The role of the expanded endocannabinoid system in cognitive impairments induced by prenatal and lactation alcohol exposure in mice

Alcohol exposure during gestation and lactation leads to physical and behavioral disabilities known as fetal alcohol spectrum disorder. Although cognitive dysfunction is highly frequent and compromises the patients’ quality of life, the pathophysiological mechanisms underlying these symptoms remain unclear. Previous research has demonstrated that alcohol exposure during other periods of life alters the expanded endocannabinoid system (ECS). Furthermore, this system is involved in neurodevelopment and cognition. Thus, we sought to evaluate its role in cognitive deficits induced by prenatal and lactation alcohol exposure (PLAE) in C57BL/6 mice. Our findings indicate that PLAE primarily alters the hippocampal expanded ECS in a time-dependent manner. Of those alterations, we identified that early changes in peroxisome proliferator-activated receptor gamma (PPAR-γ) in the hippocampal astrocytes contributes to long-lasting memory impairments induced by PLAE. Moreover, our data reveal that the pharmacological modulation of the expanded ECS’ mediators, and specifically PPAR-γ, during a childhood-like period mitigates memory deficits in adult PLAE mice. Altogether, our findings indicate that targeting the expanded ECS might be a promising therapeutic tool towards memory dysfunction induced by early alcohol exposure.L'exposició a l'alcohol durant la gestació i la lactància provoca discapacitats físiques i conductuals conegudes com a trastorn de l'espectre alcohòlic fetal. Tot i que la disfunció cognitiva és molt freqüent i compromet la qualitat de vida dels pacients, els mecanismes fisiopatològics subjacents a aquests símptomes encara no es coneixen. Prèvies investigacions han demostrat que l'exposició a l'alcohol durant altres períodes de la vida altera el sistema endocannabinoide (ECS) expandit. A més, aquest sistema està implicat en el neurodesenvolupament i la cognició. Així, en aquesta tesi hem tractat d’avaluar el seu paper en els dèficits cognitius induïts per l'exposició a l'alcohol durant l’etapa prenatal i de lactància (PLAE) en ratolins C57BL/6. Els nostres resultats indiquen que el PLAE altera principalment l'ECS expandit de l'hipocamp de manera dependent del temps. D'aquestes alteracions, vam identificar que les pertorbacions primerenques del receptor gamma activat per proliferadors de peroxisomes (PPAR-γ) en els astròcits de l'hipocamp contribueixen als dèficits de memòria de llarga durada induïts pel PLAE. A més, les nostres dades revelen que la modulació farmacològica de mediadors de l'ECS expandit, i específicament de PPAR-γ, durant un període semblant a la infància mitiga els dèficits de memòria en ratolins PLAE adults. En conjunt, els nostres resultats indiquen que l'ECS expandit podria ser una diana amb potencial terapèutic per al tractament de la disfunció de la memòria induïda per l'exposició primerenca a l'alcohol.Programa de Doctorat en Biomedicin

Reviewing the role of the endocannabinoid system in the pathophysiology of depression

Major depressive disorder is a high-impact, debilitating disease and it is currently considered the most prevalent mental illness. It is associated with disability, as well as increased morbidity and mortality. Despite its significant repercussions in our society, its exact pathophysiology remains unclear and therefore, available antidepressant treatment options are limited and, in some cases, ineffective. In the past years, research has focused on the development of a multifactorial theory of depression. Simultaneously, evidence supporting the role of the endocannabinoid system in the neurobiology of neuropsychiatric diseases has emerged. Studies have shown that the endocannabinoid system strongly impacts neurotransmission, and the neuroendocrine and neuroimmune systems, which are known to be dysfunctional in depressive patients. Accordingly, common antidepressants were shown to have a direct impact on the expression of cannabinoid receptors throughout the brain. Therefore, the relationship between the endocannabinoid system and major depressive disorder is worth consideration. Nevertheless, most studies focus on smaller pieces of what is undoubtedly a larger mosaic of interdependent processes. Therefore, the present review summarizes the existing literature regarding the role of the endocannabinoid system in depression aiming to integrate this information into a holistic picture for a better understanding of the relationship between the two.This work was supported by Ministerio de Economía y Competitividad: PID 2019-104077-RB-100/AEI/10.3389/fphar.2021.762738, Ministerio de Sanidad, Asuntos Sociales e Igualdad (Retic-ISCIII-RD/16/0017/0010-FEDER and Plan Nacional Sobre Drogas (#2018/007). AG-B received a FI-AGAUR grant from the Generalitat de Catalunya (2019FI_B0081). The Department of Experimental and Health Sciences (UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (CEX 2018-000792-M)

Early-life stress exacerbates the effects of WIN55,212-2 and modulates the cannabinoid receptor type 1 expression

Early-life stress induces an abnormal brain development and increases the risk of psychiatric diseases, including depression, anxiety and substance use disorders. We have developed a reliable model for maternal neglect, named maternal separation with early weaning (MSEW) in CD1 mice. In the present study, we evaluated the long-term effects on anxiety-like behaviours, nociception as well as the Iba1-positive microglial cells in this model in comparison to standard nest (SN) mice. Moreover, we investigated whether MSEW alters the cannabinoid agonist WIN55,212-2 effects regarding reward, spatial and emotional memories, tolerance to different cannabinoid responses, and physical dependence. Adult male offspring of MSEW group showed impaired responses on spatial and emotional memories after a repeated WIN55,212-2 treatment. These behavioural impairments were associated with an increase in basolateral amygdala and hippocampal CB1-expressing fibres and higher number of CB1-containing cells in cerebellum. Additionally, MSEW promotes a higher number of Iba1-positive microglial cells in basolateral amygdala and cerebellum. As for the cannabinoid-induced effects, rearing conditions did not influence the rewarding effects of WIN55,212-2 in the conditioned place preference paradigm. However, MSEW mice showed a delay in the development of tolerance to the cannabinoid effects. Moreover, CB1-positive fibres were reduced in limbic areas in MSEW mice after cannabinoid withdrawal precipitated with the CB1 antagonist SR141617A. These findings support that early-life stress promotes behavioural and molecular changes in the sensitivity to cannabinoids, which are mediated by alterations in CB1 signalling in limbic areas and it induces an increased Iba1-microglial marker which could interfere in emotional memories formation.This study was supported by the Ministerio de Economia y Competitividad (grant number SAF2016-75966-R-FEDER and PID2019-104077RB-100), Ministerio de Sanidad (Retic-ISCIII, RD16/017/010 and Plan Nacional sobre Drogas 2018/007). L.A.Z received a FPI grant (BES-2017-080066) from Ministerio de Economia y Competitividad. A.G-B received a FI-AGAUR grant from the Generalitat de Catalunya (2019FI_B0081). A.C-Z received CONACYT grant (276577) from the Mexican government

The FAAH inhibitor URB597 reduces cocaine intake during conditioned punishment and mitigates cocaine seeking during withdrawal

The endocannabinoid system is prominently implicated in the control of cocaine reinforcement due to its relevant role in synaptic plasticity and neurotransmitter modulation in the mesocorticolimbic system. The inhibition of fatty acid amide hydrolase (FAAH), and the resulting increase in anandamide and other N-acylethanolamines, represents a promising strategy for reducing drug seeking. In the present study, we aimed to assess the effects of the FAAH inhibitor URB597 (1 mg/kg) on crucial features of cocaine addictive-like behaviour in mice. Therefore, we tested the effects of URB597 on acquisition of cocaine (0.6 mg/kg/inf) self-administration, compulsive-like cocaine intake and cue-induced drug-seeking behaviour during withdrawal. URB597 reduced cocaine intake under conditioned punishment while having no impact on acquisition. This result was associated to increased cannabinoid receptor 1 gene expression in the ventral striatum and medium spiny neurons activation in the nucleus accumbens shell. Moreover, URB597 mitigated cue-induced drug-seeking behaviour during prolonged abstinence and prevented the withdrawal-induced increase in FAAH gene expression in the ventral striatum. In this case, URB597 decreased activation of medium spiny neurons in the nucleus accumbens core. Our findings evidence the prominent role of endocannabinoids in the development of cocaine addictive-like behaviours and support the potential of FAAH inhibition as a therapeutical target for the treatment of cocaine addiction

The role of PPAR-γ in memory deficits induced by prenatal and lactation alcohol exposure in mice

Data de publicació electrònica: 25-07-2023Patients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates underlying these deficits remain unclear. Here, we show that prenatal and lactation alcohol exposure (PLAE) in mice induces FASD-like memory impairments. This is accompanied by a reduction of N-acylethanolamines (NAEs) and peroxisome proliferator-activated receptor gamma (PPAR-γ) in the hippocampus specifically in a childhood-like period (at post-natal day (PD) 25). To determine their role in memory deficits, two pharmacological approaches were performed during this specific period of early life. Thus, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase NAEs, with GW9662, a PPAR-γ antagonist; ii) pioglitazone, a PPAR-γ agonist. We observed that URB597 suppresses PLAE-induced memory deficits through a PPAR-γ dependent mechanism, since its effects are prevented by GW9662. Direct PPAR-γ activation, using pioglitazone, also ameliorates memory impairments. Lastly, to further investigate the region and cellular specificity, we demonstrate that an early overexpression of PPAR-γ, by means of a viral vector, in hippocampal astrocytes mitigates memory deficits induced by PLAE. Together, our data reveal that disruptions of PPAR-γ signaling during neurodevelopment contribute to PLAE-induced memory dysfunction. In turn, PPAR-γ activation during a childhood-like period is a promising therapeutic approach for memory deficits in the context of early alcohol exposure. Thus, these findings contribute to the gaining insight into the mechanisms that might underlie memory impairments in FASD patients.This work was supported by the Ministerio de Economia y Competitividad (#PID2019-104077RB-100 - MCIN/AEI/10.13039/501100011033), Ministerio de Sanidad (Plan Nacional sobre Drogas #2018/007 and ISCIII-Feder-RIAPAd-RICORS #RD21/0009/001) by the EU NextGeneration and by the Generalitat de Catalunya, AGAUR (#2021SGR00485). AG-B received a FI-AGAUR grant from the Generalitat de Catalunya (#2019FI_B0081). IG-L obtained a grant from the Ministerio de Ciencia e Innovación (#PRE2020-091923) The Department of Medicine and Health Sciences (UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (#CEX2018-000792-M). OV is recipient of an ICREA Academia Award (Institució Catalana de Recerca i Estudis Avançats, Generalitat de Catalunya). The authors wish to thank Xavier Puig-Reyne for the technical support

Effects of fast-acting antidepressant drugs on a postpartum depression mice model

Postpartum depression (PPD) is a severe psychiatric disorder with devastating consequences on child development and mother's health. Dysregulation of glutamatergic and GABAergic signalling has been described in the corticolimbic system of PPD patients, who also show a downregulation of allopregnanolone levels in serum. Consequently, a synthetic allopregnanolone-based treatment is the current eligible drug to treat PPD patients. Alternatively, ketamine appears to be a promising medication for preventing PPD, nevertheless the differences in efficacy between both treatments remains unknown due to the lack of comparative studies. On this basis, the present study aims to compare the effectiveness of allopregnanolone and ketamine on a PPD-like mouse model. Our results show that postpartum females undergoing a maternal separation with early weaning (MSEW) protocol show increased despair-like behaviour, anhedonia and disrupted maternal care. Such symptoms are accompanied by lower allopregnanolone serum levels, reduction of vesicular transporters of GABA (VGAT) and glutamate (VGLUT1) in the infralimbic cortex (IL), as well as decreased hippocampal cellular proliferation. Furthermore, both drugs prevent despair-like behaviour while only ketamine reverts anhedonia. Both treatments increase hippocampal neurogenesis, while only allopregnanolone raises VGAT and VGLUT1 markers in IL. These findings suggest that ketamine might be even more effective than allopregnanolone, which points out the necessity of including ketamine in clinical studies for PPD patients. Altogether, we propose a new mice model that recapitulates the core symptomatology and molecular alterations shown in PPD patients, which allows us to further investigate both the neurobiology of PPD and the therapeutic potential of antidepressant drugs.This work was supported by Ministerio de Ciencia e Innovación (grants number PID2019-104077-RB-100/AEI/10.13039/501100011033), Ministerio de Sanidad, Asuntos Sociales e Igualdad (Retic-ISCIII-RD/16/0017/0010-FEDER; RICORS, grant number RD21/0009/0001), and Plan Nacional Sobre Drogas (#2018/007) to O.V. A.G-B received a FI-AGAUR grant from the Generalitat de Catalunya (2019FI_B0081) and I.G-L. obtained a grant from the Ministerio de Ciencia e Innovación (PRE2020-091923). The Department of Medicine and Life Sciences (MELIS-UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (CEX2018-000792-M). O.V. is recipient of an ICREA Academia Award (Institució Catalana de Recerca i Estudis Avançats, Generalitat de Catalunya). The authors are indebted to Javier Valle-García (Proteomics and Protein Chemistry Group; Universitat Pompeu Fabra) and Marc González-Colell (Synthetic Biology for Medical Application, Universitat Pompeu Fabra)

Cannabidiol decreases motivation for cocaine in a behavioral economics paradigm but does not prevent incubation of craving in mice

Cocaine is a highly consumed drug worldwide which directly targets brain areas involved in reinforcement processing and motivation. Cannabidiol is a phytocannabinoid that exerts protecting effects upon cocaine-induced addictive behavior, although many questions about the mechanisms of action and the specific affected processes remain unknown. Moreover, its effects on cue-induced cocaine-craving incubation have never been addressed. The present study aimed to assess the effects of cannabidiol (20 mg/kg, i.p.) administered during the acquisition of cocaine self-administration (0.75 mg/kg/infusion) and demand task or during cocaine abstinence and craving. Moreover, we measured the alterations in expression of AMPAR subunits and ERK1/2 phosphorylation due to cannabidiol treatment or cocaine withdrawal. Our results showed that cannabidiol reduced cocaine intake when administered during the acquisition phase of the self-administration paradigm, increased behavioral elasticity and reduced motivation for cocaine in a demand task. Cannabidiol also reduced GluA1/2 ratio and increased ERK1/2 phosphorylation in amygdala. No effects over cocaine-craving incubation were found when cannabidiol was administered during abstinence. Furthermore, cocaine withdrawal induced changes in GluA1 and GluA2 protein levels in the prelimbic cortex, ventral striatum and amygdala, as well as a decrease in ERK1/2 phosphorylation in ventral striatum. Taken together, our results show that cannabidiol exerts beneficial effects attenuating the acquisition of cocaine self-administration, in which an operant learning process is required. However, cannabidiol does not affect cocaine abstinence and craving.This study was funded by the Ministerio de Ciencia, Innovación y Universidades (MCIU) and the Agencia Estatal de Investigación (AEI) (PID2019-104077RB-I00/AEI doi:10.1016/j.biopha.2022.112708.), Ministerio de Sanidad (RETICS-ISCIII, RD16/017/010 and Plan Nacional sobre Drogas 2018/007). L.A-Z received a FPI grant (BES-2017-080066) from Ministerio de Economia y Competitividad. P.B-S received a FI-AGAUR grant from the Generalitat de Catalunya (2021FI_B00205). A.G-B received a FI-AGAUR grant from the Generalitat de Catalunya (2019FI_B0081). The Department of Experimental and Health Sciences (UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (CEX2018-000792-M)

A Prospective Study of the Serological, Clinical, and Epidemiological Features of a SARS-CoV-2 Positive Pediatric Cohort

Background: SARS-CoV-2 was a global pandemic. Children develop a mild disease and may have a different rate of seroconversion compared to adults. The objective was to determine the number of seronegative patients in a pediatric cohort. We also reviewed the clinical–epidemiological features associated with seroconversion. Methods: A multicenter prospective observational study during September–November 2020, of COVID-19, confirmed by reverse transcription-polymerase chain reaction. Data were obtained 4–8 weeks after diagnosis. Blood samples were collected to investigate the humoral response, using three different serological methods. Results: A total of 111 patients were included (98 symptomatic), 8 were admitted to hospital, none required an Intensive Care Unit visit. Median age: 88 months (IQR: 24–149). Median time between diagnosis and serological test: 37 days (IQR: 34–44). A total of 19 patients were non-seroconverters when using three serological techniques (17.1%; 95% CI: 10.6–25.4); most were aged 2–10 years (35%, p < 0.05). Univariate analysis yielded a lower rate of seroconversion when COVID-19 confirmation was not present amongst household contacts (51.7%; p < 0.05). Conclusions: There was a high proportion of non-seroconverters. This is more commonly encountered in childhood than in adults. Most seronegative patients were in the group aged 2–10 years, and when COVID-19 was not documented in household contacts. Most developed a mild disease. Frequently, children were not the index case within the family

Role of cannabinoids in alcohol-induced neuroinflammation

Alcohol is a psychoactive substance highly used worldwide, whose harmful use might cause a broad range of mental and behavioural disorders. Underlying brain impact, the neuroinflammatory response induced by alcohol is recognised as a key contributing factor in the progression of other neuropathological processes, such as neurodegeneration. These sequels are determined by multiple factors, including age of exposure. Strikingly, it seems that the endocannabinoid system modulation could regulate the alcohol-induced neuroinflammation. Although direct CB1 activation can worsen alcohol consequences, targeting other components of the expanded endocannabinoid system may counterbalance the pro-inflammatory response. Indeed, specific modulations of the expanded endocannabinoid system have been proved to exert anti-inflammatory effects, primarily through the CB2 and PPARγ signalling. Among them, some endo- and exogeneous cannabinoids can block certain pro-inflammatory mediators, such as NF-κB, thereby neutralizing the neuroinflammatory intracellular cascades. Furthermore, a number of cannabinoids are able to activate complementary anti-inflammatory pathways, which are necessary for the transition from chronically overactivated microglia to a regenerative microglial phenotype. Thus, cannabinoid modulation provides cooperative anti-inflammatory mechanisms that may be advantageous to resolve a pathological neuroinflammation in an alcohol-dependent context.This study was funded by Ministerio de Economia y Competitividad (grant number SAF2016-75966-R-FEDER), Ministerio de Sanidad (Retic-ISCIII, RD16/017/010 and Plan Nacional sobre Drogas2018/007). This study was funded by FI-AGAUR (grant number 2019FI_B 0008) and by Ministerio de Economía and Competitividad (FPI, grant number BES-2017-080066). The Department of Experimental and Health Sciences (UPF) is an “Unidad de Excelencia María de Maeztu” funded by the MINECO (Ref. MDM-2014-0370)