nous incitent à explorer davantage les avantages et les risques des cannabinoïdes dans la prise en charge de ces maladies.

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain's initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2 Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK-targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC-NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

Altered brain levels of arachidonic acid-derived inflammatory eicosanoids in a rodent model of anorexia nervosa.

Increasing evidence underline the role of inflammation in the behavioral, emotional and cognitive dysregulations displayed in anorexia nervosa (AN). Among the inflammatory mediators acting at both peripheral and central levels, growing attention receives a class of lipids derived from arachidonic acid (AA), called eicosanoids (eiCs), which exert a complex, multifaceted role in a wide range of neuroinflammatory processes, peripheral inflammation, and generally in immune system function. To date, little is known about their possible involvement in the neurobiological underpinnings of AN. The present study evaluated whether the activity-based model of AN (ABA) may alter AA-metabolic pathways by changing the levels of AA-derived eiCs in specific brain areas implicated in the development of the typical anorexic-like phenotype, i.e. in prefrontal cortex, cerebral cortex, nucleus accumbens, caudate putamen, amygdala, hippocampus, hypothalamus and cerebellum. Our results point to brain region-specific alterations of the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 epoxygenase (CYP) metabolic pathways rendering altered levels of AA-derived eiCs (i.e. prostaglandins, thromboxanes and hydroxyeicosatetraenoic acids) in response to induction of and recovery from the ABA condition. These changes, supported by altered messenger RNA (mRNA) levels of genes coding for enzymes involved in eiCs-related methabolic pathways (i.e., PLA2, COX-2, 5-LOX and 15-LOX), underlie a widespread brain dysregulation of pro- and anti-inflammatory eiC-mediated processes in the ABA model of AN. These data suggest the importance of eiCs signaling within corticolimbic areas in regulating key neurobehavioral functions and highlight eiCs as biomarker candidates for monitoring the onset and development of AN, and/or as possible targets for pharmacological management.

Gene knockout animal models of depression, anxiety and obsessive compulsive disorders.

In the past decades, the improving knowledge of genes implicated in the pathogenesis of psychiatric disorders together with the advancements in genetic engineering has led to the creation of mice in which one or more genes are inactivated or 'knocked out'. Knockout mice are extensively used to better investigate the molecular and cellular mechanisms underlying these diseases as well as the biological role of specific genes. Moreover, they are also useful tools for developing new therapeutic strategies. The success of using knockout mice is possible due to availability of several models used to mimic some clinical manifestations reported in psychiatric patients. In the present review, we will give an update of the most used gene knockout models in the field of psychiatric disorders including depression, anxiety, and obsessive-compulsive disorder.

Impaired brain endocannabinoid tone in the activity-based model of anorexia nervosa.

OBJECTIVE: Despite the growing knowledge on the functional relationship between an altered endocannabinoid (eCB) system and development of anorexia nervosa (AN), to date no studies have investigated the central eCB tone in the activity-based anorexia (ABA) model that reproduces key aspects of human AN. METHOD: We measured levels of two major eCBs, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), those of two eCB-related lipids, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), and the cannabinoid type-1 receptor (CB1R) density in the brain of female ABA rats, focusing on areas involved in homeostatic and rewarding-related regulation of feeding behavior (i.e., prefrontal cortex, nucleus accumbens, caudato putamen, amygdala, hippocampus and hypothalamus). Analysis was carried out also at the end of recovery from the ABA condition. RESULTS: At the end of the ABA induction phase, 2-AG was significantly decreased in ABA rats in different brain areas but not in the caudato putamen. No changes were detected in AEA levels in any region, whereas the levels of OEA and PEA were decreased exclusively in the hippocampus and hypothalamus. Furthermore, CB1R density was decreased in the dentate gyrus of hippocampus and in the lateral hypothalamus. After recovery, both 2-AG levels and CB1R density were partially normalized in some areas. In contrast, AEA levels became markedly reduced in all the analyzed areas. DISCUSSION: These data demonstrate an altered brain eCB tone in ABA rats, further supporting the involvement of an impaired eCB system in AN pathophysiology that may contribute to the maintenance of some symptomatic aspects of the disease.

Brain activity of anandamide: a rewarding bliss?

Anandamide is a lipid mediator that acts as an endogenous ligand of CB1 receptors. These receptors are also the primary molecular target responsible for the pharmacological effects of Δ9-tetrahydrocannabinol, the psychoactive ingredient in Cannabis sativa. Several studies demonstrate that anandamide exerts an overall modulatory effect on the brain reward circuitry. Several reports suggest its involvement in the addiction-producing actions of other abused drugs, and it can also act as a behavioral reinforcer in animal models of drug abuse. Importantly, all these effects of anandamide appear to be potentiated by pharmacological inhibition of its metabolic degradation. Enhanced brain levels of anandamide after treatment with inhibitors of fatty acid amide hydrolase, the main enzyme responsible for its degradation, seem to affect the rewarding and reinforcing actions of many drugs of abuse. In this review, we will provide an overview from a preclinical perspective of the current state of knowledge regarding the behavioral pharmacology of anandamide, with a particular emphasis on its motivational/reinforcing properties. We will also discuss how modulation of anandamide levels through inhibition of enzymatic metabolic pathways could provide a basis for developing new pharmaco-therapeutic tools for the treatment of substance use disorders.

Sex and Feeding Status Differently Affect Natural Reward Seeking Behavior in Olfactory Bulbectomized Rats.

Substance abuse and depression are common psychiatric disorders with a high rate of comorbidity. Both conditions affect differently men and women and preclinical research has showed many sex differences in drug addiction and depression. The most common approach for modeling depression-addiction comorbidity is the combination of the intravenous drug self-administration and the olfactory bulbectomy (OBX) models in rats. Such a combination has revealed enhanced drug-taking and drug-seeking behaviors in OBX rats, but no study has investigated so far potential sex differences in operant responding and motivation for natural reinforcers in OBX rats. This study investigated for the first time operant self-administration of palatable food pellets in male and female OBX rats under different feeding status, i.e., ad libitum vs. restricted food, and schedules of reinforcement, i.e., a continuous ratio schedule fixed ratio 1 (FR1) vs. a complex (FR5(x)) second order schedule of reinforcement. In the FR1 experiment, OBX rats of both sexes exhibited lower operant responding and intake of palatable food pellets than sham-operated controls, with food restriction leading to increased operant responding in both OBX and SHAM groups. Female rats showed higher responding than males but this effect was abolished by the OBX lesion. Similarly, in the (FR5(x)) second order schedule of reinforcement both male and female OBX rats showed lower responding and food intake, with SHAM and OBX females showing higher operant responding than corresponding male groups. Overall, our findings showed that: (i) responding for food was lower in OBX than in SHAM rats under both FR1 and (FR5(x)) schedules of reinforcement; (ii) sex and food restriction affect operant responding for palatable food; and (iii) the suppressing effect of OBX lesion on food intake was consistently present in both sexes and represents the most robust factor in the analysis. This may represent anhedonia which is associated with depressive-like phenotype and palatable food self-administration may serve as a robust behavioral index of anhedonia in the OBX model.

New Perspectives on the Use of Cannabis in the Treatment of Psychiatric Disorders.

Following the discovery of the endocannabinoid system and its potential as a therapeutic target for various pathological conditions, growing interest led researchers to investigate the role of cannabis and its derivatives for medical purposes. The compounds Δ9-tetrahydrocannabinol and cannabidiol are the most abundant phytocannabinoids found in cannabis extracts, as well as the most studied. The present review aims to provide an overview of the current evidence for their beneficial effects in treating psychiatric disorders, including schizophrenia, anxiety, and depression. Nevertheless, further investigations are required to clarify many pending issues, especially those relative to the assessment of benefits and risks when using cannabis for therapeutic purposes, thereby also helping national and federal jurisdictions to remain updated.

Cannabinoid Modulation of Eukaryotic Initiation Factors (eIF2α and eIF2B1) and Behavioral Cross-Sensitization to Cocaine in Adolescent Rats.

Reduced eukaryotic Initiation Factor 2 (eIF2)α phosphorylation (p-eIF2α) enhances protein synthesis, memory formation, and addiction-like behaviors. However, p-eIF2α has not been examined with regard to psychoactive cannabinoids and cross-sensitization. Here, we find that a cannabinoid receptor agonist (WIN 55,212-2 mesylate [WIN]) reduced p-eIF2α in vitro by upregulating GADD34 (PPP1R15A), the recruiter of protein phosphatase 1 (PP1). The induction of GADD34 was linked to ERK/CREB signaling and to CREB-binding protein (CBP)-mediated histone hyperacetylation at the Gadd34 locus. In vitro, WIN also upregulated eIF2B1, an eIF2 activator subunit. We next found that WIN administration in vivo reduced p-eIF2α in the nucleus accumbens of adolescent, but not adult, rats. By contrast, WIN increased dorsal striatal levels of eIF2B1 and ΔFosB among both adolescents and adults. In addition, we found cross-sensitization between WIN and cocaine only among adolescents. These findings show that cannabinoids can modulate eukaryotic initiation factors, and they suggest a possible link between p-eIF2α and the gateway drug properties of psychoactive cannabinoids.