[Primary hyperoxaluria: case report and therapeutic perspectives].

Primary hyperoxaluria (PH) is a rare genetic disorder with autosomal recessive transmission, characterized by high endogenous production and markedly excessive urinary excretion of oxalate (Ox). It causes the accumulation of calcium oxide crystals in organs and tissues including bones, heart, arteries, skin and kidneys, where it may cause oxalo-calcic nephrolithiasis, nephrocalcinosis and chronic renal failure. Some forms are secondary to enteric diseases, drugs or dietetic substances, while three primitive forms, caused by various enzymatic defects, are currently known: PH1, PH2 and PH3. An early diagnosis, with the aid of biochemical and genetic investigations, helps prevent complications and establish a therapeutic strategy that often includes liver and liver-kidney transplantation, improving the prognosis of these patients. In this work we describe the clinical case of a patient with PH1 undergoing extracorporeal hemodialysis treatment and we report the latest research results that could change the life of patients with PH.

Ketamine administration induces early and persistent neurochemical imbalance and altered NADPH oxidase in mice.

Administration in adulthood of subanaesthetic doses of ketamine, an NMDA receptor (NMDA-R) antagonist, is commonly used to induce psychotic-like alterations in rodents. The NADPH oxidase (NOX) derived-oxidative stress has been shown to be implicated in ketamine-induced neurochemical dysfunctions and in the loss of parvalbumin (PV)-positive interneurons associated to the administration of this NMDA receptor antagonist in adult mice. However, very few data are available on the effects of early ketamine administration and its contribution to the development of long-term dysfunctions leading to psychosis. Here, by administering a subanaesthetic dose of ketamine (30 mg/kg i.p.) to mice at postnatal days (PNDs) 7, 9 and 11, we aimed at investigating early neurochemical and oxidative stress-related alterations induced by this NMDA-R antagonist in specific brain regions of mice pups, i.e. prefrontal cortex (PFC) and nucleus accumbens (NAcc) and to assess whether these alterations lasted until the adult period. To this purpose, we evaluated glutamatergic, glutamine and GABAergic tissue levels, as well as PV amount in the PFC, both two hours after the last ketamine injection (PND 11) and at 10  weeks of age. Dopamine (DA) tissue levels and DA turnover were also evaluated in the NAcc at the same time points. Levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a reliable biomarker of oxidative stress, as well as of the free radical producers NOX1 and NOX2 enzymes, were also assessed in both PFC and NAcc of ketamine-treated pups and adult mice. Ketamine-treated pups showed increased cortical levels of glutamate (GLU) and glutamine, as well as similar GABA amount compared to controls, together with an early reduction of cortical PV levels. In the adult period, the same was observed for GLU and PV, whereas GABA levels were increased and no changes in glutamine amount were detected. Ketamine administration in early life induced a decrease in DA tissue levels and an increase of DA turnover which were also detectable at 10 weeks of age. These alterations were accompanied by 8-OHdG elevations in both PFC and NAcc at the two considered life stages. The expression of NOX1 was significantly reduced in these brain regions following ketamine administration at early life stages, while, in the adult period, significant elevation of this enzyme was observed. Levels of NOX2 were found increased at both time points. Our results suggest that an early increase of NOX2-derived oxidative stress may contribute to the development of neurochemical imbalance in PFC and NAcc, induced by ketamine administration. Modifications of NOX1 expression might represent, instead, an early response of the developing brain to a neurotoxic insult, followed by a later attempt to counterbalance ketamine-related detrimental effects.

The Heme Oxygenase/Biliverdin Reductase System as Effector of the Neuroprotective Outcomes of Herb-Based Nutritional Supplements.

Over the last few years, several preclinical studies have shown that some herbal products, such as ferulic acid, Ginkgo biloba, and resveratrol, exert neuroprotective effects through the modulation of the heme oxygenase/biliverdin reductase system. Unfortunately, sufficient data supporting the shift of knowledge from preclinical studies to humans, particularly in neurodegenerative diseases, are not yet available in the literature. The purpose of this review is to summarize the studies and the main results achieved on the potential therapeutic role of the interaction between the heme oxygenase/biliverdin reductase system with ferulic acid, G. biloba, and resveratrol. Some critical issues have also been reported, mainly concerning the safety profile and the toxicological sequelae associated to the supplementation with the herbs mentioned above, based on both current literature and specific reports issued by the competent Regulatory Authorities.

Curcumin and Heme Oxygenase: Neuroprotection and Beyond.

Curcumin is a natural polyphenol component of Curcuma longa Linn, which is currently considered one of the most effective nutritional antioxidants for counteracting free radical-related diseases. Several experimental data have highlighted the pleiotropic neuroprotective effects of curcumin, due to its activity in multiple antioxidant and anti-inflammatory pathways involved in neurodegeneration. Although its poor systemic bioavailability after oral administration and low plasma concentrations represent restrictive factors for curcumin therapeutic efficacy, innovative delivery formulations have been developed in order to overwhelm these limitations. This review provides a summary of the main findings involving the heme oxygenase/biliverdin reductase system as a valid target in mediating the potential neuroprotective properties of curcumin. Furthermore, pharmacokinetic properties and concerns about curcumin's safety profile have been addressed.

[The unusual couple: a clinical case of coexistence between aHUS and Fabry's disease].

Atypical hemolytic-uremic syndrome (aHUS) is a rare, potentially lethal (1-4) systemic disorder, capable of affecting both adults and children, causing thrombotic microangiopathy (TMA) (5) that leads to the formation of thrombus within small blood vessels with multiple organ failure. The pathogenesis of the aHUS is part of a sort of chronic and uncontrolled activation of the complement system by genetic mutation of some proteins usually responsible for its self-regulation (6,7). Today, the rapid diagnosis of the disease and the timely start of treatment with eculizumab, improve outcomes of renal failure, stroke and heart attack (8-10). Fabry disease is a rare tesaurismosis, X linked, due to the deficiency of the lysosomal enzyme alpha-galactosidase A (11-13), necessary for the physiological catabolism of glycosphingolipids. Multisystem clinical manifestations lead to a serious degenerative pathology. The diagnostic suspicion based on anamnesis and careful research of the symptoms and then confirmed by the enzymatic dosage of alpha galactosidase or by molecular analysis, allows the early treatment of the patient with enzyme replacement therapy, guaranteeing the resolution and/or slowing down the evolution of the disease, especially in the brain, heart and kidneys. In this report, we describe the clinical case of a patient who is a carrier of both rare diseases.

The Visible Burrow System: A behavioral paradigm to assess sociability and social withdrawal in BTBR and C57BL/6J mice strains.

Disrupted sociability and consequent social withdrawal are (early) symptoms of a wide variety of neuropsychiatric diseases, such as schizophrenia, autism spectrum disorders, depressive disorders and Alzheimer's disease. The paucity of objective measures to translationally assess social withdrawal characteristics has been an important limitation to study this behavioral phenotype, both in human and rodents. The aim of the present study was to investigate sociability and social withdrawal in rodents using an ethologically valid behavioral paradigm, the Visible Burrow System (VBS). The VBS mimics a natural environment, with male and female rodents housed together in an enclosure where a large open arena is connected to a continuously dark burrow system that includes 4 nest boxes. In this study, mixed-sex colonies of C57BL/6J and of BTBR mice have been investigated (n = 8 mice per colony). Results showed marked differences between the two strains, in terms of sociability as well as social withdrawal behaviors. In particular, BTBR mice performed less social behaviors and have a preference for non-social behaviors compared to C57BL/6J mice. Neurobiologically, the decreased sociability of BTBR was accompanied by reduced GABA and increased glutamate concentrations in brain prefrontal cortex (PFC) and amygdala regions. In conclusion, our study validated the use of the VBS as an ethologically relevant behavioral paradigm in group-housed mice to investigate individual sociability and social withdrawal features and their underlying neurobiology. This paradigm may provide new insights to develop new therapeutic treatments for behavioral dysfunctions that may be relevant across neuropsychiatric diseases.

Celecoxib Prevents Cognitive Impairment and Neuroinflammation in Soluble Amyloid ß-treated Rats.

Recent findings suggest that soluble forms of amyloid-ß (sAß) peptide contribute to synaptic and cognitive dysfunctions in early stages of Alzheimer's disease (AD). On the other hand, neuroinflammation and cyclooxygenase-2 (COX-2) enzyme have gained increased interest as key factors involved early in AD, although the signaling pathways and pathophysiologic mechanisms underlying a link between sAß-induced neurotoxicity and inflammation are still unclear. Here, we investigated the effects of selective COX-2 enzyme inhibition on neuropathological alterations induced by sAß administration in rats. To this purpose, animals received an intracerebroventricular (icv) injection of predominantly monomeric forms of sAß and, 7 days after, behavioral as well as biochemical parameters and neurotransmitter alterations were evaluated. During this period, rats also received a sub-chronic treatment with celecoxib. Biochemical results demonstrated that icv sAß injection significantly increased both COX-2 and pro-inflammatory cytokines expression in the hippocampus (Hipp) of treated rats. In addition, the number of hypertrophic microglial cells and astrocytes were upregulated in sAß-treated group. Interestingly, rats treated with sAß showed long-term memory deficits, as confirmed by a significant reduction of discrimination index in the novel object recognition test, along with reduced brain-derived neurotrophic factor expression and increased noradrenaline levels in the Hipp. Systemic administration of celecoxib prevented behavioral dysfunctions, as well as biochemical and neurotransmitter alterations. In conclusion, our results suggest that sAß neurotoxicity might be associated to COX-2-mediated inflammatory pathways and that early treatment with selective COX-2 inhibitor might provide potential remedies to counterbalance the sAß-induced effects.

Ferulic Acid Improves Cognitive Skills Through the Activation of the Heme Oxygenase System in the Rat.

Over the last years, many studies reported on the antioxidant effects of ferulic acid (FA) in preclinical models of dementia through the activation of the heme oxygenase/biliverdin reductase (HO/BVR) system. However, only a few studies evaluated whether FA could improve neurological function under milder conditions, such as psychological stress. The aim of this study was to investigate the effects of FA (150 mg/kg intraperitoneal route) on cognitive function in male Wistar rats exposed to emotional arousal. Animals were randomly assigned to two experimental groups, namely not habituated or habituated to the experimental context, and the novel object recognition test was used to evaluate their cognitive performance. The administration of FA significantly increased long-term retention memory in not habituated rats. Ferulic acid increased the expression of HO-1 in the hippocampus and frontal cortex of not habituated rats only, whereas HO-2 resulted differently modulated in these cognitive brain areas. No significant effects on either HO-1 or HO-2 or BVR were observed in the cerebellum of both habituated and not habituated rats. Ferulic acid activated the stress axis in not habituated rats, as shown by the increase in hypothalamic corticotrophin-releasing hormone levels. Pre-treatment with Sn-protoporphyrin-IX [0.25 µmol/kg, intracerebroventricular route (i.c.v.)], a well-known inhibitor of HO activity through which carbon monoxide (CO) and biliverdin (BV) are generated, abolished the FA-induced improvement of cognitive performance only in not habituated rats, suggesting a role for HO-derived by-products. The CO-donor tricarbonyldichlororuthenium (II) (30 nmol/kg i.c.v.) mimicked the FA-related improvement of cognitive skills only in not habituated rats, whereas BV did not have any effect in any group. In conclusion, these results set the stage for subsequent studies on the neuropharmacological action of FA under conditions of psychological stress.

The contribution of transgenic and nontransgenic animal models in Alzheimer's disease drug research and development.

Over the last few years, several papers have become available in the literature on both the main hallmarks of Alzheimer's disease (AD) and the several intracellular pathways whose alteration is responsible for its onset and progression. The use of transgenic and nontransgenic animal models has played a key role in achieving such a remarkable amount of preclinical data, allowing researchers to dissect the cellular changes occurring in the AD brain. In addition, the huge amount of preclinical evidence arising from these animal models was necessary for the further clinical development of pharmacological agents capable of interfering with most of the impaired neural pathways in AD patients. In this respect, a significant role is played by the dysfunction of excitatory and inhibitory neurotransmission responsible for the cognitive and behavioral symptoms described in AD patients. The aim of this review is to summarize the main animal models that contributed toward unraveling the pathological changes in neurotransmitter synthesis, release, and receptor binding in AD preclinical studies. The review also provides an updated description of the current pharmacological agents - still under clinical development - acting on the neurotransmitter systems.

Long-lasting alterations of hippocampal GABAergic neurotransmission in adult rats following perinatal Δ9-THC exposure.

The long-lasting effects of gestational cannabinoids exposure on the adult brain of the offspring are still controversial. It has already been shown that pre- or perinatal cannabinoids exposure induces learning and memory disruption in rat adult offspring, associated with permanent alterations of cortical glutamatergic neurotransmission and cognitive deficits. In the present study, the risk of long-term consequences induced by perinatal exposure to cannabinoids on rat hippocampal GABAergic system of the offspring, has been explored. To this purpose, pregnant rats were treated daily with Delta9-tetrahydrocannabinol (Δ9-THC; 5mg/kg) or its vehicle. Perinatal exposure to Δ9-THC induced a significant reduction (p<0.05) in basal and K+-evoked [3H]-GABA outflow of 90-day-old rat hippocampal slices. These effects were associated with a reduction of hippocampal [3H]-GABA uptake compared to vehicle exposed group. Perinatal exposure to Δ9-THC induced a significant reduction of CB1 receptor binding (Bmax) in the hippocampus of 90-day-old rats. However, a pharmacological challenge with either Δ9-THC (0.1µM) or WIN55,212-2 (2µM), similarly reduced K+-evoked [3H]-GABA outflow in both experimental groups. These reductions were significantly blocked by adding the selective CB1 receptor antagonist SR141716A. These findings suggest that maternal exposure to cannabinoids induces long-term alterations of hippocampal GABAergic system. Interestingly, previous behavioral studies demonstrated that, under the same experimental conditions as in the present study, perinatal cannabinoids exposure induced cognitive impairments in adult rats, thus resembling some effects observed in humans. Although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of hippocampus aminoacidergic transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users, is supported.

Lifelong Nutritional Omega-3 Deficiency Evokes Depressive-Like State Through Soluble Beta Amyloid.

Recent evidence pointed out that the prevalence of depression has reached epidemic proportions in last decades. This increase has been linked to many environmental factors, among these the influence of dietary factors has gained great attention. In particular, it has been reported that low n-3 polyunsaturated fatty acid (n-3 PUFA) intake in diet is correlated to the development of depressive and anxiety-like symptoms. Furthermore, maternal malnutrition is a widely accepted risk factor for developing mental illness in later adulthood; among others, depression has been strongly associated to this event. On the other hand, we have previously found that acute intracerebral injection of the soluble beta amyloid 1-42 (Aß1-42) peptide induces a depressive-like behavior in rats, associated to altered hypothalamic-pituitary-adrenal (HPA) axis activation and reduced cortical serotonin and neurotrophin levels. The aim of the present work was to study the effect of pre- and post-natal (5 weeks post-weaning) exposure to diets differently enriched in n-3, n-6, as well as n-6/n-3 PUFA balanced, on immobility time displayed on the forced swimming test (FST), along with neuroendocrine quantification in offspring rats. Results showed that n-6 PUFA-enriched diet increased depressive- and anxiety-like behaviors, as shown by the elevation in the immobility time in the FST test and self-grooming in the open field test. Those effects were accompanied by reduced cortical serotonin, high plasmatic corticosterone and hypothalamic corticotropin-releasing factor levels. Finally, enhanced plasmatic Aß1-42 levels after n-6 PUFA diet and reduced plasmatic Aß1-42 levels after n-3 PUFA were found. Taken together, our data indicate that Aß1-42 might be crucially involved in behavioral alterations found after n-6 rich PUFA diet and strongly endorse the protective role of n-3 and the detrimental effect of improper n-6 PUFA diet consumption.

Early Loss of Blood-Brain Barrier Integrity Precedes NOX2 Elevation in the Prefrontal Cortex of an Animal Model of Psychosis.

The social isolation rearing of young adult rats is a model of psychosocial stress and provides a nonpharmacological tool to study alterations reminiscent of symptoms seen in psychosis. We have previously demonstrated that social isolation in rats leads to increased oxidative stress and to cerebral NOX2 elevations. Here, we investigated early alterations in mRNA expression leading to increased NOX2 in the brain. Rats were exposed to a short period of social isolation (1 week) and real-time polymerase chain reaction (PCR) for mRNA expression of genes involved in blood-brain barrier (BBB) formation and integrity (ORLs, Vof 21 and Vof 16, Leng8, Vnr1, and Trank 1 genes) was performed. Real-time PCR experiments, immunohistochemistry, and Western blotting analysis showed an increased expression of these genes and related proteins in isolated rats with respect to control animals. The expression of specific markers of BBB integrity, such as matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), occludin 1, and plasmalemmal vesicle associated protein-1 (PV-1), was also significantly altered after 1 week of social isolation. BBB permeability, evaluated by quantification of Evans blue dye extravasation, as well as interstitial fluid, was significantly increased in rats isolated for 1 week with respect to controls. Isolation-induced BBB disruption was also accompanied by a significant increase of Interleukin 6 (IL-6) expression. Conversely, no differences in NOX2 levels were detected at this time point. Our study demonstrates that BBB disruption precedes NOX2 elevations in the brain. These results provide new insights in the interplay of mechanisms linking psychosocial stress to early oxidative stress in the brain, disruption of the BBB, and the development of mental disorders.

Interacting Cannabinoid and Opioid Receptors in the Nucleus Accumbens Core Control Adolescent Social Play.

Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological, and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R) or mu-opioid receptor (MOR) antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC). Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors.

Chronic Psychosocial Stress Impairs Bone Homeostasis: A Study in the Social Isolation Reared Rat.

Chronic psychosocial stress is a key player in the onset and aggravation of mental diseases, including psychosis. Although a strong association between this psychiatric condition and other medical co-morbidities has been recently demonstrated, few data on the link between psychosis and bone homeostasis are actually available. The aim of this study was to investigate whether chronic psychosocial stress induced by 4 or 7 weeks of social isolation in drug-naïve male Wistar rats could alter bone homeostasis in terms of bone thickness, mineral density and content, as well as markers of bone formation and resorption (sclerostin, cathepsin K, and CTX-I). We found that bone mineral density was increased in rats exposed to 7 weeks of social isolation, while no differences were detected in bone mineral content and area. Moreover, 7 weeks of social isolation lead to increase of femur thickness with respect to controls, suggesting the development of a hyperostosis condition. Isolated rats showed no changes in sclerostin levels, a marker of bone formation, compared to grouped animals. Conversely, bone resorption markers were significantly altered after 7 weeks of social isolation in terms of decrease in cathepsin K and increase of CTX-I. No alterations were found after 4 weeks of isolation rearing. Our observations suggest that chronic psychosocial stress might affect bone homeostasis, more likely independently from drug treatment. Thus, the social isolation model might help to identify possible new therapeutic targets to treat the burden of chronic psychosocial stress and to attempt alternative therapy choices.

Soluble beta amyloid evokes alteration in brain norepinephrine levels: role of nitric oxide and interleukin-1.

Strong evidence showed neurotoxic properties of beta amyloid (Aß) and its pivotal role in the Alzheimer's disease (AD) pathogenesis. Beside, experimental data suggest that Aß may have physiological roles considering that such soluble peptide is produced and secreted during normal cellular activity. There is now suggestive evidence that neurodegenerative conditions, like AD, involve nitric oxide (NO) in their pathogenesis. Nitric oxide also possess potent neuromodulatory actions in brain regions, such as prefrontal cortex (PFC), hippocampus (HIPP), and nucleus accumbens (NAC). In the present study, we evaluated the effect of acute Aß injection on norepinephrine (NE) content before and after pharmacological manipulations of nitrergic system in above mentioned areas. Moreover, effects of the peptide on NOS activity were evaluated. Our data showed that 2 h after i.c.v. soluble Aß administration, NE concentrations were significantly increased in the considered areas along with increased iNOS activity. Pre-treatment with NOS inhibitors, 7-Nitroindazole (7-NI), and N6-(1-iminoethyl)-L-lysine-dihydrochloride (L-NIL), reversed Aß-induced changes. Ultimately, pharmacological block of interleukin1 (IL-1) receptors prevented NE increase in all brain regions. Taken together our findings suggest that NO and IL-1 are critically involved in regional noradrenergic alterations induced by soluble Aß injection.

"Natural" relief of pregnancy-related symptoms and neonatal outcomes: above all do no harm.

ETHNOPHARMACOLOGICAL RELEVANCE: In the South of Italy the use of herbal remedies to alleviate pregnancy-related symptoms is very common. OBJECTIVES: To investigate the proportion, prevalence of use, attitude and knowledge base in a sample of Italian pregnant women in the South of Italy. To explore the possible influence and risks of herbal consumption on pregnancy and neonatal outcomes. METHODS: A retrospective observational study was conducted during the study period November 2010-September 2013. Six hundred and thirty expectant mothers were interviewed within three days after childbirth in a public Hospital in the South of Italy. RESULTS: Due to a lack of data, a total of six hundred interviews were considered. Four hundred and eighty six women (81%) reported to have constantly used at least one herbal product throughout the pregnancy period. The study enrolled mostly women between 31 and 40 years of age, with a middle-high level of education, married and employed. The most commonly used herbal products, taken by oral route and for the entire period of pregnancy, were chamomile, fennel, propolis, cranberry, lemon balm, ginger, valerian and mallow. The most relevant source of information for the majority of participants was the doctor (95%), and most of the women (72%) informed their doctors about their use of herbal remedies. CONCLUSIONS: The regular chamomile consumption resulted in a higher risk of pre-term delivery, lower birth weight and lower length of the newborn. Also a regular use of fennel resulted in a shorter gestational age. Finally, ginger intake resulted in a shorter gestational age and in a smaller circumference of the newborn's skull.

Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats.

To date, our understanding of the relative contribution and potential overlapping roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of brain function and behavior is still limited. To address this issue, we investigated the effects of systemic administration of JZL195, that simultaneously increases AEA and 2-AG signaling by inhibiting their hydrolysis, in the regulation of socio-emotional behavior in adolescent and adult rats. JZL195, administered at the dose of 0.01mg/kg, increased social play behavior, that is the most characteristic social activity displayed by adolescent rats, and increased social interaction in adult animals. At both ages, these behavioral effects were antagonized by the CB1 cannabinoid receptor antagonist SR141716A and were associated with increased brain levels of 2-AG, but not AEA. Conversely, at the dose of 1mg/kg, JZL195 decreased general social exploration in adolescent rats without affecting social play behavior, and induced anxiogenic-like effects in the elevated plus-maze test both in adolescent and adult animals. These effects, mediated by activation of CB1 cannabinoid receptors, were paralleled by simultaneous increase in AEA and 2-AG levels in adolescent rats, and by an increase of only 2-AG levels in adult animals. These findings provide the first evidence for a role of 2-AG in social behavior, highlight the different contributions of AEA and 2-AG in the modulation of emotionality at different developmental ages and suggest that pharmacological inhibition of AEA and 2-AG hydrolysis is a useful approach to investigate the role of these endocannabinoids in neurobehavioral processes.

Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training.

Previous studies have provided extensive evidence that administration of cannabinoid drugs after training modulates the consolidation of memory for an aversive experience. The present experiments investigated whether the memory consolidation is regulated by endogenously released cannabinoids. The experiments first examined whether the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are released by aversive training. Inhibitory avoidance training with higher footshock intensity produced increased levels of AEA in the amygdala, hippocampus, and medial prefrontal cortex (mPFC) shortly after training in comparison with levels assessed in rats trained with lower footshock intensity or unshocked controls exposed only to the training apparatus. In contrast, 2-AG levels were not significantly elevated. The additional finding that posttraining infusions of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which selectively increases AEA levels at active synapses, administered into the basolateral complex of the amygdala (BLA), hippocampus, or mPFC enhanced memory strongly suggests that the endogenously released AEA modulates memory consolidation. Moreover, in support of the view that this emotional training-associated increase in endocannabinoid neurotransmission, and its effects on memory enhancement, depends on the integrity of functional interactions between these different brain regions, we found that disruption of BLA activity blocked the training-induced increases in AEA levels as well as the memory enhancement produced by URB597 administered into the hippocampus or mPFC. Thus, the findings provide evidence that emotionally arousing training increases AEA levels within prefrontal-limbic circuits and strongly suggest that this cannabinoid activation regulates emotional arousal effects on memory consolidation.

Memantine prevents memory consolidation failure induced by soluble beta amyloid in rats.

It has been well documented that ß-amyloid (Aß) peptide accumulation and aggregation in the brain plays a crucial role in the pathophysiology of Alzheimer's disease (AD). However, a new orientation of the amyloid cascade hypothesis has evidenced that soluble forms of the peptide (sAß) are involved in Aß-induced cognitive impairment and cause rapid disruption of the synaptic mechanisms underlying memory. The primary aim of this study was to elucidate the effects of sAß, acutely injected intracerebrally (i.c.v., 4 µM), on the short term and long term memory of young adult male rats, by using the novel object recognition task. Glutamatergic receptors have been proposed as mediating the effect of Aß on synaptic plasticity and memory. Thus, we also investigated the effects of sAß on prefrontal cortex (PFC) glutamate release and the specific contribution of N-methyl-D-aspartate (NMDA) receptor modulation to the effects of sAß administration on the cognitive parameters evaluated. We found that a single i.c.v. injection of sAß 2 h before testing did not alter the ability of rats to differentiate between a familiar and a novel object, in a short term memory test, while it was able to negatively affect consolidation/retrieval of long term memory. Moreover, a significant increase of glutamate levels was found in PFC of rats treated with the peptide 2 h earlier. Interestingly, memory deficit induced by sAß was reversed by a NMDA-receptor antagonist, memantine (5 mg/kg i.p), administered immediately after the familiarization trial (T1). On the contrary, memantine administered 30 min before T1 trial, was not able to rescue long term memory impairment. Taken together, our results suggest that an acute i.c.v. injection of sAß peptide interferes with the consolidation/retrieval of long term memory. Moreover, such sAß-induced effect indicates the involvement of glutamatergic system, proposing that NMDA receptor inhibition might prevent or lead to the recovery of early cognitive impairment.

Strain- and context-dependent effects of the anandamide hydrolysis inhibitor URB597 on social behavior in rats.

Genetic and environmental factors play an important role in the cannabinoid modulation of motivation and emotion. Therefore, the aim of the present study was to test whether anandamide modulation of social behavior is strain- and context-dependent. We tested the effects of the anandamide hydrolysis inhibitor URB597 on social behavior and 50-kHz ultrasonic vocalizations (USVs) in adolescent and adult Wistar and Sprague-Dawley rats tested in different emotionally arousing conditions (familiarity/unfamiliarity to the test cage, low/high light). Under all experimental conditions, adolescent and adult Sprague-Dawley rats displayed higher levels of social behavior and emitted more 50-kHz USVs than Wistar rats. URB597 enhanced social play behavior in adolescent Wistar rats under all experimental conditions. However, URB597 only increased social interaction in adult Wistar rats under unfamiliar/high light conditions. URB597 did not affect adolescent social play behavior and adult social interaction in Sprague-Dawley rats under any experimental condition. Moreover, URB597 increased the USVs emitted during social interaction by adolescent Wistar and adult Sprague-Dawley rats tested under familiar/high light and unfamiliar/high light, respectively. These results show that anandamide has distinct roles in adolescent and adult social behaviors. Anandamide modulation of adolescent social play behavior is strain- but not context-dependent. Conversely, anandamide modulation of adult social behavior and USV emission depends upon both strain and experimental context. Furthermore, these results confirm that profound behavioral differences exist between Wistar and Sprague-Dawley rats, which may explain the sometimes contradictory effects of cannabinoid drugs on emotionality in different strains of rodents.