Lysophosphatidic Acid (LPA) and Its Receptors in Mood Regulation: A Systematic Review of the Molecular Mechanisms and Therapeutic Potential.

Mood disorders affect over 300 million individuals worldwide, often characterized by their chronic and refractory nature, posing significant threats to patient life. There has been a notable increase in mood disorders among American adolescents and young adults, with a rising number of suicide attempts and fatalities, highlighting a growing association between mood disorders and suicidal outcomes. Dysregulation within the neuroimmune-endocrine system is now recognized as one of the fundamental biological mechanisms underlying mood and mood disorders. Lysophosphatidic acid (LPA), a novel mediator of mood behavior, induces anxiety-like and depression-like phenotypes through its receptors LPA1 and LPA5, regulating synaptic neurotransmission and plasticity. Consequently, LPA has garnered substantial interest in the study of mood regulation. This study aimed to elucidate the molecular mechanisms of lysophosphatidic acid and its receptors, along with LPA receptor ligands, in mood regulation and to explore their potential therapeutic efficacy in treating mood disorders. A comprehensive literature search was conducted using the PubMed and Web of Science databases, identifying 208 articles through keyword searches up to June 2024. After excluding duplicates, irrelevant publications, and those restricted by open access limitations, 21 scientific papers were included in this review. The findings indicate that LPA/LPA receptor modulation could be beneficial in treating mood disorders, suggesting that pharmacological agents or gintonin, an extract from ginseng, may serve as effective therapeutic strategies. This study opens new avenues for future research into how lysophosphatidic acid and its receptors, as well as lysophosphatidic acid receptor ligands, influence emotional behavior in animals and humans.

Sixty years of recurrence prevention in mood disorders. / Szescdziesiat lat profilaktyki nawrotów chorób afektywnych.

This year, we observe sixty's anniversary of the article by a British psychiatrist, Geoffrey Hartigan, demonstrating, for the first time, the possibility of preventing of the recurrence of mood disorders by using lithium salts. Herein, a history of prevention of recurrences of mood disorders both worldwide and in Poland will be presented concerning both lithium and other mood-stabilizing drugs. The merit for verifying the prophylactic lithium effect in the 1960-1970s should be given to Danish researchers, Mogens Schou and Poul Baastrup. In Poland, the first paper on prophylactic lithium appeared already in 1971. In the 1970s, French researchers showed prophylactic activity of valproic acid amide, and Japanese researchers - carbamazepine. In the 1980th, studies on valproic acid amide were performed in the 2nd Psychiatric Clinic of the Institute of Psychiatry and Neurology led by Prof. Puzynski. Since the mid-1990s, 2nd generation of mood-stabilizing drugs has been introduced, including some atypical antipsychotics (clozapine, olanzapine, quetiapine, aripiprazole, risperidone) and anticonvulsant drug, lamotrigine, showing prophylactic activity in bipolar mood disorder. The studies on lithium resulted in the identification of factors connected with its prophylactic efficacy as well as the antisuicidal, antiviral, and neuroprotective effects of this drug. From a sixty-year perspective following Hartigan's article, it seems that his pioneering concept on the possibility of pharmacological influence on the course of mood disorders was fully confirmed. Current Polish recommendations on pharmacological prophylaxis of mood disorders were presented in the books "Standardy leczenia niektórych zaburzen psychicznych" and "Psychofarmakologia kliniczna", both published in 2022.

Newer Treatments for Mood and Anxiety Disorders.

For more than 20 years, the mainstay of pharmacologic treatment for depression and anxiety disorders has been serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors. There are newer medications, many with novel mechanisms of action, that have come to market; however, first-line treatments remain the same. There are now more robust data on the use of various augmentation agents in the treatment of major depressive disorder providing better recommendations for use by the primary care provider. Data to support the use of psychedelic-assisted psychotherapy in the treatment of mood and anxiety disorders are not robust enough to recommend generalized use at this time.

Minocycline Abrogates Individual Differences in Nerve Injury-Evoked Affective Disturbances in Male Rats and Prevents Associated Supraspinal Neuroinflammation.

Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for differences in pain-related disability are not well understood, supraspinal neuroimmune interactions are implicated. Minocycline has antidepressant effects in humans and attenuates affective disturbances in rodent models of pain, and acts by reducing neuroinflammation in both the spinal cord and brain. Previous studies, however, tend not to investigate how minocycline modulates individual affective responses to nerve injury, or rely on non-naturalistic behavioural paradigms that fail to capture the complexity of rodent behaviour. We investigated the development and resolution of pain-related affective disturbances in nerve-injured male rats by measuring multiple spontaneous ethological endpoints on a longitudinal naturalistic foraging paradigm, and the effect of chronic oral minocycline administration on these changes. Disrupted foraging behaviours appeared in 22% of nerve-injured rats - termed 'affected' rats - and were present at day 14 but partially resolved by day 21 post-injury. Minocycline completely prevented the emergence of an affected subgroup while only partly attenuating mechanical allodynia, dissociating the relationship between pain and affect. This was associated with a lasting downregulation of ΔFosB expression in ventral hippocampal neurons at day 21 post-injury. Markers of microglia-mediated neuroinflammation were not present by day 21, however proinflammatory microglial polarisation was apparent in the medial prefrontal cortex of affected rats and not in CCI minocycline rats. Individual differences in affective disturbances following nerve injury are therefore temporally related to altered microglial morphology and hippocampal neuronal activation, and are abrogated by minocycline.

Targeting inflammasome complexes as a novel therapeutic strategy for mood disorders.

INTRODUCTION: Inflammasome complexes, especially NLRP3, have gained great attention as a potential therapeutic target in mood disorders. NLRP3 triggers a caspase 1-dependent release of the inflammatory cytokines IL-1ß and IL-18, and seems to interact with purinergic and kynurenine pathways, all of which are implicated in mood disorders development and progression. AREAS COVERED: Emerging evidence supports NLRP3 inflammasome as a promising pharmacological target for mood disorders. We discussed the available evidence from animal models and human studies and provided a reflection on drawbacks and perspectives for this novel target. EXPERT OPINION: Several studies have supported the involvement of NLRP3 inflammasome in MDD. However, most of the evidence comes from animal models. The role of NLRP3 inflammasome in BD as well as its anti-manic properties is not very clear and requires further exploration. There is evidence of anti-manic effects of P2×R7 antagonists associated with reduction in the brain levels of IL-1ß and TNF-α in a murine model of mania. The involvement of other NLRP3 inflammasome expressing cells besides microglia, like astrocytes, and of other inflammasome complexes in mood disorders also deserves further investigation. Preclinical and clinical characterization of NLRP3 and other inflammasomes in mood disorders is needed before considering translational approaches, including clinical trials.

The use of prolonged-release melatonin in circadian medicine: a systematic review.

INTRODUCTION: Melatonin, a hormone produced by the pineal gland, regulates the sleep-wake cycle and is effective in restoring biological rhythms. Prolonged-release melatonin (PRM) is designed to mimic the natural physiological pattern of melatonin release. In circadian medicine, PRM can be used to treat sleep and circadian rhythm disorders, as well as numerous organic diseases associated with sleep disorders. EVIDENCE ACQUISITION: This systematic review analyzed 62 studies and adhered to the PRISMA guidelines, examining the effectiveness of PRM in organic pathologies and mental disorders. EVIDENCE SYNTHESIS: The main evidence concerns primary insomnia in subjects over the age of 55, showing significant improvements in sleep quality. In neurodevelopmental disorders, there is evidence of a positive impact on sleep quality and quality of life for patients and their caregivers. PRM shows efficacy in the treatment of sleep disorders in mood disorders, schizophrenia, and neurocognitive disorders, but requires further confirmation. The additional use of PRM is supported for the withdrawal of chronic benzodiazepine therapies. The tolerability and safety of PRM are excellent, with ample evidence supporting the absence of tolerance and dependence. CONCLUSIONS: Overall, PRM in circadian medicine is an effective chronopharmaceutical for restoring the sleep-wake rhythm in patients with insomnia disorder. This efficacy may also extend to sleep disorders associated with mood, neurodevelopmental and neurocognitive disorders, suggesting a further potential role in insomnia associated with various organic diseases.

Prenatal Exposure to Valproic Acid Across Various Indications for Use.

Importance: Teratogenic outcomes associated with valproic acid use represent a substantial concern for persons of childbearing age. Regulatory agencies worldwide have enhanced warnings or implemented risk minimization programs to reduce exposure during pregnancy. Objectives: To determine pregnancy rates during valproic acid use and concomitant contraception use across indications. Design, Setting, and Participants: This retrospective cohort study used data from the Merative MarketScan commercial claims databases from January 1, 2005, to December 31, 2020, to identify female patients aged 12 to 44 years who initiated valproic acid treatment and had continuous insurance enrollment 6 months before initiation and 9 months after treatment end. A treatment episode included consecutive prescription fills that occurred within 7 days from the end of the days' supply of the previous dispensing. Data were analyzed from March 1 to September 10, 2023. Main Outcomes and Measures: Treatment episodes were categorized by inferred indication using diagnoses preceding treatment initiation, including epilepsy, migraine or headache, mood disorders, and unknown or off-label uses. Pregnancy incidence rate ratios (IRRs) were calculated and were adjusted for age and calendar year. Contraceptive use (prescription contraceptives, intrauterine devices, and implants) during treatment was examined. Results: The cohort included 165 772 valproic acid treatment episodes among 69 390 women (mean [SD] age, 29.8 [10.0] years). Mood disorders (42.5%) were the most common indication, followed by migraine or headache (20.1%), with epilepsy playing a minor role (14.9%). Pregnancy incidence rates during valproic acid use remained unchanged, with a rate of 1.74 (95% CI, 1.14-2.53) per 100 person-years in 2005 and a rate of 1.90 (95% CI, 1.16-3.12) per 100 person-years in 2019. Compared with epilepsy, pregnancy rates were more than double for mood disorder (IRR, 2.16 [95% CI, 1.93-2.42]) and migraine or headache (IRR, 2.01 [95% CI, 1.92-2.09]). Few treatment episodes coincided with contraceptive use (37 012 [22.3%]), and oral dosage forms were the most common (27 069 [73.1%]). Conclusions and Relevance: In this cohort study of patients of childbearing age who used valproic acid, pregnancy rates during valproic acid use did not decrease despite enhanced US Food and Drug Administration safety communications, and contraception use remained low. Patients with migraine and mood disorders accounted for the largest proportion of valproic acid use and had the highest pregnancy rates, while patients with epilepsy had the lowest. These findings suggest a need to enhance efforts to mitigate prenatal exposure to valproic acid, especially for indications where the risk of use during pregnancy outweighs the benefit.

Systematic Review and Meta-Analysis: Pharmacological and Nonpharmacological Interventions for Disruptive Mood Dysregulation Disorder.

Objectives: Disruptive mood dysregulation disorder (DMDD) is a relatively new diagnosis that comprises severe, nonepisodic irritability and recurrent outbursts of emotional instability in adolescents. This meta-analysis examined the efficacy of the available pharmacological and nonpharmacological interventions for DMDD. Methods: Literature searches were conducted in July 2023. To determine relevant articles, 330 abstracts were reviewed, and 39 articles were identified for full review. A random-effects model was used for the meta-analysis, and a subgroup analysis was performed to assess the effects of study design and intervention type. Results: Eleven studies were reviewed, including six pharmacological and five nonpharmacological. Despite high heterogeneity in effects (I2 = 85%), we showed statistically significant improvements in irritability symptoms following intervention. We showed statistically significant enhancements in symptoms of irritability following the intervention. The subgroup analysis revealed that, compared with randomized controlled trials (RCTs), open trials showed significant improvements in irritability. In addition, drug intervention significantly improved irritability compared to nondrug interventions. Atomoxetine (ATX), optimized stimulants, and stimulants combined with other drugs and behavioral therapy effectively improved irritability. Conclusions: With research indicating potential benefits for irritability from a combination of pharmacological interventions and therapy, including ATX, stimulants in conjunction with antipsychotic or antidepressant medications, and cognitive-behavioral techniques such as Dialectical Behavior Therapy for Children. Future large-scale RCTs are essential to further explore and refine these treatment approaches, especially focusing on the efficacy of combining pharmacological with effective nonpharmacological to improve irritability and overall outcomes in this population.

Long-term follow-up of participants in ketamine clinical trials for mood disorders.

BACKGROUND: Participants who received ketamine at the NIMH were among the first to receive ketamine for depression in controlled clinical trials, providing a unique opportunity to assess long-term outcomes. This analysis evaluated the relationship between participating in a ketamine clinical trial and subsequent ketamine/esketamine use after leaving the research setting. METHODS: Participants seen within the NIMH Experimental Therapeutics and Pathophysiology Branch from 2002 to 2022 (n = 1000) were contacted for follow-up assessment. Participants reported whether they had used ketamine/esketamine, sought non-prescribed ketamine, attempted suicide, or been psychiatrically hospitalized since discharge. Information regarding their recent depressive symptoms, dissociative symptoms, and hallucinations was also collected. RESULTS: Of the 203 participants in follow-up assessments (55 % female, average time since leaving NIMH = 9.04 years), 52 (25.6 %) had originally received ketamine at the NIMH, and the rest had participated in non-ketamine studies. Individuals who had received ketamine at the NIMH were more likely to have received ketamine/esketamine post-discharge than those who did not receive ketamine at the NIMH (OR = 0.25, p < .001). Participants who reported using ketamine/esketamine post-discharge reported more depressive symptoms than those who had not (p < .001). Receiving ketamine at the NIMH was not associated with differences in suicide attempts, psychiatric hospitalizations, dissociation, hallucinations, or attempt to obtain non-prescribed ketamine. LIMITATIONS: Low follow-up study participation rate; varying time since discharge. CONCLUSIONS: Participants who received ketamine in an NIMH clinical trial were more likely to receive ketamine/esketamine post-discharge, but none reported symptoms indicating abuse. Results underscore the critical need for long-term follow-up of individuals receiving these and other rapid-acting antidepressants. CLINICAL TRIALS IDENTIFIER: NCT04877977.

[Atypical antipsychotics in the treatment of depression in affective disorders and schizophrenia (using the aripiprazole model)]. / Atipichnye antipsikhotiki pri terapii depressii v ramkakh affektivnykh rasstroistv i shizofrenii (na modeli aripiprazola).

The review discusses aspects of the use of atypical antipsychotics in the treatment of depression in affective disorders and schizophrenia using the model of aripiprazole, a partial agonist of dopamine receptors. According to numerous studies, aripiprazole is the drug of choice for augmentative therapy of major depressive disorder, as well as for relieving and long-term maintenance monotherapy and combination therapy of various affective episodes of bipolar affective disorder and depression in schizophrenia.

Frequencies of CYP2C19 and CYP2D6 gene variants in a German inpatient sample with mood and anxiety disorders.

OBJECTIVES: Previous results demonstrated that CYP2D6 and CYP2C19 gene variants affect serum concentrations of antidepressants. We implemented a PGx service determining gene variants in CYP2D6 and CYP2C19 in our clinical routine care and report on our first patient cohort. METHODS: We analysed CYP2D6 and CYP2C19 allele, genotype, and phenotype frequencies, and actionable pharmacogenetic variants in this German psychiatric inpatient cohort. Two-tailed z-test was used to investigate for differences in CYP2D6 and CYP2C19 phenotypes and actionable/non-actionable genetic variant frequencies between our cohort and reference cohorts. RESULTS: Out of the 154 patients included, 44.8% of patients were classified as CYP2D6 normal metabolizer, 38.3% as intermediate metabolizers, 8.4% as poor metabolizers, and 2.6% as ultrarapid metabolizers. As for CYP2C19, 40.9% of patients were classified as normal metabolizers, 19.5% as intermediate metabolizers, 2.6% as poor metabolizers, 31.2% as rapid metabolizers, and 5.8% as ultrarapid metabolizers. Approximately, 80% of patients had at least one actionable PGx variant. CONCLUSION: There is a high prevalence of actionable PGx variants in psychiatric inpatients which may affect treatment response. Physicians should refer to PGx-informed dosing guidelines in carriers of these variants. Pre-emptive PGx testing in general may facilitate precision medicine also for other drugs metabolised by CYP2D6 and/or CYP2C19.

Perceptions, Experiences, and Patterns of Cannabis Use in Individuals with Mood and Anxiety Disorders in the Context of Cannabis Legalization and Medical Cannabis Program in Canada - A Qualitative Study.

INTRODUCTION: Perceptions of cannabis as a potential medical treatment for mood and anxiety disorders have been increasing in the context of legalizations, availability, and medical cannabis programs, though current evidence predominately indicates risks and negative effects of cannabis use (CU) on mental health outcomes. This study aims to understand motivations, perceptions, effects, and patterns of CU in individuals with mood and anxiety disorders. METHODS: Thirty-six adult patients diagnosed with mood or anxiety disorders, obsessive-compulsive disorder, or posttraumatic stress disorder who were currently using cannabis completed an in-depth qualitative interview on individual motivations, perceptions, experiences, effects, and patterns of their CU. The thematic analysis focused on phases of CU and sources of cannabis products and information. RESULTS: Reported motivations for initiation of CU included curiosity, peer pressure, and dissatisfaction with conventional treatments. Factors such as psychotropic effects and coping with mental health symptoms and insomnia contributed to the continuation of CU. More negative effects, including cognitive dysfunction, worsening of mood, and anxiety symptoms, were acknowledged with ongoing CU. Concerning findings included common initiation of CU before age 18, combined medical and recreational CU, rare consultation of medical professionals on CU, and potential effects and harms. DISCUSSION: Findings indicate individual complexity of motivations, perceptions, and patterns of CU in the study population. The reported potential beneficial effects of specific cannabis products should be further investigated. Findings emphasize patient-provider dialogue on both CU and conventional treatments. Information from this study can contribute to and inform the development of education, prevention, and intervention strategies.

Effects of erythropoietin on cognitive impairment and prefrontal cortex activity across affective disorders: A randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Persistent cognitive impairment is frequent across bipolar disorder (BD) and major depressive disorder (MDD), highlighting an urgent need for pro-cognitive treatments. AIM: This study investigated effects of erythropoietin (EPO) on cognitive impairment and dorsal prefrontal cortex (dPFC) activity in affective disorders. METHODS: In this randomized, double-blinded, placebo-controlled trial, cognitively impaired patients with remitted BD or MDD received 1 weekly recombinant human EPO (40,000 IU/mL) or saline infusion for a 12-week period. Assessments were conducted at baseline, after 2 weeks of treatment (week 3), immediately after treatment (week 13) and at 6-months follow-up. Participants underwent functional MRI during performance on a n-back working memory (WM) task at baseline and week 3, and for a subgroup 6 weeks post-treatment (week 18). The primary outcome was a cognitive composite score at week 13, whereas secondary outcomes comprised sustained attention and functioning. WM-related dPFC activity was a tertiary outcome. RESULTS: Data were analysed for 101 of the 103 included patients (EPO, n = 58; saline, n = 43). There were no effects of EPO over saline on any cognitive or functional outcomes or on WM-related dPFC activity. CONCLUSIONS: The absence of treatment-related changes in cognition and neural activity was unexpected and contrasts with multiple previous preclinical and clinical studies. It is possible that the lack of effects resulted from a recent change in the manufacturing process for EPO. Nevertheless, the findings support the validity of dPFC target engagement as a biomarker model for pro-cognitive effects, according to which treatments that do not improve cognition should not modulate dPFC activity. TRIAL REGISTRATIONS: EudraCT no.: 2016-004023-24; ClinicalTrials.gov identifier: NCT03315897.

The effect of lavender on mood disorders associated with the use of combined oral contraceptives (COCs): a triple-blinded randomized controlled trial.

BACKGROUND: The use of contraceptive methods is influenced by their effectiveness, availability, and minimal side effects. OCPs are one of the most effective and widely used methods of pregnancy prevention worldwide. This method not only prevents pregnancy but also helps prevent and treat other diseases. One of the main reasons for discontinuing this method is the emotional disturbances associated with its use. Lavender is an evergreen, fragrant plant that has gained significant attention for its anti-anxiety effects. This study was conducted to investigate the effect of lavender essential oil capsules on mood disorders during the use of COCs. METHODS: This triple-blinded clinical trial was conducted on 60 married women (aged 15-49 years old) who were consumers of COCs, referring to 26 health centers in Tabriz, Iran. The participants were randomly assigned to either the intervention (consuming one gelatin capsule containing 80 mg LEO daily) or control (consuming one placebo capsule daily) group. The intervention continued for 56 days. Scores for positive and negative were determined using the Positive and Negative Affect Schedule (PANAS) questionnaire; and for stress, depression, and anxiety were measured using the DASS-21 questionnaire on day's 28th and 56th post-intervention. Data analysis was conducted using the t-test and ANOVA with repeated measures, and a p-value of < 0.05 was considered significant for all analyses. RESULTS: A statistically significant difference was observed in mood disorders, stress, and depression between women receiving LEO or placebo. The consumption of LEO increased the positive mood on day 28 [MD (95% CI): 4.5 (2.1 to 7.0), p = 0.001] and day 56 [5.9 (3.4 to 8.3), p < 0.001] while decreased the negative mood on day 28 [MD (95% CI): -3.5 (-5.3 to -1.3), p < 0.001] and day 56 [-4.3 (-6.3 to -2.2), p < 0.001], stress on day 28 [MD (95% CI): -4.9 (-7.1 to -2.8), p = 0.001] and day 56 [-5.3 (-7.6 to -3.1), p < 0. 001], and depression on day 28 [MD (95% CI): -3.0 (-4.9 to 1.1), p = 0.003] and day 56 [-3.1 (-5.0 to 1.2), p = 0.002]. There was no statistically significant difference between the two groups in terms of anxiety. CONCLUSIONS: The consumption of LEO with COCs improved mood disorders and reduced stress and depression. The use of hormonal contraceptives and mood changes should be considered by providers. Therefore, regarding the possibility of mood changes, it is expected that appropriate counseling and education will be provided to women who consume COC., providing appropriate solutions, including the simultaneous use of LEO.

French Society for Biological Psychiatry and Neuropsychopharmacology and French-speaking Marcé Society guidelines for the management of mood disorders in women before, during, and after pregnancy.

PURPOSE: The French Society for Biological Psychiatry and Neuropsychopharmacology and the French-speaking Marcé Society have joined forces to establish expert recommendations on the prescription of psychotropic drugs before, during, and after pregnancy in women with major depressive disorder (MDD) and bipolar disorder (BD). METHODS: To elaborate recommendations, we used the RAND/UCLA Appropriateness Method, which combines scientific evidence and expert clinicians' opinions. A written survey was completed by 48 psychiatrists, who have expertise in the management of mood disorders and/or in perinatal psychiatry. Key recommendations are provided by the scientific committee based on data analysis and interpretation of the results of the survey. RESULTS: The recommendations address the following three areas that are deemed essential in women with mood disorders, with an emphasis on screening, treatment options, and monitoring: (i) management of mood disorders in women of childbearing age, (ii) management during pregnancy, (iii) management during the post-partum period. As first-line strategies, experts recommend treating mood symptoms during pregnancy and maintaining a pharmacological treatment, even in euthymic or stabilized patients. First-line options include only medications with no teratogenic risk, and during breastfeeding, only medications without evidence of adverse effects in nursing infants. CONCLUSION: The expert consensus guidelines will help facilitate treatment decisions for clinicians in the daily assessment and management of mood disorders in women of childbearing age, during pregnancy, and in the post-partum period.

Effects of cannabidiol in post-stroke mood disorders in neonatal rats.

BACKGROUND: Neonatal rats can manifest post-stroke mood disorders (PSMD) following middle cerebral artery occlusion (MCAO). We investigated whether cannabidiol (CBD) neuroprotection, previously demonstrated in neonatal rats after MCAO, includes prevention of PSMD development. METHODS: Seven-day-old Wistar rats (P7) underwent MCAO and received either vehicle or 5 mg/kg CBD treatment. Brain damage was quantified by MRI, and neurobehavioral and histological (TUNEL) studies were performed at P14 and P37. PSMD were assessed using the tail suspension test, forced swimming test, and open field tests. The dopaminergic system was evaluated by quantifying dopaminergic neurons (TH+) in the Ventral Tegmental Area (VTA), measuring brain dopamine (DA) concentration and DA transporter expression, and assessing the expression and function D2 receptors (D2R) through [35S]GTPγS binding. Animals without MCAO served as controls. RESULTS: CBD reduced MCAO-induced brain damage and improved motor performance. At P14, MCAO induced depressive-like behavior, characterized by reduced TH+ cell population and DA levels, which CBD did not prevent. However, CBD ameliorated hyperactivity observed at P37, preventing increased DA concentration by restoring D2R function. CONCLUSIONS: These findings confirm the development of PSMD following MCAO in neonatal rats and highlight CBD as a neuroprotective agent capable of long-term functional normalization of the dopaminergic system post-MCAO. IMPACT: MCAO in neonatal rats led to post-stroke mood disorders consisting in a depression-like picture in the medium term evolving towards long-term hyperactivity, associated with an alteration of the dopaminergic system. The administration of CBD after MCAO did not prevent the development of depressive-like behavior, but reduced long-term hyperactivity, normalizing dopamine receptor function. These data point to the importance of considering the development of depression-like symptoms after neonatal stroke, a well-known complication after stroke in adults. Our work confirms the interest of CBD as a possible treatment for neonatal stroke.