Biology subjects

Garcia-Baos, A.

Publications and source records attributed to Garcia-Baos, A..

4 recordsLinked to original sources

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↗

bioRxiv2023

PPAR-γ is a promising therapeutic target for memory deficits induced by early alcohol exposure.

BackgroundPatients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates of these deficits remain unclear. Here, we studied the participation of the expanded endocannabinoid system (ECS), which is known to be affected by alcohol in other life periods, and it is involved in memory impairments of neurodevelopmental disorders. MethodsC57BL/6 female mice were exposed to a time-limited access to either water or alcohol to model prenatal and lactation alcohol exposure (PLAE). The expanded ECS was analyzed in the prefrontal cortex and the hippocampus of the offspring at post-partum day (PD) 25 and 70. Then, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase N-acylethanolamines (NAEs), and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-{gamma}) antagonist; ii) pioglitazone, a PPAR-{gamma} agonist. Finally, we used a viral approach to upregulate astrocytic PPAR-{gamma} in the hippocampus to restore memory deficits. ResultsWe report that PLAE causes a hippocampal reduction of NAEs and PPAR-{gamma} at PD25. Moreover, URB597 suppresses PLAE-induced memory deficits through PPAR-{gamma}, since its effects are prevented by GW9662. Direct PPAR-{gamma} activation, using pioglitazone, also ameliorates memory impairments. Lastly, we demonstrate that the upregulation of PPAR-{gamma} in hippocampal astrocytes is sufficient to rescue PLAE-induced memory deficits. ConclusionOur data reveal a bidirectional link between memory deficits and expanded ECS alterations in the context of early alcohol exposure. Furthermore, we proved that PPAR-{gamma} in hippocampal astrocytes represents a specific therapeutic target for memory deficits in FASD.

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↗