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Substance Use Disorder (SUD) has been conceptualized as an outcome of a dysregulated reward system. However, individuals with SUD suffer from anxiety with an intensity depending on the abstinence period length. This review discusses the role of anxiety as a major contributor to the initiation and perpetuation of SUD, and its dependence on an up-regulated defense-antireward system. In addition, it is discussed that sleep debt, and its psychosocial consequences, promote anxiety, contributing to SUD generation and maintenance. Healthy sleep patterns can be disrupted by diverse medical conditions and negative psychosocial interactions, resulting in accumulated sleep debt and anxiety. Within this narrative review, we discuss the interplay between the motivation-reward and defense-antireward systems, framing the progression from recreational drug use to addiction. This interplay is nuanced by sleep debt-induced anxiety and its psychosocial consequences as contributory vulnerability factors in the genesis of addiction.
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Individuals considered resilient can overcome adversity, achieving normal physical and psychological development, while those deemed vulnerable may not. Adversity promotes structural and functional alterations in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, activity-dependent synaptic plasticity is intricately linked to neuronal shaping resulting from experiences. We hypothesize that this plasticity plays a crucial role in resilience processes. However, there is a notable absence of studies investigating this plasticity and behavioral changes following social adversity at different life stages. Consequently, we evaluated the impact of social adversity during early postnatal development (maternal separation [MS]), adulthood (social defeat [SD]), and a combined exposure (MS + SD) on behavioral outcomes (anxiety, motivation, anhedonia, and social interaction). We also examined cFos expression induced by social interaction in mPFC and hippocampus of adult male rats. Behavioral analyses revealed that SD-induced anhedonia, whereas MS + SD increased social interaction and mitigated SD-induced anhedonia. cFos evaluation showed that social interaction heightened plasticity in the prelimbic (PrL) and infralimbic (IL) cortices, dentate gyrus (DG), CA3, and CA1. Social interaction-associated plasticity was compromised in IL and PrL cortices of the MS and SD groups. Interestingly, social interaction-induced plasticity was restored in the MS + SD group. Furthermore, plasticity was impaired in DG by all social stressors, and in CA3 was impaired by SD. Our findings suggest in male rats (i) two adverse social experiences during development foster resilience; (ii) activity-dependent plasticity in the mPFC is a foundation for resilience to social adversity; (iii) plasticity in DG is highly susceptible to social adversity.
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Privação Materna , Plasticidade Neuronal , Córtex Pré-Frontal , Resiliência Psicológica , Animais , Plasticidade Neuronal/fisiologia , Masculino , Ratos , Anedonia/fisiologia , Interação Social , Derrota Social , Hipocampo , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Ratos Wistar , Comportamento Animal/fisiologia , Comportamento Social , Ansiedade/fisiopatologiaRESUMO
Introduction: The amygdala is a limbic region of high value for understanding anxiety and its treatment. Dopamine D2 receptors (D2Rs) and oxytocin receptors (OXTRs) have both been shown to participate in modulating anxiety involving effects in the amygdala. The goal is to understand if D2R-OXTR heterocomplexes exist in the central amygdala and if, through enhancing allosteric receptor-receptor interactions, may enhance anxiolytic actions. Methods: The methods used involve the shock-probe burying test, the in situ proximity ligation assay (PLA), image acquisition and analysis, and the BRET2 assay. Bilateral cannulas were introduced into the amygdala, and the effects of the coadministration of oxytocin and the D2R-like agonist quinpirole into the amygdala were studied. Results: The combination treatment enhanced the anxiolytic effects compared to the single treatment. The D2R/D3R antagonist raclopride blocked the effects of the combination treatment of oxytocin and the D2R agonist, although oxytocin is regarded as a distinct modulator of fear-mediating anxiolytic effects. In situ PLA results indicate the existence of D2R-OXTR heteroreceptor complexes and/or the co-location of OXTR and D2R within the same cell membrane nanodomains in the central amygdala. With BRET2, evidence is given for the existence of D2R-OXTR heteromers in HEK293 cells upon co-transfection. Discussion: The enhanced behavioral effects observed upon co-treatment with OXTR and D2R agonists may reflect the existence of improved positive receptor-receptor interactions in the putative D2R-OXTR heterocomplexes in certain neuronal populations of the basolateral and central amygdala. The D2R-OXTR heterocomplex, especially upon agonist co-activation in the central amygdala, may open a new pharmacological venue for the treatment of anxiety.
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Patterns of drug ingestion may have a dissimilar impact on the brain, and therefore also the development of drug addiction. One pattern is binge intoxication that refers to the ingestion of a high amount of drug on a single occasion followed by an abstinence period of variable duration. In this study, our goal was to contrast the effect of continuous low amounts with intermittent higher amounts of Arachidonyl-chloro-ethylamide (ACEA), a CB1R agonist, on amphetamine seeking and ingestion, and describe the effects on the expression of CB1R and CRFR1 in the central nucleus of the amygdala (CeA) and in the nucleus accumbens shell (NAcS). Adult male Wistar rats were treated with a daily administration of vehicle or 20 µg of ACEA, or four days of vehicle followed by 100 µg of ACEA on the fifth day, for a total of 30 days. Upon completion of this treatment, the CB1R and CRFR1 expression in the CeA and NAcS was evaluated by immunofluorescence. Additional groups of rats were evaluated for their anxiety levels (elevated plus maze, EPM), amphetamine (AMPH) self-administration (ASA) and breakpoint (A-BP), as well as AMPH-induced conditioned place preference (A-CPP). Results indicated that ACEA induced changes in the CB1R and CRFR1 expression in both the NAcS and CeA. An increase in anxiety-like behavior, ASA, A-BP and A-CPP was also observed. Since the intermittent administration of 100 µg of ACEA induced the most evident changes in most of the parameters studied, we concluded that binge-like ingestion of drugs induces changes in the brain that may make the subject more vulnerable to developing drug addiction.
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Anfetamina , Núcleo Accumbens , Ratos , Masculino , Animais , Núcleo Accumbens/metabolismo , Anfetamina/farmacologia , Ratos Wistar , Tonsila do Cerebelo , Condicionamento ClássicoRESUMO
Resumen El opio y sus derivados, y recientemente los opioides, han acompañado a la humanidad desde las civilizaciones más antiguas hasta la actualidad. Sus efectos analgésicos, hipnóticos y placenteros no pasaron desapercibidos para los antiguos, los consideraron de utilidad médica y beneficiosa para el estado de ánimo. Hoy en día no existe otro tipo de medicamentos que puedan tratar el dolor más intenso tan eficientemente como estos potentes analgésicos. Sin embargo, el uso médico y recreativo de los opiáceos y los opioides conlleva riesgos para la salud, como la tolerancia, la hiperalgesia y la adicción. Actualmente, además de ser indiscutiblemente el tratamiento médico más poderoso para mitigar el sufrimiento ocasionado por el dolor, se ha convertido también en un problema de salud pública debido a la alta cantidad de personas con trastorno por uso de opioides y por las muertes ocasionadas por sobredosis. En esta revisión se hará mención de las bondades de los opiáceos y opioides, y también de los efectos no deseados que estos producen.
Abstract Opium and its derivatives, and recently the opioids have accompanied the humankind since the ancient civilizations to the present day. Its analgesic, hypnotic and pleasant effects did not go unnoticed by ancient people, which considered most of these effects of medical utility and noticed that they had remarkable mood benefits. Currently, there are no other kind of drugs that can palliate intense pain as efficiently as these powerful analgesics. However, the medical and recreational use of opiates and opioids may carry health risks such as tolerance, hyperalgesia, and addiction. Nowadays, in addition to being indisputably the most powerful medical treatment to alleviate the suffering caused by pain, it has also become a public health problem due to the high number of people with opioid use disorder that have facilitated deaths caused by opioids overdose. In this review we will discuss the medical benefits of opiates and opioids, as much as the unwanted effects they produce.
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Histaminergic, orexinergic, and cannabinoid systems play a role in both physiologic and oncogenic mechanisms in digestive tissues. These three systems are important mediators of tumor transformation, as they are associated with redox alterations, which are key aspects in oncological disorders. The three systems are known to promote alterations in the gastric epithelium through intracellular signaling pathways, such as oxidative phosphorylation, mitochondrial dysfunction, and increased Akt, which might promote tumorigenesis. Histamine promotes cell transformation through redox-mediated alterations in the cell cycle, DNA repair, and immunological response. The increase in histamine and oxidative stress generates angiogenic and metastatic signals through the VEGF receptor and H2R-cAMP-PKA pathway. Immunosuppression in the presence of histamine and ROS is linked to a decrease in dendritic and myeloid cells in gastric tissue. These effects are counteracted by histamine receptor antagonists, such as cimetidine. Regarding orexins, overexpression of the Orexin 1 Receptor (OX1R) induces tumor regression through the activation of MAPK-dependent caspases and src-tyrosine. OX1R agonists are candidates for the treatment of gastric cancer by stimulating apoptosis and adhesive interactions. Lastly, cannabinoid type 2 (CB2) receptor agonists increase ROS, leading to the activation of apoptotic pathways. In contrast, cannabinoid type 1 (CB1) receptor agonists decrease ROS formation and inflammation in gastric tumors exposed to cisplatin. Overall, the repercussion of ROS modulation through these three systems on tumor activity in gastric cancer depends on intracellular and/or nuclear signals associated with proliferation, metastasis, angiogenesis, and cell death. Here, we review the role of these modulatory systems and redox alterations in gastric cancer.
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Adenocarcinoma , Canabinoides , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Histamina/metabolismo , Espécies Reativas de Oxigênio , Oxirredução , Receptor CB2 de Canabinoide/metabolismoRESUMO
The rewarding effects of psychostimulants appear to be distinct between dominant and subordinate individuals. In turn, the endocannabinoid system is an important modulator of drug reward in the nucleus accumbens and medial prefrontal cortex, however the connection with social dominance is yet to be established. Male rats were classified as dominant or subordinate on the basis of their spontaneous agonistic interactions and drug reward was assessed by means of conditioned place preference with amphetamine (AMPH). In addition, the expression of CB1R, CB2R, FAAH1, and DAGLa was quantified from accumbal and cortical tissue samples. Our findings demonstrate that dominant rats required a lesser dose of AMPH to acquire a preference for the drug-associated compartment, thereby suggesting a higher sensitivity to the rewarding effects of AMPH. Furthermore, dominants exhibited a lower expression of CB1R in the medial prefrontal cortex and nucleus accumbens. This study illustrates how CBR1 expression could differentiate the behavioral phenotypes associated to social dominance.
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Anfetamina , Estimulantes do Sistema Nervoso Central , Receptor CB1 de Canabinoide , Animais , Masculino , Ratos , Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/metabolismo , Núcleo Accumbens/metabolismo , Recompensa , Receptor CB1 de Canabinoide/genéticaRESUMO
Episodic memory allows us to remember three main elements regarding an event: what (it is), where (it is in space), and when (it appears). The brain's electrical activity signaling the occurrence of these processes has been studied separately, revealing different patterns of ERP components and changes in the EEG theta band amplitude. However, how these patterns signal the retrieval of the temporal and spatial contexts of the same episode is unknown. The objective of this study was to evaluate the ERP components and the EEG theta band in association to the retrieval of the what, where, and when of the same episode through a source memory task. Three types of trials were identified here: total retrieval (what, where, and when), spatial retrieval (what and where), and correct rejections (correctly identified as new items). Attentional components, N200 and P300, and theta band were sensitive to the amount of information retrieved from episodic memory. Total retrieval and spatial trials elicited higher mean amplitude of FN400 and LPC, familiarity and recollection markers, respectively, than correct rejections. Our results suggest that early attention mechanisms can discern the strength of retrieval; in turn, familiarity and recollection mechanisms participate in the retrieval of the main contexts of episodic memory, but not in a cumulative way.
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Memória Episódica , Encéfalo/fisiologia , Eletroencefalografia/métodos , Potenciais Evocados/fisiologia , Rememoração Mental/fisiologiaRESUMO
Attention allows us to select relevant information from the background. Although several studies have described that cannabis use induces deleterious effects on attention, it remains unclear if cannabis dependence affects the attention network systems differently. OBJECTIVES: To evaluate whether customary consumption of cannabis or cannabis dependence impacts the alerting, orienting, and executive control systems in young adults; to find out whether it is related to tobacco or alcohol dependence and if cannabis use characteristics are associated with the attention network systems. METHOD: One-hundred and fifty-four healthy adults and 102 cannabis users performed the Attention Network Test (ANT) to evaluate the alerting, orienting, and executive control systems. RESULTS: Cannabis use enhanced the alerting system but decreased the orienting system. Moreover, those effects seem to be associated with cannabis dependence. Out of all the cannabis-using variables, only the age of onset of cannabis use significantly predicted the efficiency of the orienting and executive control systems. CONCLUSION: Cannabis dependence favors tonic alertness but reduces selective attention ability; earlier use of cannabis worsens the efficiency of selective attention and resolution of conflicts.
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Alcoolismo , Abuso de Maconha , Função Executiva , Humanos , Abuso de Maconha/complicações , Abuso de Maconha/epidemiologia , Orientação , Tempo de Reação , Adulto JovemRESUMO
Resumen La proporción de usuarios de una sustancia de abuso que desarrolla problemas con su consumo (abuso o dependencia) representa solo una parte de esta población. En México, el 63.8 % de la población consume alcohol, y de ellos, el 15 % desarrolla algún trastorno por consumo de alcohol (TCA). Se ha observado una relación causal entre el trastorno por consumo de sustancias (TCS) y la falta de autocontrol. Es decir, satisfacer necesidades de manera impulsiva, v. gr., consumir una droga sin evaluar las consecuencias. La corteza prefrontal (CPF) es el principal sustrato neuroanatómico del autocontrol y característicamente la CPF alcanza la madurez alrededor de los 30 años, sugieriendo que el autocontrol se alcanza despues de esta edad. Se ha propuesto que todos los grupos etarios que no han consolidado el uso del autocontrol son vulnerables al TCS. Similarmente ocurre con aquellos sujetos que por algún trastorno psiquiátrico tienen como característica una limitada función prefrontal. La CPF coordina una red subcortical cuya interacción depende de distintos sistemas de neurotransmisión, entre ellos, endocanabinoides. En este trabajo se revisó la función de la CPF y del sistema de endocanabinoides (sECB) y su relación con la vulnerabilidad a la adicción y otros trastornos psiquiátricos.
Abstract The proportion of users of a substance of abuse who develop problems with its use (abuse or dependence) represents only a part of this population. In Mexico, 63.8% of the population consumes alcohol and only 15% of them develop an alcohol use disorder (AUD). A causal relation has been observed between substance use disorder (SUD) and the lack of self-control. Which means, satisfying needs in an impulsive way, v.gr. using a drug, without considering the consequences. The prefrontal cortex (PFC) is the main neuroanatomical substrate of self-control and characteristically reaches maturity around the age of 30, suggesting that self-control is reached after this age. We suggest that all age groups that have not consolidated the use of self-control are vulnerable to SUD. The same occurs with those who, due to a psychiatric disorder, have the characteristic of a limited prefrontal function. The PFC coordinates a subcortical network whose interaction depends on different neurotransmission systems among them, the endocannabinoids system (ECBs). In this work we will review the function of the PFC, the ECBs and its relationship with vulnerability to addiction and other psychiatric disorders.
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Consumo de Bebidas Alcoólicas , Transtornos Relacionados ao Uso de Substâncias , Comportamento Impulsivo , Transmissão Sináptica , Endocanabinoides , Etanol , Alcoolismo , Autocontrole , Transtornos MentaisRESUMO
Attention and working memory (WM) are under high genetic regulation. Single nucleotide polymorphisms (SNPs) of the CNR1 gene, that encode for CB1R, have previously been shown to be related with individual differences in attentional control and WM. However, it remains unclear whether there is an allele-dosage or a dominant contribution of polymorphisms of CNR1 affecting attention and WM performance. This study evaluated the associations between attention and WM performance and three SNPs of CNR1: rs1406977, rs2180619, and rs1049353, previously associated with both processes. Healthy volunteers (n = 127) were asked to perform the Attention Network Task (ANT) to evaluate their overall attention and alerting, orienting, and executive systems, and the n-back task for evaluating their WM. All subjects were genotyped using qPCR with TaqMan assays; and dominant and additive models were assessed using the risk alleles of each SNP as the predictor variable. Results showed an individual association of the three SNPs with attention performance, but the composite genotype by the three alleles had the greatest contribution. Moreover, the additive-dosage model showed that for each G-allele added to the genotypic configuration, there was an increase in the percentage of correct responses respect to carriers who have no risk alleles in their genotypic configuration. The number of risk alleles in the genotypic configurations did not predict efficiency in any of the attention systems, nor in WM performance. Our model showed a contribution of three single nucleotide polymorphisms of the CNR1 gene to explain 9% of the variance of attention in an additive manner.
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Memória de Curto Prazo , Polimorfismo de Nucleotídeo Único , Receptor CB1 de Canabinoide/genética , Alelos , Atenção , Genótipo , Humanos , Receptores de CanabinoidesRESUMO
The sleep-wake cycle is a complex process that includes wake (W), non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. Each phase is regulated by specialized brain structures that, by means of different neurotransmitters, maintain the constant expression of the sleep-wake cycle. Molecules like orexin, serotonin, noradrenaline, histamine, for waking; GABA, adenosine, prostaglandins, for NREM sleep and acetylcholine and glutamate for REM sleep, among other molecules are responsible for the expression and maintenance of each phase. When the endocannabinoid system was being described for the first time, almost three decades ago, oleamide's sleep promoting properties were highlighted. Nowadays, enough evidence has been cumulated to support the endocannabinoid system role in the sleep-wake cycle regulation. The endocannabinoids oleamide anandamide, and 2-arachidonylglycerol promote NREM and/or REM sleep via the CB1R, thereby making this system a target to treat sleep disorders, such as insomnia.
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Canabinoides , Encéfalo , Eletroencefalografia , Neurotransmissores , Sono , Sono REM , VigíliaRESUMO
Drug dependence is a debilitating disorder, affecting 30 million people worldwide. In this short review we discuss about the plasticity changes in the reward and defense brain systems induced by early-life psychosocial stressful experiences. Such changes may render persons more vulnerable to illicit drugs use, facilitating behaviors of abuse and development of addiction. We propose that underlying plasticity changes render brain reward system as increasingly fragile because of tolerance and other physiological effects that reduce responsiveness with repeated use. In contrast, we propose that brain defense system makes maintain antifragile mechanisms that generate more robust responses with the prolonged consumption of drugs. Investigating the underlying mechanisms of these brain plasticity changes may advance the development of more efficacious pharmacologic and psychotherapeutic approaches to rehabilitate patients and more efficacious prevention policies to protect children from stressful experiences.
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Recompensa , Transtornos Relacionados ao Uso de Substâncias , Encéfalo/fisiologia , Criança , Humanos , Plasticidade Neuronal/fisiologiaRESUMO
The endocannabinoid system has been associated with antiproliferative effects in several types of tumors through cannabinoid receptor-mediated cell death mechanisms. Oleamide (ODA) is a CB1/CB2 agonist associated with cell growth and migration by adhesion and/or ionic signals associated with Gap junctions. Antiproliferative mechanisms related to ODA remain unknown. In this work, we evaluated the effects of ODA on cell viability and morphological changes in a rat RG2 glioblastoma cell line and compared these effects with primary astrocyte cultures from 8-day postnatal rats. RG2 and primary astrocyte cultures were treated with ODA at increasing concentrations (25, 50, 100, and 200 µM) for different periods of time (12, 24, and 48 h). Changes in RG2 cell viability and morphology induced by ODA were assessed by viability/mitochondrial activity test and phase contrast microscopy, respectively. The ratios of necrotic and apoptotic cell death, and cell cycle alterations, were evaluated by flow cytometry. The roles of CB1 and CB2 receptors on ODA-induced changes were explored with specific receptor antagonists. ODA (100 µM) induced somatic damage, detachment of somatic bodies, cytoplasmic polarization, and somatic shrinkage in RG2 cells at 24 and 48 h. In contrast, primary astrocytes treated at the same ODA concentrations exhibited cell aggregation but not cell damage. ODA (100 µM) increased apoptotic cell death and cell arrest in the G1 phase at 24 h in the RG2 line. The effects induced by ODA on cell viability of RG2 cells were independent of CB1 and CB2 receptors or changes in intracellular calcium transient. Results of this novel study suggest that ODA exerts specific antiproliferative effects on RG2 glioblastoma cells through unconventional apoptotic mechanisms not involving canonical signals.
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Morte Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Ácidos Oleicos/toxicidade , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Animais , Morte Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Hipnóticos e Sedativos/toxicidade , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidoresRESUMO
Adverse early life experiences, i.e. abusive parenting, during postnatal development, induce long-lasting effects on the stress response systems and behavior. Such changes persist throughout an individual's life, making him/her vulnerable to suffer psychiatric disorders, including anxiety disorders and drug addiction. Rat pup maternal separation (MS) is a widely used rodent early-life stress model. MS induces changes in the dopamine and endocannabinoid systems in the nucleus accumbens (NAcc) that facilitate alcohol consumption. In this study, our endeavor was to determine if social isolation during adolescence (aSI) was as efficient as MS to facilitate alcohol intake; and moreover, if their combination (MS + aSI) induces even higher alcohol intake and exacerbates anxiety-like behaviors. Also, we evaluated dopamine and endocannabinoid receptors in the NAcc to describe potential changes caused by MS, aSI or both. Wistar rats were reared under 4 different conditions: non-MS + social housing (SH), MS + SH, non-MS + aSI and MS + aSI. Once these rats became adults they were submitted to a voluntary alcohol intake protocol for 10 days. Similar groups of rats with no exposure to alcohol whatsoever, were sacrificed to dissect out the NAcc to analyze the expression of cannabinoid (CB1R and CB2R) and dopamine (D2R and D3R) receptors. Results showed that MS, aSI and MS + aSI increase both CB1R, D2R and D3R expression in the NAcc and also increase alcohol intake and anxiety. These results suggest that early life adverse experiences induce a reprogramming of the brain's dopamine and endocannabinoid systems which increases subject's vulnerability to develop anxiety, alcohol abuse and dependence.
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Consumo de Bebidas Alcoólicas/metabolismo , Encéfalo/metabolismo , Dopamina/metabolismo , Endocanabinoides/metabolismo , Privação Materna , Isolamento Social , Animais , Ratos , Ratos Wistar , Estresse Psicológico/metabolismoRESUMO
A number of physiological responses in the central nervous system (CNS) are regulated by the endocannabinoid system (ECS). Inhibition of neuronal excitability via activation of cannabinoid receptors (CBr) constitutes a potential protective response against neurotoxic insults. Oleamide (ODA) is a fatty acid amide with endocannabinoid profile exerting several effects in the CNS, though its neuroprotective properties remain unknown. The tryptophan metabolite quinolinic acid (QUIN) elicits toxic effects via overactivation of N-methyl-D-aspartate receptors (NMDAr) after its accumulation in the CNS under pathological conditions. Here, we investigated the protective properties of ODA against the excitotoxic damage induced by QUIN in rat brain synaptosomes and cortical slices, and whether these effects are linked to the stimulation of the endocannabinoid system via CB1 and/or CB2 receptor activation. ODA (1-50 µM) prevented the QUIN (100 µM)-induced loss of mitochondrial reductive capacity in synaptosomes in a mechanism partially mediated by CB1 receptor, as evidenced by the recovery of mitochondrial dysfunction induced by co-incubation with the CB1 receptor antagonist/inverse agonist AM281 (1 µM). In cortical slices, ODA prevented the short-term QUIN-induced loss of cell viability and the cell damage in a partial CB1 and CB2 receptor-dependent manner. Altogether, these findings demonstrate the neuroprotective and modulatory properties of ODA in biological brain preparations exposed to excitotoxic insults and the partial role that the stimulation of CB1 and CB2 receptors exerts in these effects.
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Sobrevivência Celular/fisiologia , Córtex Cerebral/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ácidos Oleicos/farmacologia , Receptor CB1 de Canabinoide/fisiologia , Receptor CB2 de Canabinoide/fisiologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Morfolinas/farmacologia , Ácidos Oleicos/antagonistas & inibidores , Pirazóis/farmacologia , Ácido Quinolínico/antagonistas & inibidores , Ácido Quinolínico/toxicidade , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistasRESUMO
Resumen A pesar de que el uso de marihuana se considera ilegal en la mayoría de los países del mundo, es una de las drogas más utilizadas. El 8,6% de la población mexicana, entre 12 y 65 años, ha probado la marihuana alguna vez (2017). Este porcentaje ha aumentado significativamente en los últimos años. Casos fatales asociados con el consumo de cannabis no se documentaron durante mucho tiempo; sin embargo, recientemente se ha informado de muertes causada por un síndrome de hiperémesis de cannabis (CHS) y muerte por automutilación. Si bien se ha documentado que la marihuana sintetiza sustancias activas con potenciales propiedades terapéuticas, en la actualidad, el mayor uso de la marihuana en nuestro país y en el mundo es recreativo. Esta revisión analiza las consecuencias del uso recreativo de marihuana, el contexto social y de salud con respecto a la legalización y los posibles usos terapéuticos de compuestos extraídos de la planta, de acuerdo a estudios reportados en la literatura científica. La contribución que hacemos es alertar sobre el impacto negativo en la salud del uso recreativo de marihuana y la urgencia de favorecer la investigación sobre sus efectos en el cerebro. Asimismo, identificar los principios activos que tengan potencial para el uso terapéutico.
Abstract Despite the fact that the use of marihuana is illegal in most countries of the world, it still is one of the most commonly used drugs worldwide. 8.6% of the Mexican population, between 12-65 years old, has smoked marihuana at least once in their lifetime (2017). There has been a significant increase in the number of consumers in the last few years. Fatal cases associated with cannabis use had not been recognized for a long time, however, lately, deaths due to a cannabis hyperemesis syndrome (CHS) and deaths from self-mutilation have been reported. Although marihuana synthesizes several active substances with potential therapeutic properties, nowadays, the greatest use of marihuana in our country and in the world is recreational. This review discusses the consequences of using marihuana for recreational use, the social and health contexts regarding legalization and potential therapeutic uses of compounds isolated from the plant based on the scientific literature. Our contribution is to warn people about the potential negative impact on the health of recreational use marihuana and the urgency of supporting the research of its effects on the brain. Similarly, we aim to identify the active principles with potential therapeutic use.
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Abusive alcohol consumption is a health problem, worldwide. There is extensive literature indicating that cannabinoid 1 receptor (CB1R) plays a crucial role in mediating alcohol's reward effects. Maternal care deprivation (MCD) is a reliable rodent model of early life stress that leads to high levels of anxiety and alterations in motivation, which may increase vulnerability to alcohol consumption. The present study researched whether anxiety-like behaviors and the level of motivation for a natural reward, and CB1R expression in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) can predict alcohol consumption in non-MCD and MCD male rats. Results indicate that MCD increases anxiety-like behaviors, i.e., reduces time in open arms in the elevated plus maze and increases alcohol intake. In turn, the motivation for a palatable reward, i.e., a chocolate flavored pellet, was not affected by MCD. MCD reduces CB1R expression in the PFC and increases it in the NAcc. Hence, both higher anxiety-like behaviors and higher CB1R expression in the NAcc and lower CB1R expression in the PFC are associated with higher alcohol intake. These results suggest that early life adverse experiences induce a reprogramming of the brain's endocannabinoid system that very likely contributes to making the brain vulnerable to develop alcohol abuse and dependence.
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Consumo de Bebidas Alcoólicas/metabolismo , Ansiedade/metabolismo , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Recompensa , Consumo de Bebidas Alcoólicas/psicologia , Animais , Ansiedade/etiologia , Masculino , Privação Materna , Motivação/fisiologia , Ratos Wistar , Estresse Psicológico/complicaçõesRESUMO
In this study, we have pursued to assess oleamide's potential role in reward and aversion mechanisms. To reach this goal we infused oleamide, either 1 µg into the nucleus accumbens shell (NAccS) and evaluated its effects on conditioned place preference (CCP) or 10 µg, to evaluate conditioned place aversion (CPA). Extinction and reinstatement were also evaluated in both cases. We sought to determine if CPP occurs via cannabinoid receptor 1 (CB1R) and CPA via serontoninergic 2c receptor (5HT2cR). Results revealed that 1 µg of oleamide administered bilaterally into the NAccS induced CPP, while 10 µg induced CPA. In both conditions CPP or CPA, reinstatement after extinction was induced. AM251 (CB1R inverse-agonist) prevented CPP induced with 1 µg; while SB242084 (5HT2cR antagonist) not only prevented CPA induced with 10 µg but caused a switch to CPP. These results suggest that oleamide at low doses promotes reward through CB1R, and aversion at high doses via 5HT2cR.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ácidos Oleicos/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Recompensa , Aminopiridinas/farmacologia , Animais , Condicionamento Operante/fisiologia , Extinção Psicológica/efeitos dos fármacos , Indóis/farmacologia , Masculino , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologiaRESUMO
The consequences of marijuana consumption during pregnancy and its effects on the function of the immune system have been little studied. Marijuana is one of the most consumed recreational drugs among pregnant women, and it is known that gestational exposure to marijuana can have serious effects on the offspring after birth. In this study, we challenged the immune system of Wistar rats by infecting them with the parasitic nematode Trichinella spiralis. A treatment group of these animals was prenatally exposed to the cannabinoid WIN 55,212-2; a control group was not exposed. At 5 days of infection, the treated animals were less effective in eliminating intestinal parasites; moreover, this effect was correlated with a deficiency in mucus production, lower recruitment of eosinophils in the duodenum, and a reduced percentage of Tγδ and NK cells. In conclusion, the gestational administration of the synthetic cannabinoid WIN 55,212-2 induces lasting changes to the function of the immune system against infection with T. spiralis in male Wistar rats, making them more susceptible to infection.