Oregano and thyme essential oils are used for therapeutic, aromatic and gastronomic purposes due to their richness in active substances, like carvacrol; however, the effects of the latter on the central nervous system have been poorly investigated. The aim of our study was to define the effects of carvacrol on brain neurochemistry and behavioural outcome in rats. Biogenic amine content in the prefrontal cortex and hippocampus after chronic or acute oral carvacrol administration was measured. Animals were assessed by a forced swimming test. Carvacrol, administered for seven consecutive days (12.5 mg/kg p.o.), was able to increase dopamine and serotonin levels in the prefrontal cortex and hippocampus. When single doses were used (150 and 450 mg/kg p.o.), dopamine content was increased in the prefrontal cortex at both dose levels. On the contrary, a significant dopamine reduction in hippocampus of animals treated with 450 mg/kg of carvacrol was found. Acute carvacrol administration only significantly reduced serotonin content in either the prefrontal cortex or in the hippocampus at the highest dose. Moreover, acute carvacrol was ineffective in producing changes in the forced swimming test. Our data suggest that carvacrol is a brain-active molecule that clearly influences neuronal activity through modulation of neurotransmitters. If regularly ingested in low concentrations, it might determine feelings of well-being and could possibly have positive reinforcer effects.

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.

Several studies have attempted to clarify molecular pathways leading to drug addiction. Increased reactive oxygen species production in the central nervous system has been recently proposed to play a pivotal role in the neuropathology induced by drug abuse. In this review, we summarize current knowledge on the involvement of oxidative stress in the development of neural dysfunctions induced by prolonged exposure to specific drugs of abuse: N-methyl-D-aspartate receptor antagonists (ketamine, phencyclidine and dizocilpine maleate), cocaine, heroin, marijuana, gammahydroxybutyrate, amphetamine and methamphetamine. Understanding the role of increased oxidative damage in the central nervous system following abuse of these compounds may provide original molecular perspectives leading to innovative therapeutic strategies.

The importance of the endocannabinoid system (ECS) in the modulation functions of the central nervous system has been extensively investigated during the last few years. In particular, accumulated evidence has implicated ECS in the pathophysiology of Alzheimer s disease (AD), that is a progressive, degenerative, and irreversible disorder characterized by the accumulation in the brain of beta-amyloid fragments forming insoluble plaques, and of intracellular neurofibrillary tangles (NTFs) associated with synaptic and neuronal loss. In all the processes involved in the formation of both plaques and NFTs, the key-role played by the ECS has been documented. Here, we review current knowledge and future directions of ECS modulation both in animal models of AD and in human tissues, underlying the role of endocannabinoid signaling in the development of AD hallmarks. Overall, the available data suggest that next generation therapeutics might target distinct ECS elements, for instance CB2 receptor or fatty acid amide hydrolase, as a promising approach to halt or at least to slow down disease progression.

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.

In recent years, a great deal of research has been devoted to identify new natural sources of phytosterols and to improve methods for their recovery and purification. In this regard, unexplored natural sources of bioactive ingredients are gaining much attention since they can lead to the isolation of new compounds or bioactivities. The field of available natural sources has been further increased by including algae and, even more interestingly, microalgae. In the present study, a multidisciplinary approach has been used considering, in an integrated view, extraction, chemical composition and bioactivity of phytosterols from the microalga Dunaliella tertiolecta. A novel methodology to extract, separate and characterize microalgal-derived phytosterols has been developed. In addition, recoverable and reusable eluents have been selected in order to reduce the quantities of employed organic solvents. Finally, we addressed the question whether orally administered phytosterols reach the brain and if those interfere with the major neurotransmitter systems, such as the dopaminergic, serotoninergic and noradrenergic ones, in several brain areas of rats. Flash Liquid Chromatography has been used to separate the Total Sterol (TS) fraction, composed of twelve sterols, with a purity of 97.87% and a recovery percentage of 98%, while the "flash version" of Silver Ion Liquid Chromatography has been used to purify the most abundant phytosterols in TS, (22E,24R)- methylcholesta-5,7,22-trien-3β-ol (ergosterol) and (22E,24R)-ethylcholesta-5,7,22-trien-3β-ol (7-dehydroporiferasterol), with a purity of 97.4%. These two combined methods did not need sophisticated technologies but only cheap laboratory supplies. Moreover, the possibility of recovering and recycling the solvents used as eluents made it a cleaner process. Finally, for the first time, a neuromodulatory action of Dunaliella tertiolecta-derived phytosterols has been found in selective brain areas of rats.

Oxidative stress is thought to be involved in the development of behavioral and histopathological alterations in animal models of psychosis. Here we investigate the causal contribution of reactive oxygen species generation by the phagocyte NADPH oxidase NOX2 to neuropathological alterations in a rat model of chronic psychosocial stress. In rats exposed to social isolation, the earliest neuropathological alterations were signs of oxidative stress and appearance of NOX2. Alterations in behavior, increase in glutamate levels and loss of parvalbumin were detectable after 4 weeks of social isolation. The expression of the NOX2 subunit p47 phox was markedly increased in pyramidal neurons of isolated rats, but below detection threshold in GABAergic neurons, astrocytes and microglia. Rats with a loss of function mutation in the NOX2 subunit p47 phox were protected from behavioral and neuropathological alterations induced by social isolation. To test reversibility, we applied the antioxidant/NOX inhibitor apocynin after initiation of social isolation for a time period of 3 weeks. Apocynin reversed behavioral alterations fully when applied after 4 weeks of social isolation, but only partially after 7 weeks. Our results demonstrate that social isolation induces rapid elevations of the NOX2 complex in the brain. Expression of the enzyme complex was strongest in pyramidal neurons and a loss of function mutation prevented neuropathology induced by social isolation. Finally, at least at early stages, pharmacological targeting of NOX2 activity might reverse behavioral alterations. © 2012 Macmillan Publishers Limited All rights reserved.

There is growing evidence that inflammation plays a major role in the pathogenesis of neural damage caused by deposition of amyloid β (Aβ) in the brain. Nimodipine has received attention as a drug that might improve learning and reduce cognitive deficits in Alzheimer's disease, but the mechanism of action is poorly known. In this study, we tested the hypothesis that nimodipine inhibited Aβ-stimulated IL-1β release from microglia.

Objective: Isolation rearing of rats provides a non-pharmacological method of inducing behavioural changes in rodents that resemble schizophrenia or depression. Nevertheless, results are variable within different strains. We focused on neurochemical changes in several in vivo and post-mortem brain regions of Wistar (W) and Lister Hooded (LH) rats following post-weaning social separation. Methods: Experiments were conducted after 68 weeks of isolation. For post-mortem studies, prefrontal cortex (PFC), nucleus accumbens (NAC), hippocampus (Hipp) and striatum (St) were collected by tissue dissection. In vivo experiments were conducted by microdialysis in the PFC. Analyses of dopamine (DA), serotonin (5-HT) levels and relative turnover were performed by using high-performance liquid chromatography. Results: We found significant strain-related differences in biogenic amine content. LH rats were characterised by markedly raised DA, along with its turnover reduction, in all the post-mortem brain regions examined as well as in microdialysis samples, while in W rats 5-HT tissue concentration was lower in PFC and St and higher in NAC and Hipp. Cortical extracellular 5-HT concentrations were increased in group housed and decreased in isolated W animals. Moreover, isolation increased DA concentrations in the PFC of LH rats, and decreased 5-HT in W rats in NAC and Hipp. Lately, 5-HT turnover was also affected by both strain and isolation conditions. Conclusions: This study suggests that W and LH rats have markedly different neurochemical profiles in response to isolation, resulting in altered monoamine levels that vary according to brain area and rat strain. These findings highlight the importance of selecting an appropriate rat strain when considering isolation rearing to model symptoms of schizophrenia and/or depression.

Significance. Severe life stress (SLS), as opposed to trivial every day stress, is defined as a serious psychosocial event with the potential to cause an impacting psychological traumatism. Recent Advances. Numerous studies have attempted to understand how the central nervous system (CNS) responds to SLS. This response includes a variety of morphological and neurochemical modifications; among them oxidative stress is almost invariably observed. Oxidative stress is defined as disequilibrium between oxidant generation and the antioxidant response. Critical Issues. In this review, we discuss how SLS leads to oxidative stress in the CNS, and how the latter impacts pathophysiological outcomes. We also critically discuss experimental methods to measure oxidative stress in the CNS. The review covers animal models and human observations. Animal models of SLS include sleep deprivation, maternal separation and social isolation in rodents, and the establishment of hierarchy in non-human primates. In humans, SLS, caused by traumatic events such as child abuse, war and divorce, is also accompanied by oxidative stress in the CNS. Future Directions. Outcome of SLS in humans ranges from resilience, over post-traumatic stress disorder, to development of chronic mental disorders. Defining sources of oxidative stress in SLS might on the long run provide new therapeutic avenues.

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. © 2014 Elsevier B.V. and ECNP.

Chronic Levodopa (L-DOPA), the gold standard therapy for Parkinson's disease (PD), causes disabling motor complications (dyskinesias) that are associated with changes in the activity of striatal protein kinase A (PKA) and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). In this study, we showed that systemic administration of the cannabinoid agonist WIN55212-2 ameliorated L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-OHDA rat model of PD and reversed L-DOPA-induced PKA hyperactivity via a CB(1)-mediated mechanism. This effect was accompanied by increased phosphorylation of DARPP-32 at threonine 34, which was partially blocked by CB(1) antagonism. Striatal PKA activity was positively correlated with the severity of L-DOPA-induced axial and limb dyskinesias, suggesting a role for the cAMP/PKA signaling pathway in the expression of these motor disturbances. Our results indicate that activation of CB(1) receptors, as well as reduction of striatal PKA hyperactivity, might be an effective strategy for the treatment of L-DOPA-induced dyskinesias.

Amyloid-β oligomers (AβO) are species mainly involved in the synaptic and cognitive dysfunction in Alzheimer's disease. Although their action has been described mainly at neuronal level, it is now clear that glial cells govern synaptic activity in their resting state, contributing to new learning and memory establishment. In contrast, when activated, they may lead to synaptic and cognitive dysfunction. Using a reliable acute AβO-mediated mouse model of AD, we explored whether the memory alteration AβOs induce relies on the activation of glial cells, and if Toll-like receptor 4 (TLR4), pivotal in the initiation of an immune response, is involved.