A potential role of hippocampus on impulsivity and alcohol consumption through CB1R.

There are a few studies suggesting that the hippocampus is involved in the regulation of impulsivity, and which attempt to explain drug seeking behavior in addiction. In addition, cannabinoid receptor 1 (CB1R) is highly expressed in the hippocampus (HPP). To further understand the potential role of the hippocampal CB1R in impulsive and drug seeking behaviors, we characterized impulsivity in adolescent and adult male rats, by means of a delay discounting task (DDT) by evaluating preference and seeking motivation for alcohol (10 % v/v) consumption, and analyzing CB1R expression in CA1, CA3 and the dentate gyrus (DG) of the HPP as well as in the medial prefrontal cortex (mPFC). Our results show that adolescent rats display more impulsive choices than adult rats in the DDT. The k value is statistically higher in adolescents, further supporting that they are more impulsive. Besides, adolescent rats have higher forced and voluntary alcohol consumption and display a higher alcohol conditioned place preference (CPP) vs. adult rats. In addition, CB1R expression in CA3 and the DG is higher in adolescent vs. adult rats. Our data further support the role of the hippocampus in impulsivity with the potential involvement of the endocannabinoid system, considering that CB1R in CA3 and DG is higher in adolescents, who display impulsivity and alcohol seeking and consumption.

Performance in working memory and attentional control is associated with the rs2180619 SNP in the CNR1 gene.

Individual differences in cognitive performance are partly dependent, on genetic polymporhisms. One of the single-nucleotide polymorphisms (SNP) of the CNR1 gene, which codes for cannabinoid receptor 1 (CB1R), is the rs2180619, located in a regulatory region of this gene (6q14-q15). The alleles of the rs2180619 are A > G; the G allele has been associated with addiction and high levels of anxiety (when the G allele interacts with the SS genotype of the 5-HTTLPR gene). However, GG genotype is observed also in healthy subjects. Considering G allele as risk for 'psychopathological conditions', it is possible that GG healthy subjects do not be addicted or anxious, but would have reduced performance, compared to AA subjects, in attentional control and working memory processing. One hundred and sixty-four healthy young Mexican-Mestizo subjects (100 women and 64, men; mean age: 22.86 years, SD=2.72) participated in this study, solving a task where attentional control and working memory were required. GG subjects, compared to AA subjects showed: (1) a general lower performance in the task (P = 0.02); (2) lower performance only when a high load of information was held in working memory (P = 0.02); and (3) a higher vulnerability to distractors (P = 0.03). Our results suggest that, although the performance of GG subjects was at normal levels, a lower efficiency of the endocannabinoid system, probably due to a lowered expression of CB1R, produced a reduction in the performance of these subjects when attentional control and working memory processing is challenged.

Maternal separation and proclivity for ethanol intake: a potential role of the endocannabinoid system in rats.

Maternal separation (MS) during the first postnatal weeks induces alcohol intake and a reduction in the expression of glucocorticoid receptors (GR). Adults' alcohol consumption may depend on changes in the endocannabinoid system (eCBs). Our goal was to evaluate the status of the eCBs before the exposition to alcohol to support the notion that eCBs' alterations prompt rats to drink alcohol. To reach this goal we subjected rats to MS for the first 2 postnatal weeks. Then, we allowed rats to grow with no further manipulation until they reached adulthood. Thereafter, rats were exposed to an alcohol solution (10% of alcohol in water) as the only source of drinking liquid (forced alcohol ingestion). At the end of this period, tap water was added as an option for drinking liquid (voluntary alcohol ingestion) for another 10 days. Different groups of rats (non-MS, and MS) were sacrificed when adult but with no exposition to alcohol whatsoever, to dissect frontal cortex (FCx), ventral striatum (VS) and hippocampus (HIP) to analyze the following: The expression of cannabinoid receptor 1 (CB1R), CB2R, GR and methylated CpG-binding protein 2 (MeCP2). Levels of GABA and glutamate were quantified in the same brain structures. We found CB1 receptor expression increased in the VS while it was decreased in the FCx in MS subjects. No changes in the CB2R or in the MeCP2 were detected. We found GABA levels increased in FCx and HIP but decreased in VS in MS. Likewise, glutamate levels increased in the FCx but decreased in the HIP in MS subjects. These findings suggest that MS induces changes in the CB1R expression, which might contribute to induce a proclivity to ingest alcohol and, potentially, other drugs.

The anorexigenic peptide cocaine-and-amphetamine-regulated transcript modulates rem-sleep in rats.

It is known that the sleep-waking cycle is modulated by several molecules that may also regulate food intake, among them several neuropeptides. The cocaine-and-amphetamine-regulated transcript has been studied in relation to food ingestion, but it seems to have several other functions that may include sleep regulation. In this context, we studied the effect of the intracerebroventricular administration of the cocaine-and-amphetamine-regulated transcript (0.15, 0.3, 0.6, 0.9nmol) on the sleep-waking cycle (12-h recordings), as well as its effect on food intake in rats. Additionally, we analyzed the neuronal activity as measured by c-Fos expression induced by the cocaine-and-amphetamine-regulated transcript in neurons of nuclei involved in the regulation of sleep and feeding behavior. Our main finding is that 0.3nmol of the cocaine-and-amphetamine-regulated transcript increases rapid-eye-movement sleep. In addition, our results further support that this neuropeptide triggers satiety; c-Fos expression suggested that the cocaine-and-amphetamine-regulated transcript activates specific hypothalamic nuclei without affecting other brain structures known to be involved in sleep regulation. These data further support the notion that a few neuropeptides are involved in the regulation of both the sleep-waking and the hunger-satiety cycles.

[Sleep genes]. / Genes del sueño.

INTRODUCTION: Sleep is a non-learned adaptive strategy that depends on the expression of several neurotransmitters and other molecules. The expression of some of these molecules depends on a number of different genes. Sleep disorders are associated with an inadequate expression of some molecules, which therefore indicates that these genes that code for these molecules participate in the regulation of normal sleep. AIM: To discuss the evidence on gene regulation over the occurrence of sleep and its architecture, as well as of sleep disorders, which supports the participation of specific genes. DEVELOPMENT: We describe the evidence on sleep in mammals, particularly in humans, in addition to studies with twins that demonstrate the influence of genes on sleep regulation. We also discuss several sleep disorders, which in this study only serves to emphasise how certain specific genes, under normal conditions, participate in the expression of sleep. Furthermore, evidence is also provided for other molecules, such as endocannibinoids, involved in sleep regulation. Lastly, we report on studies conducted with different strains of mice that show differences in the amount of sleep they express, possibly as an epiphenomenon of their different genetic loads. CONCLUSIONS: A number of different genes have been described as those responsible for making us sleep, although sleeping also depends on our interaction with the environment. This interaction is what makes us express sleep at times that are best suited to favouring our survival.

Genes del sueño / Sleep Genes

Resumen. Introducción. El sueño es una estrategia adaptativa no aprendida que depende de la expresión de diversos neurotransmisores y otras moléculas. La expresión de varias de estas moléculas depende de diversos genes. Alteraciones del dormir se asocian con una inadecuada expresión de algunas moléculas, que indican entonces que estos genes que codifican estas moléculas participan en la regulación del sueño normal. Objetivo. Discutir la evidencia de la regulación de los genes sobre la ocurrencia del sueño y su arquitectura, así como de alteraciones del sueño, que sustenta la participación de genes específicos. Desarrollo. Se describe la evidencia sobre el sueño en mamíferos, particularmente en humanos, así como estudios con gemelos que evidencian la influencia genética en la regulación del sueño. Posteriormente, se discuten algunas alteraciones del sueño, que en esta revisión sólo sirven para enfatizar cómo ciertos genes específicos, en condiciones normales, participan en la expresión del sueño. Además, se da evidencia sobre otras moléculas, como los endocannabinoides, que participan en la regulación del sueño. Por último, se describen los estudios con diferentes cepas de ratones que manifiestan diferencias en la cantidad de sueño que expresan, posiblemente como epifenómeno de sus diferentes cargas genéticas. Conclusiones. Se han descrito diversos genes que nos hacen dormir, aunque dormir también depende de la interacción con el medio ambiente. Esta interacción es la que nos hace expresar el sueño en los momentos más convenientes para sobrevivir (AU)

Summary. Introduction. Sleep is a non-learned adaptive strategy that depends on the expression of several neurotransmitters and other molecules. The expression of some of these molecules depends on a number of different genes. Sleep disorders are associated with an inadequate expression of some molecules, which therefore indicates that these genes that code for these molecules participate in the regulation of normal sleep. Aim. To discuss the evidence on gene regulation over the occurrence of sleep and its architecture, as well as of sleep disorders, which supports the participation of specific genes. Development. We describe the evidence on sleep in mammals, particularly in humans, in addition to studies with twins that demonstrate the influence of genes on sleep regulation. We also discuss several sleep disorders, which in this study only serves to emphasise how certain specific genes, under normal conditions, participate in the expression of sleep. Furthermore, evidence is also provided for other molecules, such as endocannibinoids, involved in sleep regulation. Lastly, we report on studies conducted with different strains of mice that show differences in the amount of sleep they express, possibly as an epiphenomenon of their different genetic loads. Conclusions. A number of different genes have been described as those responsible for making us sleep, although sleeping also depends on our interaction with the environment. This interaction is what makes us express sleep at times that are best suited to favouring our survival (AU)

[Conjunctival blistering associated with pemphigus vulgaris: report of a case]. / Ampolla conjuntival en el contexto de pénfigo vulgar: a propósito de un caso.

CLINICAL CASE: A patient with a conjunctival blister was diagnosed with pemphigus vulgaris by immunofluorescence tests performed on a conjunctival biopsy. DISCUSSION: Pemphigus vulgaris is an uncommon but serious autoimmune disease that produces blisters of the skin and mucous membranes. Ocular findings are rare, but include conjunctivitis and marginal eyelid erosions. Conjunctival blisters and erosions related to this condition have not been previously reported in the literature. This diagnosis can be made through direct immunofluorescence tests performed on biopsy samples of affected tissue. Unless the condition is properly diagnosed and treated, it has a high mortality.

[Primary localized conjunctival amyloidosis: two case reports]. / Amiloidosis primaria conjuntival: análisis de dos casos.

CASE REPORTS: Two male patients, 21 and 61 years old presenting with hyperemia resistant to topical treatment. Ocular examination showed reddish conjunctival mass, painless, highly vascularized in bulbar conjunctiva. The conjunctival biopsy revealed the presence of amyloid within the conjunctiva itself. CONCLUSIONS: Primary localized conjunctival amyloidosis is a rare disease. Diagnosis consists of biopsy in order to detect amyloid material in the conjunctival tissue together with a systemic evaluation in order to rule out the presence of primary systemic amyloidosis.

Amiloidosis primaria conjuntival: análisis de dos casos / Primary localized conjunctival amyloidosis: two case report

Caso clínico: Se presentan dos pacientes varones de 21 y 61 años de edad con hiperemia resistente al tratamiento tópico. En el examen ocular se observó una masa rosada, no dolorosa y muy vascularizada, en conjuntiva bulbar. La biopsia excisional diagnóstica reveló la presencia de amiloide en la sustancia propia conjuntival.Conclusiones: La amiloidosis conjuntival primaria es una enfermedad rara. El diagnóstico consiste la realización de una biopsia detectando material amiloide en el tejido conjuntival junto con un examen sistémico que descarte la presencia de una amiloidosis primaria sistémica

Case Reports: Two male patients, 21 and 61 years old presenting with hyperemia resistant to topical treatment. Ocular examination showed reddish conjunctival mass, painless, highly vascularized in bulbar conjunctiva. The conjunctival biopsy revealed the presence of amyloid within the conjunctiva itself.Conclusions: Primary localized conjunctival amyloidosis is a rare disease. Diagnosis consists of biopsy in order to detect amyloid material in the conjunctival tissue together with a systemic evaluation in order to rule out the presence of primary systemic amyloidosis

[Sympathetic ophthalmia post-vitrectomy following trauma and perfluorocarbon liquid tamponade]. / Oftalmía simpática postvitrectomía tras traumatismo y taponamiento con perfluorocarbono líquido.

CASE REPORT: We report a case of sympathetic ophthalmia (SO) developed after blunt trauma and vitrectomy (complicated with a massive suprachoroidal hemorrhage) using perfluorocarbon liquid (PFCL) for tamponade. DISCUSSION: The presentation of SO in a vitrectomized patient after severe blunt trauma with extended intra-ocular tamponade with PFCL could support the hypothesis that chronic inflammation caused by PFCL could have contributed to the development of SO. Nevertheless, there are other possible causal factors such as the trauma, the vitrectomy itself or the choroidal detachment with possible uveal incarceration at wound sites.

[Symptomatic ciliary body melanocytoma: melanocytomalytic glaucoma]. / Melanocitoma de cuerpo ciliar sintomático: glaucoma melanocitomalítico.

CASE REPORT: A 33 year-old female with an asymptomatic pigmented mass in the iridocorneal angle of her right eye, arising from the ciliary body is presented. Ciliary body melanocytoma was suspected and conservative management recommended. After 36 months of follow-up the patient developed pain, inflammatory reaction and uncontrollable ocular hypertension, which was diagnosed as melanocytomalytic glaucoma. Tumor was removed by external iridecyclectomy and the histopathologic findings revealed necrotic melanocytoma. DISCUSSION: Ciliary body melanocytoma is a rare benign pigmented tumor that may present extension to the anterior chamber. Differential diagnosis mainly includes ciliary body melanoma, which carries a different prognosis and treatment.

[Experimental study on usefulness of silicone-fluorsilicone copolymer oil (SiFO) in vitreoretinal surgery]. / Estudio experimental sobre la utilidad del aceite de copolímero de silicona-fluorsilicona (SiFO) en la cirugía vitreorretiniana.

PURPOSE: To evaluate the usefulness of silicone-fluorsilicone copolymer oil (SiFO) as an intraoperative tool and a vitreous substitute in vitreoretinal surgery. METHODS: Handling properties of SiFO were tested and compared with those of perfluorooctane (PFO). The transparency of both substances was measured by spectrophotometry and subjectively assessed. Their tendency to dispersion was observed during injection in balanced saline solution (BSS) and after mechanized and manual shaking. Ease of injection and aspiration through small-gauge instruments was evaluated. Ocular tolerance to SiFO and PFO was studied after intravitreal injection in rabbit eyes: intraocular pressure, anterior segment inflammatory response and dispersion were evaluated, and a histopathological study was performed. RESULTS: Injection and aspiration of SiFO were more difficult than those of PFO because of its higher viscosity. PFO dispersed progressively into small droplets as early as two days after intravitreal injection, whereas SiFO remained as a single bubble for 14 days. Histopathologically both substances induced an inflammatory response over the inferior retina, with microvacuolated macrophages and foreign body giant cells, which were larger in eyes wearing SiFO. CONCLUSIONS: SiFO may be useful as an intraoperative tool, although its main drawback is a more difficult injection and aspiration compared to PFO. It has been well tolerated as a short-term vitreous substitute, but further clinical studies are needed.

Potential role of the cannabinoid receptor CB1 in rapid eye movement sleep rebound.

Sleep is an unavoidable activity of the brain. The delay of the time to sleep (sleep deprivation), induces an increase of slow-wave sleep and rapid-eye-movement (REM) sleep (rebound) once the subject is allowed to sleep. This drive to sleep has been hypothesized to be dependent on the accumulation of sleep-inducing molecules and on the high expression of these molecule receptors. In this study we selectively deprived rats of REM sleep for 24 h by using the flowerpot technique. One group deprived of REM sleep was treated with SR141716A, a cannabinoid receptor 1 (CB1) receptor antagonist and then allowed to sleep for the next 4 h. Two other groups were killed, one immediately after the REM sleep deprivation period and the other after 2 h of REM sleep rebound (REM sleep deprivation plus 2 h of rebound). In both groups we determined the expression of the CB1 receptor and its mRNA. Results indicated that SR141716A prevents REM sleep rebound and REM sleep deprivation does not modify the expression of the CB1 protein or mRNA. However, REM sleep deprivation plus 2 h of sleep rebound increased the CB1 receptor protein and, slightly but significantly, decreased mRNA expression. These results suggest that endocannabinoids may be participating in the expression of REM sleep rebound.

Sleep modulates cannabinoid receptor 1 expression in the pons of rats.

Endocannabinoids seem to play a role in the modulation of alertness. Therefore, we measured cannabinoid receptor 1 (CB1R) protein by Western blot and messenger RNA (mRNA) by reverse transcription-polymerase chain reaction in the pons of rats across the 24-h period. We performed evaluations every 4 h beginning at 09:00 h. Rats were under a controlled light/dark cycle 12:12 (lights on at 08:00 h). Our data suggest that the expression of CB1R gene depends on diurnal variations, with maximum expression at 13:00 h for protein and 21:00 h for mRNA, and minimum expression at 01:00 and 09:00 h, respectively. We also analyzed CB1R protein and mRNA levels in the pons of rats deprived of total sleep for 24 h and in rats with a 24-h period of sleep deprivation plus a 2-h period of sleep rebound. Unlike sleep deprivation, sleep rebound significantly increased CB1R protein while decreasing mRNA. Despite the fact that we used gentle manipulation to deprive the animals of sleep, there may be a potential influence of stress on this effect, too. However, these facts suggest that CB1R gene expression is modulated by the light/dark cycle and by sleep.

Oleamide modulates memory in rats.

Oleamide is a recently described lipid, obtained from the cerebrospinal fluid of sleep-deprived cats. It has been observed that oleamide possesses several biological effects, such as sleep induction, and immunological suppression as well as serotonin and gamma-aminobutyric acid receptors activation. In addition, oleamide also binds to the cannabinoid receptors. In this study, we have observed that oleamide facilitates memory extinction in a passive avoidance paradigm, reduces core temperature and pain perception, but does not affect significantly locomotion. These results suggest that oleamide modulates memory processes. However, we do not know if oleamide impairs the retrieval of the memory associated to the "not go" behavior, or facilitates the fast re-learning of the "go" behavior. In addition, since these effects are also induced by marijuana and anandamide, it is very likely that oleamide may be affecting the cerebral cannabinoid system to induce its effects.

Inhibition of the ERK pathway prevents HIVgp120-induced REM sleep increase.

Approximately 35% of HIV-infected subjects, both children and adults, exhibit alterations in the sleep-waking cycle. HIV surface glycoprotein gp120 has been postulated to contribute to this abnormality. For example, it has been reported that HIVgp120 modifies sleep in freely-moving rats and that it also activates the ERK pathway in brain slices. The goal of this work was to determine if sleep changes induced by HIVgp120 in normal rats are mediated by the MAPK pathway. Our results show that a single intraventricular administration of HIVgp120 selectively increases REMS and that such an increase can be prevented by U0126, an inhibitor of ERK activating enzyme, MEK. In contrast, SB202190, a MAPK-p38 inhibitor, had no effect on HIVgp120-induced increase in REMS. These results suggest that HIVgp120 increases REMS in the rat by specifically affecting the ERK signal transduction pathway.

Anandamide-induced sleep is blocked by SR141716A, a CB1 receptor antagonist and by U73122, a phospholipase C inhibitor.

Anandamide (ANA) alters sleep by increasing the amount of time spent in slow wave sleep 2 (SWS2) and rapid eye movement sleep (REMS) at the expense of wakefulness (W) in rats. In this report, we describe a similar effect of ANA when injected itracerebroventricularly (i.c.v.) or into the peduriculopontine tegmental nucleus (PPTg) and the lack of an effect when ANA is administered into the medial preoptic area (MPOA). Furthermore, the i.c.v. or PPTg administration of SR141716A, a CB1 antagonist, or U73122, a PLC inhibitor, 15 min prior to ANA, readily prevents the ANA induced changes in sleep. The present results suggest that a cannabinoid system in the PPTg may be involved in sleep regulation and that the cannabinoid effect is mediated by the CB1 receptor coupled to a PLC second messenger system.

Los endocanabinoides y el sueño / Endocannabinoids and sleep

La modulación del sueño depende de la participación de un dilatado numero de moléculas de diversa índole bioquímica. Dentro de las que más recientemente se han descrito están los lípidos. Estas moléculas que forman alrededor del 50 por ciento del peso del cerebro, y que la fisiología clásica no les ha adjudicado otro valor mas allá del de ser componentes estructurales de las membranas, participan en la transmisión de las señales neurofisiológicas. La importancia de estas moléculas en la neurotrasmisión ha venido a consolidarse con la descripción de una familia de ellas que tiene actividad de canabinoides. Dentro de ellas esta la anandamida, la oleamida y el 2-Araquidonilglicerol. Considerando que uno de los efectos que los canabinoides de origen vegetal producen es somnolencia, ha sido tarea de nuestro grupo describir, por primera vez en la ciencia, la función que los endocanabinoides cumplen en la regulación del sueño. En esta revisión discutimos los antecedentes y los hallazgos más recientes al respecto de este tema: Los endocanabinoides y el sueño (AU)