Biology subjects

Martin-Sanchez, A.

Publications and source records attributed to Martin-Sanchez, A..

8 recordsLinked to original sources

bioRxiv2025

Phenotypic characterization of a mouse model of Rett syndrome reveals pubertal dysregulation and hypothalamic-gonadal dysfunction

BackgroundMutations in the MECP2 gene, encoding the epigenetic reader Methyl-CpG binding protein 2, are the main cause of Rett syndrome, a rare neurodevelopmental disorder. Besides severe symptoms such as profound intellectual disability, loss of speech and motor skills and epilepsy, loss of function of MECP2 has been associated with pubertal dysregulation, but the biological mechanisms leading to this remain unclear. MethodsUsing a mouse model of Rett, in which males are hemizygous and females heterozygous for Mecp2 loss of function mutation, we assessed the onset and progression of puberty, together with increase in body weight and onset of neurological symptoms in post-weaning mice until puberty. In brain samples of young adult mice, we analysed hypothalamic Gonadotropin releasing hormone (GnRH) neurons by immunofluorescent labelling, and in plasma samples measured circulating GnRH, LH and testosterone concentrations. Finally, we analysed testosterone dependent arginine-vasopressin circuits. ResultsIn our mouse model we found delayed puberty in Mecp2 CD1-null males, associated with a reduced rate of weight gain, but with puberty onset occurring at a lower body weight than in wildtype controls. Despite later puberty onset, Mecp2CD1-null male mice were found to have an increased number of GnRH neurons, but displayed lower levels of circulating reproductive hormones. Consequently, Mecp2CD1-null males have deficient testosterone-dependent arginine-vasopressin innervation. In female Mecp2CD1-heterozygous mice, we found no overall significant differences in pubertal development or GnRH neurons. The lack of significant alterations in females might be related to a later onset of neurological symptoms due to heterozygosity. ConclusionsOur data supports that MECP2 is essential for typical pubertal development, with complete loss of Mecp2 in a male murine model resulting in abnormalities of pubertal timing related to lower body weight, with an observed increase in hypothalamic GnRH neurons.

neuroscience↗

bioRxiv2023

The FAAH inhibitor URB597 reduces cocaine seeking during conditioned punishment and 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 reduced 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.

neuroscience↗

bioRxiv2022

A novel mouse model of postpartum depression and the neurobiological effects of fast-acting antidepressant treatments

postpartum depression (PPD) is a severe psychiatric disorder that affects up to 15% of mothers and impairs mother-infant bonding with devastating consequences on the child development and the mother health. Several studies indicate a possible dysregulation of glutamatergic and GABAergic signalling in the corticolimbic system, as well as a downregulation of the allopregnanolone levels in serum of PPD patients. Although brexanolone, an allopregnanolone-based treatment, has recently emerged as fundamental PPD treatment, there is scarce evidence on its neurobiological action mechanism. Moreover, ketamine appears to be a promising antidepressant treatment preventing PPD, nevertheless whether it might be a more effective than allopregnanolone for some patients remain unknown. Therefore, the present study is aimed to evaluate the depressive-like phenotype of postpartum females undergoing maternal separation with early weaning (MSEW) protocol, as well as to compare the effectiveness of ketamine and allopregnanolone treatments. MSEW dams show increased despair-like behaviour, anhedonia and disrupted maternal behaviour. Moreover, lower allopregnanolone serum levels, reduction of vesicular transporters for GABA (VGAT) and glutamate (VGLUT1) in the infralimbic cortex, as well as decreased hippocampal cellular proliferation are found in MSEW females. As for the antidepressant treatments, both drugs prevent despair-like behaviour, whereas only ketamine reverts anhedonia present in MSEW females. In addition, both treatments induce pro-neurogenic effects in the dorsal hippocampus but only allopregnanolone increases the VGAT and VGLUT1, without altering the excitatory/inhibitory ratio. Altogether, we propose a new mice model that recapitulates the core symptomatology and alterations in glutamatergic and GABAergic systems shown in PPD patients, which allows us to investigate the therapeutic mechanisms of allopregnanolone and ketamine.

neuroscience↗

bioRxiv2020

Cannabidiol effects on cocaine-seeking behaviour and incubation of craving in mice.

Background and PurposeTo remain abstinent represents one of the major challenges for the treatment of cocaine use disorder. Cocaine seeking elicited by drug-associated cues progressively intensifies during abstinence in a process termed incubation of craving, representing an aggravating factor for relapse. Cannabidiol is a phytocannabinoid that exerts protecting effects upon cocaine-seeking behaviour, although its effects on cocaine-craving incubation have never been elucidated. Experimental ApproachWe developed a mouse model of behavioural economic analysis of demand curves and incubation of cue-induced cocaine craving. Changes in the protein expression of AMPAR subunits and ERK1/2 phosphorylation were analysed. We also assessed the effects of cannabidiol (20 mg{middle dot}kg-1) administered either during acquisition of cocaine self-administration or abstinence. Key ResultsMice efficiently performed the demand task and incubation of cocaine craving. Besides, changes in GluA1 and GluA2 protein levels were found along the abstinence in prelimbic cortex, ventral striatum and amygdala, as well as a decrease in ERK1/2 phosphorylation in ventral striatum. Cannabidiol reduced ongoing cocaine intake when administered during the acquisition phase of the self-administration, but failed to alter the subsequent demand task performance and incubation of cocaine craving. No effects were found when cannabidiol was administered during the abstinence period. Conclusion and ImplicationsWe provide here a novel model of behavioural economic analysis of demand curves and cue-induced incubation of cocaine-seeking behaviour for mice. Moreover, we show that cannabidiol exerts differential effects on the current model depending on the self-administration phase in which it was administered. What is already knownO_LIBehavioural economics and incubation of cocaine craving are well-stablished paradigms to evaluate cocaine seeking in rats. C_LIO_LICBD reduces cocaine-seeking and cocaine-taking behaviours. C_LI What this study addsO_LIA mouse model of behavioural economic analysis of demand curves and incubation of cue-induced cocaine craving. C_LIO_LICBD reduces cocaine self-administration and has no effect over demand task and cocaine-craving incubation. C_LI Clinical significanceO_LIA new behavioural model for studying cocaine addiction in mice. C_LIO_LICBD exerts differential effects depending on when it was administered in the addictive process. C_LI TO_SCPLOWABLESC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWOFC_SCPLOW LO_SCPLOWINKSC_SCPLOW O_TBL View this table: org.highwire.dtl.DTLVardef@654e3aorg.highwire.dtl.DTLVardef@f2d37aorg.highwire.dtl.DTLVardef@1a0396org.highwire.dtl.DTLVardef@1e19d1dorg.highwire.dtl.DTLVardef@1121b7b_HPS_FORMAT_FIGEXP M_TBL C_TBL

neuroscience↗

bioRxiv2020

Behavioural and transcriptomic characterization of the comorbidity between Alzheimer s disease and Major Depression

Major Depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimers disease (AD). Despite both diseases having a robust genetic component, the common transcriptomic signature remains unknown. In this regard, we investigated the cognitive and emotional responses in 3- and 6-month-old in APP/PSEN1-Tg mutant mice, before {beta}-amyloid plaques were detected. Then, we studied the deregulation of genes and pathways in prefrontal cortex, striatum, hippocampus and amygdala, using transcriptomic and functional data analysis. The results demonstrated that depressive-like and anxiety-like behaviours, as well as memory impairments are already present at 3-month-old together with the deregulation of several genes and gene sets, including components of the circadian rhythms, electronic transport chain and neurotransmission. Finally, DisGeNET GSEA provides translational support for common depregulated gene sets related to MD and AD. Altogether, the results demonstrate that MD could be an early manifestation of AD.

neuroscience↗

bioRxiv2020

BEHAVIOURAL AND MOLECULAR EFFECTS OF CANNABIDIOLIC ACID IN MICE

ABSTRACTAims Cannabidiolic acid (CBDA) is one of the most abundant phytocannabinoid acids in the Cannabis Sativa plant. It has been shown it is able to exert some therapeutic effects such as antiemetic, anti-inflammatory, anxiolytic or antidepressant, although some of them remain under debate. In the present study we aim to assess the potential effects of CBDA on different behaviours and on the modulation of neuroinflammatory markers in the prefrontal cortex (PFC).Main methods the effects of acute and/or chronic CBDA (0.001-1 mg/kg i.p.) treatment were evaluated on cognitive, emotional, motivational and nociceptive behaviours in male CD1 mice. For this, Y-maze and elevated plus maze paradigms, spontaneous locomotor activity, social interaction, hot-plate, formalin and tail suspension tests were used. We also studied the effects of CBDA on the rewarding responses of cocaine in the conditioned place preference (CPP) paradigm. PFC was dissected after acute and chronic CBDA treatments to evaluate inflammatory markers.Key findings acute CBDA treatment induced antinociceptive responses in the hot-plate test. A 10-day chronic CBDA treatment reduced despair-like behaviour in the tail suspension test. CBDA did not alter the remaining behavioural tests assayed, including cocaine-induced reward in the CPP. Regarding the biochemical analysis, chronic CBDA treatment diminished peroxisome proliferator-activated receptor gamma (PPAR-γ) and increased interleukin-6 (IL-6) protein levels in PFC.Significance these results show that CBDA has limited in vivo effects modulating mice behaviour, highlighting the current disagreement regarding its therapeutic potential.Competing Interest StatementThe authors have declared no competing interest.Abbreviations5-HT1ASerotonin receptor 1ACBDCannabidiolCBDACannabiodiolic acidCOX-2Ciclooxigenase-2CPPConditioned place preferenceEPMElevated plus mazeIL-6Interleukin-6PFCPrefrontal cortexPPARProliferator-activated receptorTRPA1Transient receptor potential cation channel ankyrin 1TRPM8Transient receptor potential cation channel melastatin 8TRPV1Transient receptor potential cation channel vanilloid 1TSTTail suspension testView Full Text

pharmacology and toxicology↗

bioRxiv2020

COCAINE-INDUCED IMPULSIVITY IS DIFFERENTIALLY EXPRESSED IN MALE AND FEMALE MICE EXPOSED TO MATERNAL SEPARATION AND IS ASSOCIATED WITH ALTERATIONS IN AMPA RECEPTORS SUBUNITS.

Impulsivity is a key trait in the diagnosis of major depressive disorder (MDD) and substance use disorder (SUD). MDD is a chronic illness characterized by sadness, insomnia, and loss of interest. SUD is a chronic and relapsing disorder characterized by the consumption of drugs despite their negative consequences. Among drugs of abuse, cocaine is the most consumed psychostimulant. Animal studies demonstrated that increased impulsivity predicts predisposition to acquire cocaine self-administration (SA) behaviour with an increased cocaine-intake. Moreover, early-life stress represents a vulnerability factor to develop depressive disorders and drug addiction. Maternal separation with early weaning (MSEW) is an animal model that allows examining the impact of early-life stress on cocaine abuse. In this study, we aimed to explore changes in MSEW-induced impulsivity to determine potential associations between depression-like and cocaine-seeking behaviours in male and female mice. We also evaluated possible alterations in the AMPA receptors (AMPArs) composition and glutamatergic neurotransmission. We exposed mice to MSEW and the behavioural tests were performed during adulthood. Moreover, GluA1, GluA2 mRNA and protein expression were evaluated in the medial Prefrontal Cortex (mPFC). Results showed higher impulsive cocaine-seeking in females, independently the MSEW, as well as an increase in GluA1 and GluA2 protein expression. Moreover, MSEW induced downregulation of Gria2 and increased the GluA1/GluA2 ratio, only in male mice. In conclusion, female mice expressed higher mPFC glutamatergic function, which potentiated their impulsivity during cocaine SA. Also, data indicated that MSEW alters glutamatergic function in mPFC of male mice, increasing the glutamatergic excitability.

neuroscience↗

bioRxiv2020

The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113.

Cocaine addiction is a brain disorder characterized by the consumption of the drug despite harmful consequences, the loss of control over drug intake and increased risk of relapse. Albeit prolonged research efforts, there is no available medication approved for the treatment of cocaine addiction. In the last decade, cannabinoid-based compounds have drawn increased interest for its potential therapeutic applications in various psychiatric conditions. Cannabidiol, a non-psychotomimetic constituent of the C. sativa plant, shows promising results in rodent models of anxiety, schizophrenia, depression and drug addiction. However, the specific effects and mechanisms of action of cannabidiol in a rodent model of extinction-based abstinence and drug seeking relapse remain unclear. Here, we administered cannabidiol (20 mg/kg) to male CD-1 mice trained to self-administer cocaine (0.75 mg/kg/inf) during extinction training (8-12 days). Then, we evaluated the reinstatement of cocaine seeking induced by cues, stress and drug priming. To ascertain the participation of CB1 receptors in these behavioral responses, we systemically administered the neutral cannabinoid antagonist AM4113 (5 mg/kg) before each reinstatement session. The results document that cannabidiol (20 mg/kg) does not modulate extinction training but attenuates extinction burst responding after one cannabidiol injection. Furthermore, cannabidiol specifically blocked the reinstatement of cocaine seeking triggered by a cue presentation, an effect prevented by AM4113 (5 mg/kg). Unexpectedly, cannabidiol facilitated stress-induced reinstatement of cocaine seeking behavior, also by a CB1-dependent mechanism. Finally, cannabidiol did not affect cocaine-primed (10 mg/kg) precipitation of cocaine seeking. Our results reveal a series of complex changes induced by cannabidiol treatment with opposite implications for the reinstatement of cocaine seeking behavior that may limit therapeutic opportunities. The activity of CB1 receptors seems to play a crucial role in the expression of cannabidiol-induced neuroplasticity underlying both the desirable and undesirable reinstatement effects here detailed.

neuroscience↗