The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5–5 mg/kg, i.p.) on both emotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimental settings, named High Arousal (HA) and Low Arousal (LA) conditions. The two different experimental conditions influenced emotional reactivity independently of drug administration. Indeed, vehicle-treated rats exposed to the LA condition spent more time in the center of the arena than vehicle-treated rats exposed to the HA context. Conversely, the different arousal conditions did not affect the cognitive performances of vehicle-treated animals such as the capability to discriminate a spatial displacement of the objects or an object substitution. AM404 administration did not alter locomotor activity or emotional behavior of animals exposed to both environmental conditions. Interestingly, AM404 administration influenced the cognitive parameters depending on the level of emotional arousal: it impaired the capability of rats exposed to the HA condition to recognize a novel object while it did not induce any impairing effect in rats exposed to the LA condition. These findings suggest that drugs enhancing endocannabinoid signaling induce different effects on recognition memory performance depending on the level of emotional arousal induced by the environmental conditions

Detrimental effects of the 'bath salt' methylenedioxypyrovalerone on social play behavior in male rats

Methylenedioxypyrovalerone (MDPV) is the most popular synthetic cathinone found in products marketed as 'bath salts', widely abused among teenagers and young adults. Synthetic cathinones have pharmacological effects resembling those of psychostimulants, which are known to disrupt a variety of social behaviors. However, despite the popular use of MDPV by young people in social contexts, information about its effects on social behavior is scarce. To investigate the impact of MDPV on social behavior at young age, and the underlying neurobehavioral mechanisms, we focused on social play behavior. Social play behavior is the most characteristic social behavior displayed by young mammals and it is crucial for neurobehavioral development. Treatment with MDPV reduced social play behavior in both juvenile and young adult male rats, and its play-suppressant effect was subject to tolerance but not sensitization. As the behavioral effects of MDPV have been ascribed to dopaminergic and noradrenergic neurotransmission, and given the role of these neurotransmitters in social play, we investigated the involvement of dopamine and noradrenaline in the play-suppressant effects of MDPV. The effects of MDPV on social play were blocked by either the α2 adrenoceptor antagonist RX821002 or the dopamine receptor antagonist flupenthixol, given alone or together at sub-effective doses. In sum, MDPV selectively suppresses the most vigorous social behavior of developing rats through both noradrenergic and dopaminergic mechanisms. This study provides important preclinical evidence of the deleterious effects of MDPV on social behavior, and as such increases our understanding of the neurobehavioral effects of this popular cathinone

Blended Cements Elaborated with Kaolinitic Calcined Clays

In the clinker production process, the main component of Portland cement (PC), large amount of CO2 are emitted into the atmosphere. The use of calcined kaolinitic clays as supplementary material of cement is an alternative to mitigate the environmental impact. In this paper, the influence of the replacement of PC by two calcined kaolinitic clays (15 and 30%), with high content of metakaolinite and different reactivity was studied. Calcined kaolinitic clays were characterized, the pozzolanic activity using Frattini test, the compressive strength, rate of water absorption (sorptivity), the assemblage of hydration products and the pore size distribution were determined at 28 days. The results show that the replacement of high percentage (30%) of very reactive clays improves the mechanical behavior and durable parameters compared with those obtained for plain PC.Centro de Tecnología de Recursos Minerales y Cerámic

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

Strong evidence showed neurotoxic properties of beta amyloid (Aβ) and its pivotal role in the Alzheimer's disease (AD) pathogenesis. Beside, experimental data suggest that Aβ 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 Aβ 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 Aβ 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 Aβ-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 Aβ injection

β-Adrenoreceptor Stimulation Mediates Reconsolidation of Social Reward-Related Memories

In recent years, the notion that consolidated memories become transiently unstable after retrieval and require reconsolidation to persist for later use has received strong experimental support. To date, the majority of studies on reconsolidation have focused on memories of negative emotions, while the dynamics of positive memories have been less well studied. Social play, the most characteristic social behavior displayed by young mammals, is important for social and cognitive development. It has strong rewarding properties, illustrated by the fact that it can induce conditioned place preference (CPP). In order to understand the dynamics of positive social memories, we evaluated the effect of propranolol, a β-adrenoreceptor antagonist known to influence a variety of memory processes, on acquisition, consolidation, retrieval and reconsolidation of social play-induced CPP in adolescent rats.Systemic treatment with propranolol, immediately before or after a CPP test (i.e. retrieval session), attenuated CPP 24 h later. Following extinction, CPP could be reinstated in saline--but not in propranolol-treated rats, indicating that propranolol treatment had persistently disrupted the CPP memory trace. Propranolol did not affect social play-induced CPP in the absence of memory retrieval or when administered 1 h or 6 h after retrieval. Furthermore, propranolol did not affect acquisition, consolidation or retrieval of social play-induced CPP.We conclude that β-adrenergic neurotransmission selectively mediates the reconsolidation, but not other processes involved in the storage and stability of social reward-related memories in adolescent rats. These data support the notion that consolidation and reconsolidation of social reward-related memories in adolescent rats rely on distinct neural mechanisms

Developmental consequences of perinatal cannabis exposure: behavioral and neuroendocrine effects in adult rodents

Cannabis is the most commonly used illicit drug among pregnant women. Since the endocannabinoid system plays a crucial role in brain development, maternal exposure to cannabis derivatives might result in long-lasting neurobehavioral abnormalities in the exposed offspring. It is difficult to detect these effects, and their underlying neurobiological mechanisms, in clinical cohorts, because of their intrinsic methodological and interpretative issues. The present paper reviews relevant rodent studies examining the long-term behavioral consequences of exposure to cannabinoid compounds during pregnancy and/or lactation. Maternal exposure to even low doses of cannabinoid compounds results in atypical locomotor activity, cognitive impairments, altered emotional behavior, and enhanced sensitivity to drugs of abuse in the adult rodent offspring. Some of the observed behavioral abnormalities might be related to alterations in stress hormone levels induced by maternal cannabis exposure. There is increasing evidence from animal studies showing that cannabinoid drugs are neuroteratogens which induce enduring neurobehavioral abnormalities in the exposed offspring. Several preclinical findings reviewed in this paper are in line with clinical studies reporting hyperactivity, cognitive impairments and altered emotionality in humans exposed in utero to cannabis. Conversely, genetic, environmental and social factors could also influence the neurobiological effects of early cannabis exposure in humans

Statement on safety of cannabidiol as a novel food: data gaps and uncertainties

The European Commission has determined that cannabidiol (CBD) can be considered as a novel food (NF), and currently, 19 applications are under assessment at EFSA. While assessing these, it has become clear that there are knowledge gaps that need to be addressed before a conclusion on the safety of CBD can be reached. Consequently, EFSA has issued this statement, summarising the state of knowledge on the safety of CBD consumption and highlighting areas where more data are needed. Literature searches for both animal and human studies have been conducted to identify safety concerns. Many human studies have been carried out with Epidyolex(R), a CBD drug authorised to treat refractory epilepsies. In the context of medical conditions, adverse effects are tolerated if the benefit outweighs the adverse effect. This is, however, not acceptable when considering CBD as a NF. Furthermore, most of the human data referred to in the CBD applications investigated the efficacy of Epidyolex (or CBD) at therapeutic doses. No NOAEL could be identified from these studies. Given the complexity and importance of CBD receptors and pathways, interactions need to be taken into account when considering CBD as a NF. The effects on drug metabolism need to be clarified. Toxicokinetics in different matrices, the half-life and accumulation need to be examined. The effect of CBD on liver, gastrointestinal tract, endocrine system, nervous system and on psychological function needs to be clarified. Studies in animals show significant reproductive toxicity, and the extent to which this occurs in humans generally and in women of child-bearing age specifically needs to be assessed. Considering the significant uncertainties and data gaps, the Panel concludes that the safety of CBD as a NF cannot currently be established

The endocannabinoid system: a key modulator of emotions and cognition

[No abstract available

Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy

In recent years, Cannabis use/misuse for treating pregnancy-related symptoms and other chronic conditions has increased among pregnant women, favored by decriminalization and/or legalization of its recreational uses in addition to its easy accessibility. However, there is evidence that prenatal Cannabis exposure might have adverse consequences on pregnancy progression and a deleterious impact on proper neurodevelopmental trajectories in the offspring. Maternal Cannabis use could interfere with the complex and finely controlled role performed by the endocannabinoid system in reproductive physiology, impairing multiple gestational processes from blastocyst implantation to parturition, with long-lasting intergenerational effects. In this review, we discuss current clinical and preclinical evidence regarding the role of endocannabinoids in development, function, and immunity of the maternal-fetal interface, focusing on the impact of Cannabis constituents on each of these gestational processes. We also discuss the intrinsic limitations of the available studies and the future perspectives in this challenging research field

The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder (PTSD)

Post-traumatic stress disorder (PTSD) is a psychiatric disorder of significant prevalence and morbidity, whose pathogenesis relies on paradoxical changes of emotional memory processing. An ideal treatment would be a drug able to block the pathological over-consolidation and continuous retrieval of the traumatic event, while enhancing its extinction and reducing the anxiety symptoms. While the latter benefit from antidepressant medications, no drug is available to control the cognitive symptomatology. Endocannabinoids regulate affective states and participate in memory consolidation, retrieval, and extinction. Clinical findings showing a relationship between Cannabis use and PTSD, as well as changes in endocannabinoid activity in PTSD patients, further suggest the existence of a link between endocannabinoids and maladaptive brain changes after trauma exposure. Along these lines, we suggest that endocannabinoid degradation inhibitors may be an ideal therapeutic approach to simultaneously treat the emotional and cognitive features of PTSD, avoiding the unwanted psychotropic effects of compounds directly binding cannabinoid receptors