Fatty acid ethanolamides pinpoint nicotinic receptors and modulate neuronal excitability through nuclear receptor PPARα

SPECIFIC AIMS OF THE STUDY 1) To investigate whether FAEs can suppress nicotine-induced stimulation of VTA dopamine (DA) neuron firing rate through the peroxisome-proliferator-activated receptor-α (PPARα) and to elucidate their mechanism of action in an in vitro brain slice preparation. 2) To determine whether there is an interaction between PPARα and nAChRs in VTA DA cells: particularly, to characterize the postsynaptic effects of PPARα modulation on VTA DA neurons, and to examine the contribution of nAChRs in the effects. 3) To study whether PPARα modulation of nAChRs in VTA DA neurons might confer DA cells to access distinct firing patterns and/or to change their firing frequency both in vivo and in vitro. 4) To examine the physiological relevance of PPARα modulation of nAChR stimulation through behavioral analysis

Sex-specific susceptibility to psychotic-like states provoked by prenatal THC exposure: Reversal by pregnenolone

Sociocultural attitudes towards cannabis legalization contribute to the common misconception that it is a relatively safe drug and its use during pregnancy poses no risk to the fetus. However, longitudinal studies demonstrate that maternal cannabis exposure results in adverse outcomes in the offspring, with a heightened risk for developing psychopathology. One of the most reported psychiatric outcomes is the proneness to psychotic-like experiences during childhood. How exposure to cannabis during gestation increases psychosis susceptibility in children and adolescents remains elusive. Preclinical research has indicated that in utero exposure to the major psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), deranges brain developmental trajectories towards vulnerable psychotic-like endophenotypes later in life. Here, we present how prenatal THC exposure (PCE) deregulates mesolimbic dopamine development predisposing the offspring to schizophrenia-relevant phenotypes, exclusively when exposed to environmental challenges, such as stress or THC. Detrimental effects of PCE are sex-specific because female offspring do not display psychotic-like outcomes upon exposure to these challenges. Moreover, we present how pregnenolone, a neurosteroid that showed beneficial properties on the effects elicited by cannabis intoxication, normalizes mesolimbic dopamine function and rescues psychotic-like phenotypes. We, therefore, suggest this neurosteroid as a safe “disease-modifying” aid to prevent the onset of psychoses in vulnerable individuals. Our findings corroborate clinical evidence and highlight the relevance of early diagnostic screening and preventative strategies for young individuals at risk for mental diseases, such as male PCE offspring

Fatty acid ethanolamides pinpoint nicotinic receptors and modulate neuronal excitability through nuclear receptor PPARα

SPECIFIC AIMS OF THE STUDY 1) To investigate whether FAEs can suppress nicotine-induced stimulation of VTA dopamine (DA) neuron firing rate through the peroxisome-proliferator-activated receptor-α (PPARα) and to elucidate their mechanism of action in an in vitro brain slice preparation. 2) To determine whether there is an interaction between PPARα and nAChRs in VTA DA cells: particularly, to characterize the postsynaptic effects of PPARα modulation on VTA DA neurons, and to examine the contribution of nAChRs in the effects. 3) To study whether PPARα modulation of nAChRs in VTA DA neurons might confer DA cells to access distinct firing patterns and/or to change their firing frequency both in vivo and in vitro. 4) To examine the physiological relevance of PPARα modulation of nAChR stimulation through behavioral analysis

Understanding and predicting the longitudinal course of dementia

PURPOSE OF REVIEW: To date, most research in dementia has focused either on the identification of dementia risk prediction or on understanding changes and predictors experienced by individuals before diagnosis. Despite little is known about how individuals change after dementia diagnosis, there is agreement that changes occur over different time scales and are multidomain. In this study, we present an overview of the literature regarding the longitudinal course of dementia. RECENT FINDINGS: Our review suggests the evidence is scarce and findings reported are often inconsistent. We identified large heterogeneity in dementia trajectories, risk factors considered and modelling approaches employed. The heterogeneity of dementia trajectories also varies across outcomes and domains investigated. SUMMARY: It became clear that dementia progresses very differently, both between and within individuals. This implies an average trajectory is not informative to individual persons and this needs to be taken into account when communicating prognosis in clinical care. As persons with dementia change in many more ways during their patient journey, heterogeneous disease progressions are the result of disease and patient characteristics. Prognostic models would benefit from including variables across a number of domains. International coordination of replication and standardization of the research approach is recommended

Endocannabinoid-dependent decrease of GABAergic transmission on dopaminergic neurons is associated with susceptibility to cocaine stimulant effects in pre-adolescent male MAOA hypomorphic mice exposed to early life stress.

Vulnerability to cocaine use disorder depends upon a combination of genetic and environmental risk factors. While early life adversity is a critical environmental vulnerability factor for drug misuse, allelic variants of the monoamine oxidase A (MAOA) gene have been shown to moderate its influence on the risk of drug-related problems. However, data on the interactions between MAOA variants and early life stress (ES) with respect to predisposition to cocaine abuse are limited. Here, we show that a mouse model capturing the interaction of genetic (low-activity alleles of the Maoa gene; MAOANeo) and environmental (i.e., ES) vulnerability factors displays an increased sensitivity to repeated in vivo cocaine psychomotor stimulant actions associated with a reduction of GABAA receptor-mediated inhibition of dopamine neurons of the ventral tegmental area (VTA). Depolarization-induced suppression of inhibition (DSI), a 2-arachidonoylglycerol (2AG)-dependent form of short-term plasticity, also becomes readily expressed by dopamine neurons from male MAOANeo ES mice repeatedly treated with cocaine. The activation of either dopamine D2 or CB1 receptors contributes to cocaine-induced DSI expression, decreased GABA synaptic efficacy, and hyperlocomotion. Next, in vivo pharmacological enhancement of 2AG signaling during repeated cocaine exposure occludes its actions both in vivo and ex vivo. This data extends our knowledge of the multifaceted sequelae imposed by this gene-environment interaction in VTA dopamine neurons of male pre-adolescent mice and contributes to our understanding of neural mechanisms of vulnerability for early onset cocaine use

Sex-specific tonic 2-arachidonoylglycerol signaling at inhibitory inputs onto dopamine neurons of Lister Hooded rats

Addiction as a psychiatric disorder involves interaction of inherited predispositions and environmental factors. Similarly to humans, laboratory animals self-administer addictive drugs, whose appetitive properties result from activation and suppression of brain reward and aversive pathways, respectively. The ventral tegmental area (VTA) where dopamine (DA) cells are located is a key component of brain reward circuitry, whereas the rostromedial tegmental nucleus (RMTg) critically regulates aversive behaviors. Reduced responses to either aversive intrinsic components of addictive drugs or to negative consequences of compulsive drug taking might contribute to vulnerability to addiction. In this regard, female Lister Hooded (LH) rats are more vulnerable than male counterparts to cannabinoid self-administration. We, therefore, took advantage of sex differences displayed by LH rats, and studied VTA DA neuronal properties to unveil functional differences. Electrophysiological properties of DA cells were examined performing either single cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. In vivo, DA cell spontaneous activity was similar, though sex differences were observed in RMTg-induced inhibition of DA neurons. In vitro, DA cells showed similar intrinsic and synaptic properties. However, females displayed larger depolarization-induced suppression of inhibition (DSI) than male LH rats. DSI, an endocannabinoid-mediated form of short term plasticity, was mediated by 2-arachidonoylglycerol (2-AG) activating type 1-cannabinoid (CB1) receptors. We found that sex-dependent differences in DSI magnitude were not ascribed to CB1 number and/or function, but rather to a tonic 2-AG signaling. We suggest that sex specific tonic 2-AG signaling might contribute to regulate responses to aversive intrinsic properties to cannabinoids, thus resulting in faster acquisition/initiation of cannabinoid taking and, eventually, in progression to addiction

Conjugated Linoleic Acid and Brain Metabolism: A Possible Anti-Neuroinflammatory Role Mediated by PPARα Activation

Fatty acids play a crucial role in the brain as specific receptor ligands and as precursors of bioactive metabolites. Conjugated linoleic acid (CLA), a group of positional and geometric isomers of linoleic acid (LA, 18:2 n-6) present in meat and dairy products of ruminants and synthesized endogenously in non-ruminants and humans, has been shown to possess different nutritional properties associated with health benefits. Its ability to bind to peroxisome proliferator-activated receptor (PPAR) α, a nuclear receptor key regulator of fatty acid metabolism and inflammatory responses, partly mediates these beneficial effects. CLA is incorporated and metabolized into brain tissue where induces the biosynthesis of endogenous PPAR α ligands palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), likely through a positive feedback mechanism where PPAR α activation sustains its own cellular effects through ligand biosynthesis. In addition to PPAR α, PEA and OEA may as well bind to other receptors such as TRPV1, further extending CLA own anti-neuroinflammatory actions. Future studies are needed to investigate whether dietary CLA may exert antiinflammatory activity, particularly in the setting of neurodegenerative diseases and neuropsychiatric disorders with a neuroinflammatory basis

Ni-Phosphide catalysts as versatile systems for gas-phase CO2 conversion: Impact of the support and evidences of structure-sensitivity

We report for the first time the support dependent activity and selectivity of Ni-rich nickel phosphide catalysts for CO2 hydrogenation. New catalysts for CO2 hydrogenation are needed to commercialise the reverse water–gas shift reaction (RWGS) which can feed captured carbon as feedstock for traditionally fossil fuel-based processes, as well as to develop flexible power-to-gas schemes that can synthesise chemicals on demand using surplus renewable energy and captured CO2. Here we show that Ni2P/SiO2 is a highly selective catalyst for RWGS, producing over 80% CO in the full temperature range of 350–750 °C. This indicates a high degree of suppression of the methanation reaction by phosphide formation, as Ni catalysts are known for their high methanation activity. This is shown to not simply be a site blocking effect, but to arise from the formation of a new more active site for RWGS. When supported on Al2O3 or CeAl, the dominant phase of as synthesized catalysts is Ni12P5. These Ni12P5 catalysts behave very differently compared to Ni2P/SiO2, and show activity for methanation at low temperatures with a switchover to RWGS at higher temperatures (reaching or approaching thermodynamic equilibrium behaviour). This switchable activity is interesting for applications where flexibility in distributed chemicals production from captured CO2 can be desirable. Both Ni12P5/Al2O3 and Ni12P5/CeAl show excellent stability over 100 h on stream, where they switch between methanation and RWGS reactions at 50–70% conversion. Catalysts are characterized before and after reactions via X-ray Diffraction (XRD), X-ray Photoelectron Spectroscopy (XPS), temperature-programmed reduction and oxidation (TPR, TPO), Transmission Electron Microscopy (TEM), and BET surface area measurement. After reaction, Ni2P/SiO2 shows the emergence of a crystalline Ni12P5 phase while Ni12P5/Al2O3 and Ni12P5/CeAl both show the crystalline Ni3P phase. While stable activity of the latter catalysts is demonstrated via extended testing, this Ni enrichment in all phosphide catalysts shows the dynamic nature of the catalysts during operation. Moreover, it demonstrates that both the support and the phosphide phase play a key role in determining selectivity towards CO or CH4.Financial support for this work was provided by the Department of Chemical and Process Engineering at the University of Surrey and CO2ChemUK through the EPSRC grant EP/P026435/1 as well as the Royal Society Research Grant RSGR1180353. This work was also partially sponsored by Ministry of Science and Innovation through the projects PID2019-108453 GB-C21 and JC2019-040560-I. This work was also partially sponsored by the European Commission through the H2020-MSCA-RISE-2020 BIOALL project (Grant Agreement: 101008058. SASOL is also acknowledged for kindly providing the Al2O3-based supports

Maternal immune activation disrupts dopamine system in the offspring

Background: In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia. Methods: Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology. Results: Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity. Conclusions: These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human patholog

Selective inhibition of phosphodiesterase 7 enzymes reduces motivation for nicotine use through modulation of mesolimbic dopaminergic transmission

Approximately 5 million people die from diseases related to nicotine addiction and tobacco use each year. The nicotine-induced increase of corticomesolimbic dopaminergic (DAergic) transmission and hypodopaminergic conditions occurring during abstinence are important for maintaining drug-use habits. We examined the notion of reequilibrating DAergic transmission by inhibiting phosphodiesterase 7 (PDE7), an intracellular enzyme highly expressed in the corticomesolimbic circuitry and responsible for the degradation of cyclic adenosine monophosphate (cAMP), the main second messenger modulated by DA receptor activation. Using selective PDE7 inhibitors, we demonstrated in male rats that systemic PDE7 enzyme inhibition reduced nicotine self-administration and prevented reinstatement to nicotine seeking evoked by cues or by the pharmacological stressor yohimbine. The effect was also observed by direct application of the PDE7 inhibitors into the nucleus accumbens (NAc) shell but not into the core. Inhibition of PDE7 resulted in increased DA- and cAMP-regulated neuronal phosphoprotein and cAMP response element-binding protein and their phosphorylated forms in the NAc. It also enhanced the DA D1 receptor agonism-mediated effects, indicating potentiation of protein kinase A–dependent transmission downstream of D1 receptor activation. In electrophysiological recordings from DA neurons in the lateral posterior ventral tegmental area, the PDE7 inhibitors attenuated the spontaneous activity of DA neurons. This effect was exerted through the potentiation of D1 receptor signaling and the subsequent facilitation of c-aminobutyric acid transmission. The PDE7 inhibitors did not elicit conditioned place preference and did not induce intravenous self-administration, indicating lack of reinforcing properties. Thus, PDE7 inhibitors have the potential to treat nicotine abuse