Search Results (81)

Alcohol is a prevalent psychoactive substance and a risk factor for developing injuries and non-communicable diseases, representing a significant health and economic burden. Alcohol involves numerous molecular pathways. Its metabolism is regulated by alcohol dehydrogenases and aldehyde dehydrogenases; it also stimulates cholinergic interneurons, increasing the sensitivity of 5-HT3 receptors, while chronic alcohol consumption alters the mesolimbic dopaminergic system involved in reward processing. The treatment of alcohol use disorder (AUD) is essential to manage complex patients, following an evidence-based approach. The aim of this narrative review is to provide a clear and practical summary to support and assist healthcare professionals in the Italian context. Approved pharmacological treatments for AUD include oral naltrexone and acamprosate, sodium oxybate, disulfiram, and nalmefene. Off-label therapies include baclofen, topiramate, gabapentin, pregabalin, ondansetron, and cytisine. A more informed clinical and practical approach that understands the altered neuronal signaling pathways is essential for offering effective, efficient, appropriate, and safe therapeutic algorithms for complex patients with alcohol use disorder. A comprehensive framework should include integrated treatments with a personalized approach. Full article

Opioid use induces neurobiological adaptations throughout mesolimbic brain regions, such as the orbitofrontal cortex (OFC), which mediates decision-making and emotional–cognitive regulation. Previously, we showed that a circular RNA (circRNA) species, rno_circGrin2b_011731 (circGrin2b), is upregulated in the OFC of rats following chronic self-administration (SA) of the opioid heroin. circGrin2b is derived from Grin2b, which encodes the regulatory subunit of the glutamate ionotropic NMDA receptor, GluN2B. However, the upstream regulatory mechanisms of circGrin2b biogenesis and the downstream consequences of circGrin2b dysregulation remain unknown. We hypothesized that opioid-induced elevation of circGrin2b is accompanied by regulation of circRNA biogenesis enzymes, and that circGrin2b may sponge microRNAs (miRNAs), as miRNA sponging is a well-described characteristic of circRNAs. To test these hypotheses, we established an in vitro primary cortical cell culture model to examine alterations in circGrin2b expression following exposure to the opioid morphine. We measured mRNA expression of known circRNA splicing factors and observed significant downregulation of Fused in Sarcoma (Fus), a negative regulator of circRNA biogenesis, following 90 min or 24 h of morphine exposure. Downregulation of Fus at 24 h post-morphine was accompanied by upregulation of circGrin2b and downregulation of miR-26b-3p, a predicted miRNA target of circGrin2b. Luciferase reporter assays confirmed interaction of miR-26b-3p with circGrin2b. Finally, we report a significant negative relationship between circGrin2b and miR-26b-3p expression in the OFC of rats following heroin SA. We conclude that regulation of circGrin2b is an opioid-induced neuroadaptation that may impact downstream signaling of miRNA pathways in the frontal cortex. Full article

Purpose: Obesity’s metabolic consequences are well documented; however, its neurobiological underpinnings remain elusive. This systematic review addresses a critical gap by synthesizing evidence on obesity-induced neuroplasticity across structural, functional, and molecular domains through advanced neuroimaging. Methods: According to PRISMA guidelines, we systematically searched (2015–2024) across PubMed/Web of Science, employing MeSH terms: (“Obesity” [Majr]) AND (“Neuroimaging” [Mesh] OR “Magnetic Resonance Imaging” [Mesh]). A total of 104 studies met the inclusion criteria. The inclusion criteria required the following: (1) multimodal imaging protocols (structural MRI/diffusion tensor imaging/resting-state functional magnetic resonance imaging (fMRI)/positron emission tomography (PET)); (2) pre-/post-intervention longitudinal design. Risk of bias was assessed via the Newcastle-Ottawa Scale. Key Findings: 1. Structural alterations: 7.2% mean gray matter reduction in prefrontal cortex (Cohen’s d = 0.81). White matter integrity decline (FA reduction β = −0.33, p < 0.001) across 12 major tracts. 2. Functional connectivity: Resting-state hyperactivity in mesolimbic pathways (fALFF + 23%, p-FDR < 0.05). Impaired fronto–striatal connectivity (r = −0.58 with BMI, 95% CI [−0.67, −0.49]). 3. Interventional reversibility: Bariatric surgery restored prefrontal activation (Δ = +18% vs. controls, p = 0.002). Neurostimulation (transcranial direct current stimulation (tDCS) enhanced cognitive control (post-treatment β = 0.42, p = 0.009). Conclusion: 1. Obesity induces multidomain neural reorganization beyond traditional reward circuits. 2. Neuroimaging biomarkers (e.g., striatal PET-dopamine binding potential) predict intervention outcomes (AUC = 0.79). 3. Precision neuromodulation requires tripartite integration of structural guidance, functional monitoring, and molecular profiling. Findings highlight neuroimaging’s pivotal role in developing stage-specific therapeutic strategies. Full article

We examined the neuroanatomical substrates and signaling mechanisms underlying the suppressive effect of GLP1 on homeostatic and hedonic feeding. Electrophysiological and behavioral studies were conducted in agouti-related peptide (AgRP)-cre and tyrosine hydroxylase (TH)-cre mice, and AgRP-cre/pituitary adenylyl cyclase-activating polypeptide (PACAP) type I receptor (PAC1R)^fl/fl animals. GLP1 (30 pmol) delivered directly into the arcuate nucleus (ARC) decreased homeostatic feeding and diminished the rate of consumption. This anorexigenic effect was associated with an inhibitory outward current in orexigenic neuropeptide Y (NPY)/AgRP neurons. GLP1 injected into the ventral tegmental area reduced binge feeding, coupled with decrements in the rate of consumption and the percent daily caloric consumption during the binge interval. These reductions were associated with a GLP1-induced outward current in mesolimbic (A₁₀) dopamine neurons. GLP1 administered into the ventromedial nucleus (VMN) reduced homeostatic feeding that again was associated with a diminished rate of consumption and abrogated by the GLP1 receptor antagonist exendin 9–39 and in AgRP-cre/PAC1R^fl/fl mice. This suppressive effect was linked with a GLP-induced inward current in VMN PACAP neurons, and further supported by the fact that GLP1 neurons in the nucleus tractus solitarius project to the VMN. Conversely, intra-VMN GLP1 had modest effects on binge feeding behavior. Finally, apoptotic ablation of VMN PACAP neurons obliterated the anorexigenic effect of intra-VMN GLP1 on homeostatic feeding in PACAP-cre mice but not their wildtype counterparts. Collectively, these data demonstrate that GLP1 acts within the homeostatic and hedonic circuits to curb appetitive behavior by exciting PACAP neurons, and inhibiting NPY/AgRP and A₁₀ dopamine neurons. Full article

Background/Objectives: Schizophrenia and nicotine misuse are a comorbid condition that frequently develops during adolescence. Considering the role of the nucleus accumbens (NAcc) as a common neurobiological substrate for these psychiatric disorders, label-free proteomics was employed to identify NAcc deregulated proteins in male and female mouse models of schizophrenia with a history of adolescent nicotine exposure. Methods: Phencyclidine was used to model schizophrenia, and minipump infusions were used to model nicotine misuse. Results: Enrichment Reactome pathway and protein–protein interaction analyses showed that the cytoskeleton and associated synaptic plasticity mechanisms, energy metabolism, and nervous system development were affected in both sexes. In particular, Ncam1 (Neural cell adhesion molecule 1) could be of interest as a candidate marker of synaptic plasticity disbalance. Its deregulation in the NAcc of both sexes suggests that it lies at the core of the comorbidity pathophysiology. When considering sex-selective effects, Cs (Citrate synthase) and Mapk3 (Mitogen-activated protein kinase 3) were identified as exclusively deregulated in female and male mice, respectively. Since both proteins were previously shown to be exclusively deregulated in the medial prefrontal cortex of co-modeled mice, a common mesocortical and mesolimbic system effect can be inferred, supporting the role of aberrant energy metabolism and synaptic plasticity in the comorbidity model. Conclusions: The current data provide insights into the NAcc proteome disbalance in an adolescent preclinical model of combined schizophrenia and nicotine misuse, pointing to relevant pathways and early markers of the comorbidity. Full article

The impact of weather on mental illness is widely debated, but the mechanism of this relationship remains unclear. The immunoseasonal theory suggests that in winter, a T-helper 1 (Th1) response predominates, impairing Prefrontal Cortex (PFC) control, which exacerbates symptoms of depression, while after it, in summer, a Th2 response predominates in immunologically prone individuals, activating cortical and mesolimbic centers, which can exacerbate symptoms of psychosis. In this paper, we aim to describe the validity of this theory through a narrative review of data related to weather and immunology in psychiatry. This review extends existing literature by integrating immunological findings with psychiatric seasonality research, offering a mechanistic perspective that links Th1/Th2 shifts to specific symptom exacerbations. Winter Th1 severity may worsen depression and anxiety, while summer Th2 dominance appears to be associated with exacerbations of schizophrenia, mania, impulsivity, and suicide risk. It is possible that the mechanism of Th1 response potentiation and deterioration of PFC function is common to most psychiatric entities and is nonspecific. This suggests that seasonal immune dysregulation may play a broader role in psychiatric disorders than previously recognized, challenging the idea that seasonality impacts only selected conditions. Characteristic dysfunctions within an individual determine further differences in clinical manifestations. The mechanism of Th2 potentiation may not be limited to mania and psychosis but may also be associated with increased impulsivity and suicide risk. If the immunoseasonal theory is confirmed, selected immunological markers could be used not only in the diagnosis of psychiatric exacerbations but also in predicting symptom fluctuations and tailoring treatment strategies. This could enable more personalized interventions, such as seasonally adjusted medication dosing or targeted anti-inflammatory therapies. While this mechanism seems plausible, further research, especially analyzing markers of inflammatory and anti-inflammatory responses, is needed to better understand and confirm it. Full article

Binge eating disorder (BED) is characterized by the rapid overconsumption of palatable food in a short amount of time, often leading to obesity. The endocannabinoid system (ECS), a system involved in palatable food intake, is highly expressed in reward-related brain regions and is involved in both obesity and BED. This study investigated differences in ECS expression between these conditions using male Wistar rats exposed to specific regimen over six weeks: a non-access group (NA) with a standard diet, a continuous access group (CA) with free-choice high-fat high-sugar (fcHFHS) diet modeling obesity, and an intermittent access group (IA) with intermittent fcHFHS access modeling BED. Food intake was measured, and brain tissues from the nucleus accumbens (NAc), dorsal striatum (DS), ventral tegmental area (VTA), and rostromedial tegmental nucleus (RMTg) were analyzed for ECS expression using qPCR and mass spectrometry. We identified differential ECS expression across palatable food access groups, with variations depending on the brain region (striatal or mesencephalic). Correlation analyses revealed ECS dysregulations dependent on the type (fat or sucrose) and quantity of palatable food consumed. Comparative network analysis revealed co-regulation patterns of ECS-related genes with specific signatures associated with each eating pattern, highlighting RMTg as a key region for future research in eating behavior. Full article

The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula (LHb) exerts negative control over the VTA via the GABA rostromedial tegmental nucleus (RMTg), representing a potential convergence point for drug-induced opponent processes. We hypothesized that the LHb–RMTg pathway might be causally involved in the hypodopaminergic state during cannabinoid withdrawal. To induce Δ⁹-tetrahydrocannabinol (THC) dependence, adult male Sprague–Dawley rats were treated with THC (15 mg/kg, i.p.) twice daily for 6.5–7 days. Administration of the cannabinoid antagonist rimonabant (5 mg/kg, i.p.) precipitated a robust behavioral withdrawal syndrome, while abrupt THC suspension caused milder signs of abstinence. Extracellular single unit recordings confirmed a marked decrease in the discharge frequency and burst firing of VTA dopamine neurons during THC withdrawal. The duration of RMTg-evoked inhibition was longer in THC withdrawn rats. Additionally, the spontaneous activity of RMTg neurons and of LHb neurons was strongly depressed during cannabinoid withdrawal. These findings support the hypothesis that functional changes in the habenulo–mesencephalic circuit are implicated in the mechanisms underlying substance use disorders. Full article

There is a gap in existing knowledge of stress-triggered neurochemical and behavioral adaptations in females. This study was designed to explore the short-term consequences of a single social defeat (SD) on accumbal dopamine (DA) dynamics and related behaviors in female Wistar rats. During the SD procedure, rats demonstrated different stress-handling strategies, which were defined as active and passive coping. The “active” subjects expressed a significantly higher level of activity directed toward handling stress experience, while the “passive” ones showed an escalated freezing pattern. Remarkably, these opposite behavioral manifestations were negatively correlated. Twenty-four hours following the SD exposure, decreased immobility latency in the Porsolt test and cognitive augmentation in the new object recognition evaluation were evident, along with an increase in electrically evoked mesolimbic DA release in passive coping rats. Rats exhibiting an active pattern of responses showed insignificant changes in immobility and cognitive performance as well as in evoked mesolimbic DA response. Furthermore, the dynamics of the decline and recovery of DA efflux under the depletion protocol were significantly altered in the passive but not active female rats. Taken together, these data suggest that female rats with a passive coping strategy are more susceptible to developing behavioral and neurochemical alterations within 24 h after stress exposure. This observation may represent both maladaptive and protective responses of an organism on a short timescale. Full article

In this review, we aim to draw a connection between drug addiction and overconsumption of highly palatable food (OHPF) by discussing common behaviors and neurochemical pathways shared by these two states. OHPF can stimulate reward pathways in the brain that parallel those triggered by drug use, increasing the risk of dependency. Behavioral similarities between food and drug addiction can be addressed by tracking their stages: loss of control when eating (bingeing), withdrawal, craving, sensitization, and cross-sensitization. The brain adapts to addiction by way of the mesolimbic dopamine system, endogenous opioids and receptors, acetylcholine and dopamine balance, and adaptations of serotonin in neuroanatomy. Studies from the current literature are reviewed to determine how various neurological chemicals contribute to the reinforcement of drug addiction and OHPF. Finally, protocols for treating food addiction are discussed, including both clinical and pharmacological modalities. There is consistent evidence that OHPF changes brain chemistry and leads to addiction in similar ways to drugs. However, more long-term research is needed on food addiction, binge eating, and their neurobiological effects. Full article

Autism spectrum disorder (ASD) is primarily characterized by core deficits in social skills, communication, and cognition and by repetitive stereotyped behaviors. These manifestations are variable between individuals, and ASD pathogenesis is complex, with over a thousand implicated genes, many epigenetic factors, and multiple environmental influences. The mesolimbic dopamine (DA) mediated brain reward system is held to play a key role, but the rapidly expanding literature reveals intricate, nuanced signaling involving a wide array of mesolimbic loci, neurotransmitters and receptor subtypes, and neuronal variants. How altered DA signaling may constitute a downstream convergence of the manifold causal origins of ASD is not well understood. A clear working framework of ASD pathogenesis may help delineate common stages and potential diagnostic and interventional opportunities. Hence, we summarize the known natural history of ASD in the context of emerging data and perspectives to update ASD reward signaling. Then, against this backdrop, we proffer a provisional framework that organizes ASD pathogenesis into successive levels, including (1) genetic and epigenetic changes, (2) disrupted mesolimbic reward signaling pathways, (3) dysregulated neurotransmitter/DA signaling, and finally, (4) altered neurocognitive and social behavior and possible antagonist/agonist based ASD interventions. This subdivision of ASD into a logical progression of potentially addressable parts may help facilitate the rational formulation of diagnostics and targeted treatments. Full article

The mesolimbic pathway connects ventral tegmental area dopaminergic neurons and striatal medium spiny neurons, playing a critical role in reward and stress behaviors. Exposure to substances of abuse during development and adulthood has been linked to adverse outcomes and molecular changes. The rise of human cell repositories and whole-genome sequences enables human functional genomics ‘in a dish’, offering insights into human-specific responses to substances of abuse. Continued development of new models is needed, and the characterization of in vitro models is also necessary to ensure appropriate experimental designs and the accurate interpretation of results. This study introduces new culture conditions for generating medium spiny neurons and dopaminergic neurons with an early common media, allowing for coculture and assembloid generation. It then provides a comprehensive characterization of these and prior models and their responses to substances of abuse. Single-cell analysis reveals cell-type-specific transcriptomic responses to dopamine, cocaine, and morphine, including compound and cell-type-specific transcriptomic signatures related to neuroinflammation and alterations in signaling pathways. These findings offer a resource for future genomics studies leveraging human stem cell-derived models. Full article

Alcohol use disorder is considered a chronic and relapsing disorder affecting the central nervous system. The serotonergic system, mainly through its influence on the mesolimbic dopaminergic reward system, has been postulated to play a pivotal role in the underlying mechanism of alcohol dependence. The study aims to analyse the association of the rs6295 polymorphism of the 5HTR1A gene in women with alcohol use disorder and the association of personality traits with the development of alcohol dependence, as well as the interaction of the rs6295, personality traits, and anxiety with alcohol dependence in women. The study group consisted of 213 female volunteers: 101 with alcohol use disorder and 112 controls. NEO Five-Factor and State-Trait Anxiety Inventories were applied for psychometric testing. Genotyping of rs6295 was performed by real-time PCR. We did not observe significant differences in 5HTR1A rs6295 genotypes (p = 0.2709) or allele distribution (p = 0.4513). The AUD subjects scored higher on the anxiety trait (p < 0.0001) and anxiety state (p < 0.0001) scales, as well as on the neuroticism (p < 0.0001) and openness (p = 0134) scales. Significantly lower scores were obtained by the AUD subjects on the extraversion (p < 0.0001), agreeability (p < 0.0001), and conscientiousness (p < 0.0001) scales. Additionally, we observed a significant effect of 5HTR1A rs6295 genotype interaction and alcohol dependency, or lack thereof, on the openness scale (p = 0.0016). In summary, this study offers a comprehensive overview of alcohol dependence among women. It offers valuable insights into this complex topic, contributing to a more nuanced understanding of substance use among this specific demographic. Additionally, these findings may have implications for developing prevention and intervention strategies tailored to individual genetic and, most importantly, personality and anxiety differences. Full article

Methamphetamine (METH) exposure increases locomotor sensitization. However, no study has explored the occurrence of cardiovascular sensitization. The present study, carried out in mice, analyzed the following: (i) METH sensitization extending to systolic blood pressure (SBP); (ii) a potential correlation between ambulatory and cardiovascular sensitization; and (iii) morphological alterations within meso-striatal, meso-limbic and pontine catecholamine systems including c-fos expression. Locomotor activity, SBP and occurrence of morphological alterations of catecholaminergic neurons were assessed in C57Bl/6J mice following daily i.p. injections of either saline or METH (1, 2 or 5 mg/kg) for 5 consecutive days and following 6 days of withdrawal. Reiterated exposure to the lower doses of METH (1 mg/kg and 2 mg/kg) produced in mice locomotor sensitization without altering SBP. In contrast, repeated treatment with the highest dose of METH (5 mg/kg) produced sensitization of SBP in the absence of locomotor sensitization. No morphological alterations but increases in c-fos expression within neurons of locus coeruleus and nucleus accumbens were detected. The present data suggest that METH produces plastic changes that extend beyond the motor systems to alter autonomic regulation. This cardiovascular sensitization occurs independently of locomotor sensitization. The persistency of increased blood pressure may underlie specific mechanisms operating in producing hypertension. Full article

Tobacco use disorder represents a significant public health challenge due to its association with various diseases. Despite awareness efforts, smoking rates remain high, partly due to ineffective cessation methods and the spread of new electronic devices. This study investigated the impact of prolonged nicotine exposure via a heat-not-burn (HnB) device on selected genes and signaling proteins involved in inflammatory processes in the rat ventral tegmental area (VTA) and nucleus accumbens (NAc), two brain regions associated with addiction to different drugs, including nicotine. The results showed a reduction in mRNA levels for PPARα and PPARγ, two nuclear receptors and anti-inflammatory transcription factors, along with the dysregulation of gene expression of the epigenetic modulator KDM6s, in both investigated brain areas. Moreover, decreased PTEN mRNA levels and higher AKT phosphorylation were detected in the VTA of HnB-exposed rats with respect to their control counterparts. Finally, significant alterations in ERK 1/2 phosphorylation were observed in both mesolimbic areas, with VTA decrease and NAc increase, respectively. Overall, the results suggest that HnB aerosol exposure disrupts intracellular pathways potentially involved in the development and maintenance of the neuroinflammatory state. Moreover, these data highlight that, similar to conventional cigarettes, HnB devices use affects specific signaling pathways shaping neuroinflammatory process in the VTA and NAc, thus triggering mechanisms that are currently considered as potentially relevant for the development of addictive behavior. Full article