Endocannabinoid system and aggression across animal species.

This narrative review article summarizes the current state of knowledge regarding the relationship between the endocannabinoid system (ECS) and aggression across multiple vertebrate species. Experimental evidence indicates that acute administration of phytocannabinoids, synthetic cannabinoids, and the pharmacological enhancement of endocannabinoid signaling decreases aggressive behavior in several animal models. However, research on the chronic effects of cannabinoids on animal aggression has yielded inconsistent findings, indicating a need for further investigation. Cannabinoid receptors, particularly cannabinoid receptor type 1, appear to be an important part of the endogenous mechanism involved in the dampening of aggressive behavior. Overall, this review underscores the importance of the ECS in regulating aggressive behavior and provides a foundation for future research in this area.

CB1R chronic intermittent pharmacological activation facilitates amphetamine seeking and self-administration and changes in CB1R/CRFR1 expression in the amygdala and nucleus accumbens in rats.

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.

Amapola, lindísima amapola: de los opiáceos y los opioides, utilidad y riesgos / Poppy, beautiful poppy: opiates and opioids, utility and risks

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.

GPR55 activation prevents amphetamine-induced conditioned place preference and decrease the amphetamine-stimulated inflammatory response in the ventral hippocampus in male rats.

Inflammatory response in the Central Nervous System (CNS) induced by psychostimulants seems to be a crucial factor in the development and maintenance of drug addiction. The ventral hippocampus (vHp) is part of the reward system involved in substance addiction and expresses abundant G protein-coupled receptor 55 (GPR55). This receptor modulates the inflammatory response in vitro and in vivo, but there is no information regarding its anti-inflammatory effects and its impact on psychostimulant consumption. The aim of the present study was to investigate whether vHp GPR55 activation prevents both the inflammatory response induced by amphetamine (AMPH) in the vHp and the AMPH-induced conditioned place preference (A-CPP). Wistar adult male rats with a bilateral cannula into the vHp or intact males were subjected to A-CPP (5 mg/kg). Upon the completion of A-CPP, the vHp was dissected to evaluate IL-1ß and IL-6 expression through RT-PCR, Western blot and immunofluorescence. Our results reveal that AMPH induces both A-CPP and an increase of IL-1ß and IL-6 in the vHp. The GPR55 agonist lysophosphatidylinositol (LPI, 10 µM) infused into the vHp prevented A-CPP and the AMPH-induced IL-1ß increase. CID 16020046 (CID, 10 µM), a selective GPR55 antagonist, abolished LPI effects. To evaluate the effect of the inflammatory response, lipopolysaccharide (LPS, 5 µg/µl) was infused bilaterally into the vHp during A-CPP acquisition. LPS strengthened A-CPP and increased IL-1ß/IL-6 mRNA and protein levels in the vHp. LPS also increased CD68, Iba1, GFAP and vimentin expression. All LPS-induced effects were blocked by LPI. Our results suggest that GPR55 activation in the vHp prevents A-CPP while decreasing the local neuro-inflammatory response. These findings indicate that vHp GPR55 is a crucial factor in preventing the rewarding effects of AMPH due to its capacity to interfere with proinflammatory responses in the vHp.

Dominance status is associated with a variation in cannabinoid receptor 1 expression and amphetamine reward.

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.

Brain electrophysiological responses associated with the retrieval of temporal and spatial contexts in episodic memory.

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.

The Alerting and Orienting Systems of Attention Are Modified by Cannabis Dependence.

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.

Allele-dosage genetic polymorphisms of cannabinoid receptor 1 predict attention, but not working memory performance in humans.

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.

Fragility of reward vs antifragility of defense brain systems in drug dependence.

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.

Marihuana: legalización y atención médica / Marihuana: Legalization and Medical Care

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.

Chloramphenicol decreases CB1 receptor expression in the nucleus accumbens and prefrontal cortex and prevents amphetamine-induced conditioned place preference in rats.

Drug dependence seems to involve a learning and memory process. Since learning and memory depend on protein synthesis, drug dependence may depend on protein synthesis, too. Drug-induced reward is a crucial effect for the development of drug-dependence. We used chloramphenicol (CAP, a protein synthesis inhibitor), to evaluate its effects on amphetamine (amph)-seeking behavior, on CB1R expression and on protein synthesis in general, in specific areas of the brain. Two groups of Wistar adult male rats were subjected to amph-induced conditioned place preference (CPP). Rats in group 1 received amph and were kept in the chamber for 30min. Once this period elapsed, they received a subcutaneous injection of saline (veh) and were returned to their home-cage. Rats in group 2 were also treated with amph but received CAP (150mg/kgsc) instead of saline. Once CPP was evaluated rats were sacrificed and the prefrontal cortex (PFC), the nucleus accumbens (NAcc) and the hippocampus (Hipp) were isolated and prepared for CB1R Western blot analysis. A vivarium reared group of rats was added as a non-experimentally manipulated control group. Results indicate that group 1 developed CPP while increasing CB1R expression in the NAcc. Group 2 did not develop CPP, had lower CB1R expression in the PFC and lacked the CB1R increase in the NAcc observed in the amph+veh group. These results support the notion that among the underlying mechanisms for amph-seeking reward is an increase in CB1R, further supporting an interaction between dopamine/endocannabinoids in CPP learning.

An integrative overview of the cannabinergic system and mental health / Una revisión exhaustiva del sistema cannabinérgico y la salud mental

Abstract Background The endocannabinoid system (eCBs) is one of the modulatory systems widely expressed in the brain. It consists of receptors expressed in the cytoplasmic (CB1 and CB2), the mitochondrial membrane (CB1), and the endogenous ligands known as endocannabinoids, such as anandamide, 2AG and oleamide. CB1 has been found in excitatory and inhibitory neurons in the pre- and post-synaptic membranes. It is expressed in several brain areas such as the hippocampus, dorsal, and ventral striatum, amygdala and prefrontal cortex. The eCBs has been involved in the regulation of learning and memory, mood, energy balance, sleep, and drug addiction. Objective Integrate existing information about the eCBs and its role in brain function and mental health. Method Review of the information of basic and clinical relevance obtained from indexed scientific journals (PubMed/Medline, Scopus). Results Basic and clinical research on eCBs related to central nervous system function is described. Discussion and conclusion At present, the study of eCBs is of importance. The development of drugs that affect this system may be clinically useful to control different debilitating diseases. This is an area of interest to the scientific community and health care providers.

Resumen Antecedentes El sistema de endocannabinoides (eCBs) es uno de los sistemas moduladores más ampliamente expresados en el cerebro. Se compone de receptores expresados en la membrana citoplasmática (CB1 y CB2) y en la membrana mitocondrial (CB1) y ligandos endógenos conocidos como endocannabinoides, como anandamida, 2AG y oleamida. El CB1 se ha encontrado en neuronas excitadoras e inhibidoras, en las membranas pre- y pos-sináptica, en varias áreas cerebrales como el hipocampo, el estriado dorsal y ventral, y en la amígdala y la corteza prefrontal. El eCBs se ha relacionado con la regulación del aprendizaje y la memoria, del estado afectivo, del equilibrio energético, del sueño y del proceso de la adicción a las drogas. Objetivo Integrar la información existente sobre el eCBs y su función sobre los procesos cerebrales y la salud mental. Método Revisión de la información de relevancia básica y clínica obtenida de revistas científicas indexadas (PubMed/Medline, Scopus). Resultados Se describe de manera concisa información de interés básico y clínico de la investigación sobre el eCBs relacionada con la función del sistema nervioso central. Discusión y conclusión En la actualidad, el estudio del eCBs es indispensable debido a su potencial terapéutico. El desarrollo de fármacos que afecten este sistema puede ser clínicamente útil para controlar diferentes enfermedades debilitantes. Ésta es un área de interés para la comunidad científica y los proveedores de salud.