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1.
Mol Psychiatry ; 28(8): 3373-3383, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37491462

RESUMO

Patients 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.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Tiazolidinedionas , Gravidez , Feminino , Humanos , Camundongos , Animais , Criança , PPAR gama , Pioglitazona/farmacologia , Lactação , Transtornos da Memória/tratamento farmacológico , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico
2.
Int J Neuropsychopharmacol ; 24(1): 77-88, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-32951039

RESUMO

BACKGROUND: Prenatal alcohol exposure is a leading cause of neurobehavioral and neurocognitive deficits collectively known as fetal alcohol spectrum disorders, including eating disorders and increased risk for substance abuse as very common issues. In this context, the present study aimed to assess the interaction between prenatal and lactation alcohol exposure (PLAE) and a high-fat diet (HFD) during childhood and adolescence. METHODS: Pregnant C57BL/6 mice underwent a procedure for alcohol binge drinking during gestation and lactation periods. Subsequently, PLAE female offspring were fed with an HFD for 8 weeks, and thereafter, nutrition-related parameters as well as their response to cocaine were assessed. RESULTS: In our model, feeding young females with an HFD increased their triglyceride blood levels but did not induce overweight compared with those fed with a standard diet. Moreover, PLAE affected how females responded to the fatty diet as they consumed less food than water-exposed offspring, consistent with a lower gain of body weight. HFD increased the psychostimulant effects of cocaine. Surprisingly, PLAE reduced the locomotor responses to cocaine without modifying cocaine-induced reward. Moreover, PLAE prevented the striatal overexpression of cannabinoid 1 receptors induced by an HFD and induced an alteration of myelin damage biomarker in the prefrontal cortex, an effect that was mitigated by an HFD-based feeding. CONCLUSION: Therefore, in female offspring, some effects triggered by one of these factors, PLAE or an HFD, were blunted by the other, suggesting a close interaction between the involved mechanisms.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/complicações , Cocaína/farmacologia , Dieta Hiperlipídica/efeitos adversos , Inibidores da Captação de Dopamina/farmacologia , Lactação , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fatores Etários , Animais , Animais Lactentes , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
3.
Addict Biol ; 26(2): e12911, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32329565

RESUMO

Early-life stress (ELS) is associated with negative consequences, including maladaptive long-lasting brain effects. These alterations seem to increase the likelihood of developing substance use disorders. However, the molecular consequences of ELS are poorly understood. In the present study, we tested the impact of ELS induced by maternal separation with early weaning (MSEW) in CD1 male mice at different phases of cocaine self-administration (SA). We also investigated the subsequent alterations on GluR2, GluR1, cAMP response element-binding (CREB), and CREB-phosphorylation (pCREB) in ventral tegmental area (VTA) and nucleus accumbens (NAc) induced by both MSEW and cocaine SA. Our results show that MSEW animals expressed a higher cocaine intake, an increased vulnerability to the acquisition of cocaine SA, and incapacity to extinguish cocaine SA behaviour. MSEW mice showed decreased GluR2 and increased GluR1 and pCREB in NAc. Also, results displayed reduction of basal levels of GluR1 and CREB and an elevation of GluR1/GluR2 ratio in the VTA. Such results hint at an enhanced glutamatergic function in NAc and increased excitability of VTA DA neurons in maternally separated mice. Altogether, our results suggest that MSEW induces molecular alterations in the brain areas related to reward processing, increasing the vulnerability to depression and cocaine-seeking behaviour.


Assuntos
Cocaína/administração & dosagem , Glutamatos/metabolismo , Privação Materna , Núcleo Accumbens/patologia , Área Tegmentar Ventral/patologia , Animais , Proteína de Ligação a CREB/metabolismo , Masculino , Camundongos , Fosforilação/fisiologia , Receptores de AMPA/metabolismo , Transdução de Sinais/fisiologia
4.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361071

RESUMO

3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the "bath salts". Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigms. In addition, we assessed the effects of the co-administration of CBD and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Furthermore, CBD exerted anxiolytic-like effects, exclusively in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice varies depending on the requirements of the learning task, resulting in a complex response. Therefore, further research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed.


Assuntos
Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Benzodioxóis/toxicidade , Canabidiol/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Pirrolidinas/toxicidade , Inibidores da Captação Adrenérgica/toxicidade , Animais , Anticonvulsivantes/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/patologia , Condicionamento Clássico/efeitos dos fármacos , Masculino , Camundongos , Catinona Sintética
5.
EMBO Rep ; 19(9)2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30002119

RESUMO

Melanoma antigen genes (Mage) were first described as tumour markers. However, some of Mage are also expressed in healthy cells where their functions remain poorly understood. Here, we describe an unexpected role for one of these genes, Maged1, in the control of behaviours related to drug addiction. Mice lacking Maged1 are insensitive to the behavioural effects of cocaine as assessed by locomotor sensitization, conditioned place preference (CPP) and drug self-administration. Electrophysiological experiments in brain slices and conditional knockout mice demonstrate that Maged1 is critical for cortico-accumbal neurotransmission. Further, expression of Maged1 in the prefrontal cortex (PFC) and the amygdala, but not in dopaminergic or striatal and other GABAergic neurons, is necessary for cocaine-mediated behavioural sensitization, and its expression in the PFC is also required for cocaine-induced extracellular dopamine (DA) release in the nucleus accumbens (NAc). This work identifies Maged1 as a critical molecule involved in cellular processes and behaviours related to addiction.


Assuntos
Comportamento Aditivo/genética , Transtornos Relacionados ao Uso de Cocaína/genética , Cocaína/farmacologia , Proteínas de Neoplasias/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Animais , Cocaína/administração & dosagem , Dependovirus , Dopamina/metabolismo , Deleção de Genes , Ácido Glutâmico/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Reforço Psicológico , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
6.
Addict Biol ; 25(4): e12778, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31162770

RESUMO

The administration of cannabidiol has shown promising evidence in the treatment of some neuropsychiatric disorders, including cocaine addiction. However, little information is available as to the mechanisms by which cannabidiol reduces drug use and compulsive seeking. We investigated the role of adult hippocampal neurogenesis in reducing cocaine voluntary intake produced by repeated cannabidiol treatment in mice. Cocaine intake was modelled using the intravenous cocaine self-administration procedure in CD1 male mice. Cannabidiol (20 mg/kg) reduced cocaine self-administration behaviour acquisition and total cocaine intake and enhanced adult hippocampal neurogenesis. Our results show that a 6-day repeated temozolomide treatment (25 mg/kg/day), a chemotherapy drug that blocks hippocampal neurogenesis, prevented cannabidiol-induced increment in the early stages of neuronal maturation and differentiation, without altering the basal levels of BrdU/NeuN and doublecortin immunostaining. The reduction of total cocaine intake and operant behaviour acquisition observed following cannabidiol exposure was attenuated by temozolomide treatment. Our results also show a similar effect of temozolamide on a cannabidiol-induced improvement of novel object recognition memory, a task influenced by the proneurogenic effects of cannabidiol (10 and 20 mg/kg). The anxiolytic effects of cannabidiol (10 and 20 mg/kg), however, remained unaffected after its proneurogenic effects decreased. The present study confirms that adult hippocampal neurogenesis is one of the mechanisms by which cannabidiol lowers cocaine reinforcement and demonstrates the functional implication of adult hippocampal neurogenesis in cocaine voluntary consumption in mice. Such findings highlight the possible use of cannabidiol for developing new pharmacotherapies to manage cocaine use disorders.


Assuntos
Canabidiol/farmacologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Temozolomida/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Bromodesoxiuridina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas do Domínio Duplacortina , Teste de Labirinto em Cruz Elevado , Hipocampo/metabolismo , Locomoção , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeos/metabolismo , Teste de Campo Aberto , Autoadministração
7.
Addict Biol ; 24(5): 1008-1018, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31237390

RESUMO

The co-occurrence of chronic pain and alcohol use disorders (AUDs) involves complex interactions between genetic and neurophysiological aspects, and the research has reported mixed findings when they both co-occur. There is also an indication of a gender-dependent effect; males are more likely to use alcohol to cope with chronic pain problems than females. Recently, a new conceptualization has emerged, proposing that the negative affective component of pain drives and maintains alcohol-related behaviors. We studied in a longitudinal fashion alterations in alcohol drinking patterns and pain thresholds in a mouse model of chronic neuropathic pain in a sex-dependent manner. Following partial denervation (spared nerve injury [SNI]), stimulus-evoked pain responses were measured before chronic alcohol consumption, during drinking, during a deprivation phase, and following an episode of excessive drinking. During the course of alcohol drinking, we observed pronounced sex differences in pain thresholds. Male mice showed a strong increase in pain thresholds, suggesting an analgesic effect induced by alcohol over time, an effect that was not observed in female mice. SNI mice did not differ from sham-operated controls in baseline alcohol consumption. However, following a deprivation phase and the reintroduction of ethanol, male SNI mice but not female mice showed more pronounced excessive drinking than controls. Finally, we observed decreased central ethanol sensitivity in male SNI mice but not in females. Together with our finding, that ethanol is able to decrease a pain-induced negative affective memory we come to following conclusion. We propose that a lower sensitivity to the intoxicating effects of alcohol together with the ability of alcohol to reduce the negative affective component of pain may explain the higher co-occurrence of AUD in male chronic pain patients.


Assuntos
Alcoolismo/fisiopatologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Neuralgia/fisiopatologia , Animais , Dor Crônica/fisiopatologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Limiar da Dor/efeitos dos fármacos , Recidiva , Reflexo Anormal/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/fisiopatologia
8.
Hum Mol Genet ; 23(24): 6481-94, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25027326

RESUMO

Williams-Beuren syndrome is a developmental multisystemic disorder caused by a recurrent 1.55-1.83 Mb heterozygous deletion on human chromosome band 7q11.23. Through chromosomal engineering with the cre-loxP system, we have generated mice with an almost complete deletion (CD) of the conserved syntenic region on chromosome 5G2. Heterozygous CD mice were viable, fertile and had a normal lifespan, while homozygotes were early embryonic lethal. Transcript levels of most deleted genes were reduced 50% in several tissues, consistent with gene dosage. Heterozygous mutant mice showed postnatal growth delay with reduced body weight and craniofacial abnormalities such as small mandible. The cardiovascular phenotype was only manifested with borderline hypertension, mildly increased arterial wall thickness and cardiac hypertrophy. The neurobehavioral phenotype revealed impairments in motor coordination, increased startle response to acoustic stimuli and hypersociability. Mutant mice showed a general reduction in brain weight. Cellular and histological abnormalities were present in the amygdala, cortex and hippocampus, including increased proportion of immature neurons. In summary, these mice recapitulate most crucial phenotypes of the human disorder, provide novel insights into the pathophysiological mechanisms of the disease such as the neural substrates of the behavioral manifestations, and will be valuable to evaluate novel therapeutic approaches.


Assuntos
Deleção Cromossômica , Cromossomos de Mamíferos , Anormalidades Craniofaciais/genética , Modelos Animais de Doenças , Síndrome de Williams/genética , Animais , Comportamento Animal , Peso Corporal , Encéfalo/patologia , Encéfalo/fisiopatologia , Cardiomegalia/fisiopatologia , Cromossomos Humanos Par 7 , Anormalidades Craniofaciais/patologia , Anormalidades Craniofaciais/fisiopatologia , Feminino , Dosagem de Genes , Genes Letais , Heterozigoto , Humanos , Hipertensão/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/patologia , Tamanho do Órgão , Sintenia , Síndrome de Williams/patologia , Síndrome de Williams/fisiopatologia
9.
Bioinformatics ; 31(18): 3075-7, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25964630

RESUMO

UNLABELLED: PsyGeNET (Psychiatric disorders and Genes association NETwork) is a knowledge platform for the exploratory analysis of psychiatric diseases and their associated genes. PsyGeNET is composed of a database and a web interface supporting data search, visualization, filtering and sharing. PsyGeNET integrates information from DisGeNET and data extracted from the literature by text mining, which has been curated by domain experts. It currently contains 2642 associations between 1271 genes and 37 psychiatric disease concepts. In its first release, PsyGeNET is focused on three psychiatric disorders: major depression, alcohol and cocaine use disorders. PsyGeNET represents a comprehensive, open access resource for the analysis of the molecular mechanisms underpinning psychiatric disorders and their comorbidities. AVAILABILITY AND IMPLEMENTATION: The PysGeNET platform is freely available at http://www.psygenet.org/. The PsyGeNET database is made available under the Open Database License (http://opendatacommons.org/licenses/odbl/1.0/). CONTACT: lfurlong@imim.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Alcoolismo/genética , Biomarcadores/análise , Transtornos Relacionados ao Uso de Cocaína/genética , Transtorno Depressivo Maior/genética , Redes Reguladoras de Genes , Bases de Conhecimento , Software , Algoritmos , Animais , Mapeamento Cromossômico , Mineração de Dados , Bases de Dados Factuais , Modelos Animais de Doenças , Humanos , Camundongos , Publicações , Ratos
10.
Open Biol ; 14(7): 240051, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39045857

RESUMO

Maintaining proper circadian rhythms is essential for coordinating biological functions in mammals. This study investigates the effects of daily arrhythmicity using Bmal1-knockout (KO) mice as a model, aiming to understand behavioural and motivational implications. By employing a new mathematical analysis based on entropy divergence, we identified disrupted intricate activity patterns in mice derived by the complete absence of BMAL1 and quantified the difference regarding the activity oscillation's complexity. Changes in locomotor activity coincided with disturbances in circadian gene expression patterns. Additionally, we found a dysregulated gene expression profile particularly in brain nuclei like the ventral striatum, impacting genes related to reward and motivation. Further investigation revealed that arrhythmic mice exhibited heightened motivation for food and water rewards, indicating a link between circadian disruptions and the reward system. This research sheds light on how circadian clock alterations impact the gene expression regulating the reward system and how this, in turn, can lead to altered seeking behaviour and motivation for natural rewards. In summary, the present study contributes to our understanding of how reward processing is under the regulation of circadian clock machinery.


Assuntos
Fatores de Transcrição ARNTL , Ritmo Circadiano , Camundongos Knockout , Motivação , Animais , Fatores de Transcrição ARNTL/metabolismo , Fatores de Transcrição ARNTL/genética , Camundongos , Regulação da Expressão Gênica , Relógios Circadianos/genética , Recompensa , Masculino , Perfilação da Expressão Gênica , Comportamento Animal , Locomoção , Transcriptoma
11.
Br J Pharmacol ; 181(22): 4491-4513, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39014975

RESUMO

BACKGROUND AND PURPOSE: New psychoactive substances such as N-ethylpentylone (NEP) are continuously emerging in the illicit drug market, and knowledge of their effects and risks, which may vary between sexes, is scarce. Our present study compares some key effects of NEP in male and female mice. EXPERIMENTAL APPROACH: Psychostimulant, rewarding and reinforcing effects were investigated by tracking locomotor activity, conditioned place preference (CPP) paradigm and through a self-administration (SA) procedure, respectively, in CD1 mice. Moreover, the expression of early genes (C-fos, Arc, Csnk1e, Pdyn, Pp1r1b and Bdnf in addiction-related brain areas) was assessed by qPCR. Finally, serum and brain levels of NEP were determined by UHPLC-MS/MS. KEY RESULTS: NEP-treated males experimented locomotor sensitisation and showed higher and longer increases in locomotion as well as higher hyperthermia after repeated administration than females. Moreover, while preference score in the CPP was similar in both sexes, extinction occurred later, and reinstatement was more easily established for males. Female mice self-administered more NEP than males at a higher dose. Differences in early gene expression (Arc, Bdnf, Csnk1e and Ppp1r1b) were found, but the serum and brain NEP levels did not differ between sexes. CONCLUSION AND IMPLICATIONS: Our results suggest that male mice are more sensitive to NEP psychostimulant and rewarding effects. These differences may be attributed to different early gene expression but not to pharmacokinetic factors. Moreover, males appear to be more vulnerable to the hyperthermic effects of NEP, while females might be more prone to NEP abuse.


Assuntos
Regulação da Temperatura Corporal , Caracteres Sexuais , Animais , Feminino , Masculino , Camundongos , Regulação da Temperatura Corporal/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Autoadministração , Expressão Gênica/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos
12.
J Neurochem ; 125(5): 736-46, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23521165

RESUMO

Ethanol and 3, 4-Methylenedioxymethamphetamine (MDMA) are popular recreational drugs widely abused by adolescents that may induce neurotoxic processes associated with behavioural alterations. Adolescent CD1 mice were subjected to ethanol intake using the drinking in the dark (DID) procedure, acute MDMA or a combination. Considering that both drugs of abuse cause oxidative stress in the brain, protein oxidative damage in different brain areas was analysed 72 h after treatment using a proteomic approach. Damage to specific proteins in treated animals was significant in the hippocampus but not in the prefrontal cortex. The damaged hippocampus proteins were then identified by mass spectrometry, revealing their involvement in energy metabolism, structural function, axonal outgrowth and stability, and neurotransmitter release. Mice treated with MDMA displayed higher oxidative damage than ethanol-treated mice. To determine whether this oxidative damage was affecting hippocampus activity, declarative memory was evaluated at 72 h after treatment using the object recognition assay and the radial arm maze. Although acquisition in the radial arm maze was not impaired by ethanol intake, MDMA treatment impaired long-term memory in both tests. Therefore, oxidative damage to specific proteins observed under MDMA treatment affects important cellular function on the hippocampus that may contribute to declarative memory deficits.


Assuntos
Etanol/toxicidade , Hipocampo/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Proteínas de Membrana/metabolismo , Transtornos da Memória/metabolismo , Camundongos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/fisiologia
13.
Cereb Cortex ; 22(3): 550-66, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21673070

RESUMO

We studied, in behaving mice, the contribution of CB1 receptors to the activity-dependent changes induced at the hippocampal CA3-CA1 synapse by associative learning and following experimentally evoked long-term potentiation (LTP). Mice were classically conditioned to evoke eyelid responses with a trace paradigm using a tone as conditioned stimulus (CS) and an electric shock as unconditioned stimulus (US). Field excitatory postsynaptic potentials (fEPSPs) were evoked at the CA3-CA1 synapse during the CS-US interval across training. Conditioning was performed in presence of an agonist (WIN55,212-2) alone or with an antagonist (AM251) of the CB1 receptor, injected either systemically or locally. Conditioned responses (CRs) and fEPSP potentiation were depressed by WIN55,212-2. LTP was evoked by high-frequency stimulation of Schaffer collaterals after systemic or local WIN55,212-2 and AM251 injections. WIN55,212-2 affected the induction phase of LTP, mainly when injected locally. The addition of AM251 canceled out the effects of WIN55,212-2. Similar experiments were carried out in animals lacking the CB1 receptor (CB1(-/-) mice) and following silencing of hippocampal CB1 receptors (CB1R-siRNA-injected animals). In this case, CRs (CB1(-/-) mice) and LTP (CB1(-/-) and CB1R-siRNA-injected mice) reached lower values than their respective controls. Results offer new insights for understanding CB1 receptor contribution to associative learning and to CA3-CA1 synaptic plasticity.


Assuntos
Aprendizagem por Associação/fisiologia , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/fisiologia , Plasticidade Neuronal/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Transmissão Sináptica/fisiologia , Animais , Região CA1 Hipocampal/metabolismo , Região CA3 Hipocampal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Plasticidade Neuronal/genética , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/deficiência , Transmissão Sináptica/genética
14.
Biomed Pharmacother ; 165: 115194, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37499453

RESUMO

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.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Síndrome de Abstinência a Substâncias , Animais , Camundongos , Amidoidrolases , Punição , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico
15.
Sci Rep ; 13(1): 18229, 2023 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-37880305

RESUMO

A single dose of cocaine abolishes endocannabinoid-mediated long-term depression (eCB-LTD) in the nucleus accumbens (NAc) within 24 h of administration. However, it is uncertain whether this altered neuroplasticity entails a behavioral deficit. As previously reported, after a single dose of cocaine (20 mg/kg), mice displayed impaired eCB-LTD in the NAc. Such cocaine-induced neuroplastic impairment was accompanied by an altered preference for saccharin and social interactions and a reduction in mRNA levels of the anandamide-catabolizing enzyme NAPE-PLD. The pharmacological increase of anandamide through the fatty acid amide hydrolase (FAAH) inhibitor URB597 (1 mg/kg) reversed the cocaine-induced loss of eCB-LTD in the NAc and restored normal social interaction in cocaine-exposed mice, but it did not affect saccharin preference. Overall, this research underlines the neuroplastic and behavioral alterations occurring after the initial use of cocaine and suggests a potential role for anandamide.


Assuntos
Cocaína , Depressão Sináptica de Longo Prazo , Animais , Camundongos , Amidoidrolases/genética , Cocaína/farmacologia , Endocanabinoides , Sacarina , Depressão Sináptica de Longo Prazo/efeitos dos fármacos
16.
Artigo em Inglês | MEDLINE | ID: mdl-34688811

RESUMO

No pharmacological treatments are yet approved for patients with cocaine use disorders. Cannabidiol, a constituent of the C. sativa plant has shown promising results in rodent models of drug addiction. However, the specific effects and mechanisms of action of cannabidiol in rodent operant models of extinction-based abstinence and drug-seeking relapse remain unclear. Cannabidiol (10 and 20 mg/kg, i.p.) was injected during extinction training to male CD-1 mice previously trained to self-administer cocaine (0.75 mg/kg/infusion). Then, we evaluated the reinstatement of cocaine seeking induced by cues and stressful stimuli (footshock). We found that cannabidiol (10 and 20 mg/kg) did not modulate extinction learning. After cannabidiol 20 mg/kg treatment, increased levels of CB1 receptor protein were found in the prelimbic and orbitofrontal regions of the prefrontal cortex, and in the ventral striatum; an effect paralleled by a reduction of striatal ∆FosB accumulation and an increment of GluR2 AMPA receptor subunits. Furthermore, cue-induced reinstatement of cocaine seeking was attenuated by cannabidiol. Unexpectedly, cannabidiol 20 mg/kg facilitated stress-induced restoration of cocaine-seeking behaviour. To ascertain the participation of CB1 receptors in these behavioural changes, we administered the CB1 antagonist AM4113 (5 mg/kg) before each reinstatement session. Both, the attenuation of cue-induced reinstatement and the facilitation of stress-induced reestablishment were abolished by AM4113 in cannabidiol 20 mg/kg-treated mice. Our results reveal a series of complex CB1-related changes induced by cannabidiol with a varying impact on the reinstatement of cocaine-seeking behaviour that could limit its therapeutic applications.


Assuntos
Canabidiol/farmacologia , Cocaína/administração & dosagem , Sinais (Psicologia) , Comportamento de Procura de Droga , Pirazóis/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Comportamento Aditivo/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Recidiva , Autoadministração , Estriado Ventral/efeitos dos fármacos
17.
Biomed Pharmacother ; 154: 113598, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36029538

RESUMO

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.


Assuntos
Depressão Pós-Parto , Ketamina , Anedonia , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão Pós-Parto/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Privação Materna , Camundongos , Pregnanolona/farmacologia , Pregnanolona/uso terapêutico
18.
Biomed Pharmacother ; 153: 113333, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35779420

RESUMO

Brain and Muscle Arnt-like Protein 1 (BMAL1) is an essential component of the molecular clock underlying circadian rhythmicity. Its function has been recently associated with mood and reward processing alterations. We investigated the behavioural and neurobiological impact of Bmal1 gene deletion in mice, and how this could affect rewarding effects of cocaine. Additionally, key clock genes and components of the dopamine system were assessed in several brain areas. Our results evidence behavioural alterations in Bmal1-KO mice, including changes in locomotor activity with impaired habituation to environments, short-term memory and social recognition impairments. In addition, Bmal1-KO mice experienced reduced cocaine-induced sensitisation and rewarding effects of cocaine as well as reduced cocaine-seeking behaviour. Furthermore, Bmal1 deletion influenced the expression of other clock-related genes in the mPFC and striatum, as well as alterations in the expression of dopaminergic elements. Overall, the present article offers a novel and extensive characterisation of Bmal1-KO animals. We suggest that reduced cocaine's rewarding effects in these mutant mice might be related to Bmal1 role as an expression regulator of MAO and TH, two essential enzymes involved in dopamine metabolism.


Assuntos
Fatores de Transcrição ARNTL , Cocaína , Disfunção Cognitiva , Fatores de Transcrição ARNTL/genética , Animais , Ritmo Circadiano/genética , Cocaína/farmacologia , Dopamina , Camundongos , Camundongos Knockout
19.
Behav Brain Res ; 416: 113545, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34437938

RESUMO

The prepulse inhibition (PPI) of the startle response can identify the rodents that are more sensitive to the effects of cocaine. Mice with a lower PPI presented a higher vulnerability to the effects of cocaine and a higher susceptibility to developing a substance use disorder (SUD). Maternal separation with early weaning (MSEW) is a relevant animal model to induce motivational alterations throughout life. Nevertheless, only a few studies on females exist, even though they are more vulnerable to stress- and cocaine-related problems. Hence, the aim of the present study was to evaluate the ability of PPI to identify females with a greater vulnerability to the long-term consequences of early stress on the motivational effects of cocaine. Female mice underwent MSEW and were classified according to their high or low PPI. They were then assessed in the cocaine-induced locomotor sensitization test, the conditioned place preference paradigm or the operant self-administration paradigm. Additionally, they were also evaluated in the passive avoidance task, the tail-suspension and the splash tests. The results revealed that the females with lower PPI presented higher consequences of MSEW on the effects of cocaine and showed an increase in anhedonia-like behaviours. Our findings support that a PPI deficit could represent a biomarker of vulnerability to the effects of cocaine induced by MSEW.


Assuntos
Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Privação Materna , Motivação , Inibição Pré-Pulso/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Anedonia/efeitos dos fármacos , Animais , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Camundongos , Autoadministração , Desmame
20.
Biomed Pharmacother ; 148: 112708, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35168076

RESUMO

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.


Assuntos
Canabidiol , Cocaína , Animais , Canabidiol/farmacologia , Cocaína/metabolismo , Cocaína/farmacologia , Fissura , Economia Comportamental , Camundongos , Motivação , Núcleo Accumbens
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