Neonatal treatment with a pegylated leptin antagonist has a sexually dimorphic effect on hypothalamic trophic factors and neuropeptide levels.

It is clear that the prenatal and early neonatal environments are important for determining the metabolic equilibrium in the adult animal, with prenatal/neonatal leptin levels being at least one of the factors involved. Leptin modulates hypothalamic development and, in particular, the neuronal circuits involved in metabolic control. We have recently reported that maternal deprivation (MD) for 24 h on postnatal day (PND) 9 modifies trophic factors and markers of cell turnover and neuronal maturation in the hypothalamus, as well as body weight and circulating leptin levels at PND13, with long- term effects on weight gain and circulating metabolic hormones in the adult. Moreover, these responses are sexually dimorphic. During MD, a dramatic decline in leptin levels is observed; thus, we aimed to determine which of the previously observed changes in markers of hypothalamic development might be attributed to the decline in this metabolic signal. Accordingly, male and female rats were treated with a pegylated leptin antagonist on PND9. In both sexes, hypothalamic signal transducer and activator of transcription 3 activation in response to acute leptin treatment was blocked by the antagonist. In females, hypothalamic mRNA levels for brain-derived neurotrophic factor, cocaine- and amphetamine-regulated transcript and the leptin receptor were increased, as were nestin and vimentin levels. There was also an increase in cell death in the hypothalamus, with a shift towards an anti-apoptotic balance in the Bcl2/BAX ratio. No hypothalamic effects were seen in males. Because antagonism of the actions of leptin at this specific neonatal stage affects hypothalamic cell turnover and maturation in a sex-specific manner, changes in this hormone, at least at this postnatal age, may differentially affect hypothalamic development in males and females, and may explain some of the reported sexually dimorphic responses to modifications in the early nutritional environment.

Maternal deprivation and adolescent cannabinoid exposure impact hippocampal astrocytes, CB1 receptors and brain-derived neurotrophic factor in a sexually dimorphic fashion.

We have recently reported that early maternal deprivation (MD) for 24 h [postnatal day (PND) 9-10] and/or an adolescent chronic treatment with the cannabinoid agonist CP-55,940 (CP) [0.4 mg/kg, PND 28-42] in Wistar rats induced, in adulthood, diverse sex-dependent long-term behavioral and physiological modifications. Here we show the results obtained from investigating the immunohistochemical analysis of CB1 cannabinoid receptors, glial fibrillary acidic protein (GFAP) positive (+) cells and brain-derived neurotrophic factor (BDNF) expression in the hippocampus of the same animals. MD induced, in males, a significant increase in the number of GFAP+ cells in CA1 and CA3 areas and in the polymorphic layer of the dentate gyrus (DG), an effect that was attenuated by CP in the two latter regions. Adolescent cannabinoid exposure induced, in control non-deprived males, a significant increase in the number of GFAP+ cells in the polymorphic layer of the DG. MD induced a decrease in CB1 expression in both sexes, and this effect was reversed in males by the cannabinoid treatment. In turn, the drug "per se" induced, in males, a general decrease in CB1 immunoreactivity, and the opposite effect was observed in females. Cannabinoid exposure tended to reduce BDNF expression in CA1 and CA3 of females, whereas MD counteracted this trend and induced an increase of BDNF in females. As a whole, the present results show sex-dependent long-term effects of both MD and juvenile cannabinoid exposure as well as functional interactions between the two treatments.

Consumo de cannabis y neurodesarrollo: ¿por qué son relevantes las diferencias de género? / Cannabis use and neurodevelopment: why are relevant the gender differences?

La aplicación de modelos animales en diversos campos de las neurociencias, incluyendo la psiquiatría y la adicción, es una herramienta fundamental para la investigación de las bases neurobiológicas de tales patologías desde una perspectiva translacional. A pesar de sus limitaciones, estos modelos resultan de gran importancia para la investigación de los mecanismos neurobiológicos subyacentes a los dimorfismos sexuales que se observan en diferentes aspectos de la psicobiología del individuo. En este artículo nos centraremos en los descritos en el ámbito de las enfermedades psiquiátricas y en los procesos de adicción, a los que no se les ha prestado una atención suficiente en los últimos años. Presentamos y discutimos datos procedentes de modelos animales de alteraciones en el neurodesarrollo y prestamos especial atención a dos períodos críticos, las etapas neonatal y adolescente, al sistema endocannabinoide como sistema regulador y al cannabis como droga de abuso. Exponemos evidencias acerca de los cambios observados en el sistema endocannabinoide como consecuencia de un episodio de separación materna temprana, y tratamos también las consecuencias del consumo de cannabis en edad adolescente, centrando la atención en los procesos de dependencia y de mayor riesgo de padecer enfermedades neuropsiquiátricas. En su conjunto, estos datos ponen de manifiesto la importancia del factor "sexo" y la necesidad de tener en cuenta su influencia tanto en la investigación preclínica, como en la clínica y la epidemiología. Proponemos, además, la profundización en una comunicación fluida entre estas tres aproximaciones, todo ello para el establecimiento de mejores estrategias de prevención y tratamiento (AU)

Animal models in neuroscience are an essential tool for the translational investigation of the neurobiological bases of psychiatric disorders, including drug addiction. Despite some limitations, these experimental models are of great relevance for the study of the neurobiological mechanisms underlying sexual dimorphisms affecting diverse psychobiological aspects. We will focus on those described for mental disorders including addiction that have been underestimated until recent years and that still require a wider and deeper investigation. Throughout the present manuscript we show and discuss data from animal models based in the neurodevelopmental theory and we pay special attention to the critical neonatal and adolescent periods, the endocannabinoid system as physiological regulator and cannabis as a drug of abuse. We show evidence for a role of the endocannabinoid system in the consequences of early maternal deprivation and also discuss long-term effects of adolescent cannabis exposure, emphasizing the risks of dependence and psychiatric disorders. All these data provide evidence for sex differences in the consequences of both neonatal stress and juvenile cannabinoid exposure, and point out the necessity of considering "sex" ("gender") as a critical factor in preclinical, clinical and epidemiological studies. We also emphasize that a fluent communication among these three approaches in needed is order to improve prevention and therapeutic strategies (AU)

Adolescent exposure to nicotine and/or the cannabinoid agonist CP 55,940 induces gender-dependent long-lasting memory impairments and changes in brain nicotinic and CB(1) cannabinoid receptors.

We have analysed the long-term effects of adolescent (postnatal day 28-43) exposure of male and female rats to nicotine (NIC, 1.4 mg/kg/day) and/or the cannabinoid agonist CP 55,940 (CP, 0.4 mg/kg/day) on the following parameters measured in the adulthood: (1) the memory ability evaluated in the object location task (OL) and in the novel object test (NOT); (2) the anxiety-like behaviour in the elevated plus maze; and (3) nicotinic and CB(1) cannabinoid receptors in cingulated cortex and hippocampus. In the OL, all pharmacological treatments induced significant decreases in the DI of females, whereas no significant effects were found among males. In the NOT, NIC-treated females showed a significantly reduced DI, whereas the effect of the cannabinoid agonist (a decrease in the DI) was only significant in males. The anxiety-related behaviour was not changed by any drug. Both, nicotine and cannabinoid treatments induced a long-lasting increase in CB(1) receptor activity (CP-stimulated GTPγS binding) in male rats, and the nicotine treatment also induced a decrease in nicotinic receptor density in the prefrontal cortex of females. The results show gender-dependent harmful effects of both drugs and long-lasting changes in CB(1) and nicotinic receptors.

Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands.

Cannabinoids, endocannabinoids and marijuana activate two well-characterized cannabinoid receptors (CB-Rs), CB1-Rs and CB2-Rs. The expression of CB1-Rs in the brain and periphery has been well studied, but neuronal CB2-Rs have received much less attention than CB1-Rs. Many studies have now identified and characterized functional glial and neuronal CB2-Rs in the central nervous system. However, many features of CB2-R gene structure, regulation and variation remain poorly characterized in comparison with the CB1-R. In this study, we report on the discovery of a novel human CB2 gene promoter transcribing testis (CB2A) isoform with starting exon located ca 45 kb upstream from the previously identified promoter transcribing the spleen isoform (CB2B). The 5' exons of both CB2 isoforms are untranslated 5'UTRs and alternatively spliced to the major protein coding exon of the CB2 gene. CB2A is expressed higher in testis and brain than CB2B that is expressed higher in other peripheral tissues than CB2A. Species comparison found that the CB2 gene of human, rat and mouse genomes deviated in their gene structures and isoform expression patterns. mCB2A expression was increased significantly in the cerebellum of mice treated with the CB-R mixed agonist, WIN55212-2. These results provide much improved information about CB2 gene structure and its human and rodent variants that should be considered in developing CB2-R-based therapeutic agents.

Implicación funcional del sistema cannabinoide endógeno en la homeostasis emocional / Functional role of the endocannabinoid system in emotional homeostasis

Introducción y desarrollo. El cannabis y sus derivados producen efectos complejos sobre las respuestas de ansiedad en humanos que van desde estados de relajación a reacciones de pánico. Diversos estudios en animales abundan en la complejidad de este mecanismo y revelan un perfil de acción bifásico. En dosis bajas parecen producir efectos de tipo ansiolítico, mientras que en dosis altas inducen efectos de tipo ansiogénico. Los mecanismos neurobiológicos subyacentes a estas diferentesrespuestas aún no se han dilucidado completamente. La observación de un fenotipo de tipo ansiogénico tras el bloqueo farmacológico y genético de los receptores cannabinoides CB1 en roedores, junto a la amplia presencia de receptores cannabinoides en regiones cerebrales relacionadas con el control emocional, como la amígdala, el hipocampo y la corteza, son algunosde los datos que apuntan a la participación del sistema cannabinoide endógeno en la regulación de los estados de ansiedad. Se han descrito además respuestas de tipo ansiolítico tras la administración de inhibidores de la degradación de los ligandos cannabinoides endógenos. Conclusiones. En su conjunto, los datos presentados a lo largo de esta revisión indican que el sistemacannabinoide endógeno participa en el control de la homeostasis emocional y sugieren que la manipulación farmacológica de este sistema podría ser una opción para el tratamiento de los trastornos de ansiedad

Introduction and development. Cannabis and derivatives induce complex effects on anxiety in humans andexperimental animals. At low doses, cannabinoid agonists seem to exert anxiolytic actions, while at high doses anxiety and panic estates are often reported. Diverse animal models confirm this particular biphasic profile; however, the underlying neurobiological mechanisms have not been completely elucidated. The anxiogenic-like behavioral phenotype observed following both pharmacological and genetic blockade of cannabinoid CB1 receptors, together with the abundant expression of cannabinoid receptors within brain areas particularly involved in emotional control, such as amygdala, hippocampus and cortex, are among the numerous evidences that account for the participation of the endocannabinoid system in the regulation of anxietystates. Moreover, blockade of endogenous cannabinoid ligands deactivation has been reported to induce anxiolytic-like responses. Conclusions. Taken together, present data reinforce the involvement of the endocannabinoid system in the control of emotional homeostasis and further suggest the pharmacological manipulation of the endocannabinoid system as a potentialtherapeutic tool in the management of anxiety-related disorders