Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.

Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-α in the brain and provide a potential new target for the treatment of nicotine addictio

Effect of acute administration of dietary Pistacia lentiscus L. essential oil on the ischemia-reperfusion-induced changes in rat frontal cortex and plasma

In this study Pistacia lentiscus L. essential oil (E.O.), a mixture of terpenes and sesquiterpenes, was tested for its protective effects in cerebral ischemia/reperfusion-induced injury in Wistar rat frontal cortex and plasma. Cerebral ischemia was produced by a 20 min bilateral common carotid artery occlusion followed by 30 min reperfusion. Pistacia lentiscus L. essential oil (E.O.) (200 mg/0, 45 ml of sunflower oil as vehicle) was administered via gavage 6 hours prior to ischemia. Rats were randomly assigned to four groups, ischemic/reperfused (I/R) and sham-operated rats treated with the vehicle or with E.O.. Different brain areas were analysed for fatty acid changes and expression of the enzyme cyclooxygenase-2 (COX-2). Ischemia/reperfusion triggered in frontal cortex a decrease of docosahexaenoic acid (DHA), the membrane highly polyunsaturated fatty acid (HPUFA) most susceptible to oxidation. Pre-treatment with E.O. prevented this change and led further to decreased levels of COX-2, as assessed by Western Blot. In plasma of ischemic/reperfused rats, E.O. administration increased both the DHA-to-eicosapentaenoic acid (EPA) ratio and levels of the endocannabinoid congeners palmytoylethanolamide (PEA) and oleoylethanolamide (OEA). The results obtained suggest that ischemia/reperfusion triggers a cerebral insult sufficient to cause a a region specific lipid peroxidation as evidenced by the detectable, significant decrease in the tissue level of DHA, the most abundant essential fatty acid of neuronal membrane phospholipids. Acute dietary pre-treatment with E.O. triggers modifications both in the frontal cortex, where COX-2 expression decreases and the decrease of DHA is apparently prevented, and in plasma, where PEA and OEA levels increase. We suggest that the activity of PEA and OEA, as endogenous ligands of the peroxisome proliferator-activated receptor (PPAR)-alpha, by inducing the peroxisomal beta oxidation, may explain the observed increase in the DHA/EPA ratio. The latter, in fact, might account for an increased metabolism of n-3 aimed at restoring DHA within damaged brain tissue. The possibility that changes in fatty acid metabolism and plasmatic availability of PEA and OEA are correlated events represents an issue worth future investigations

Downscaling Climate Change Impacts, Socio-Economic Implications and Alternative Adaptation Pathways for Islands and Outermost Regions

This book provides a comprehensive overview of the future scenarios of climate change and management concerns associated with climate change impacts on the blue economy of European islands and outermost regions. The publication collects major findings of the SOCLIMPACT project’s research outcomes, aiming to raise social awareness among policy-makers and industry about climate change consequences at local level, and provide knowledge-based information to support policy design, from local to national level. This comprehensive book will also assist students, scholars and practitioners to understand, conceptualize and effectively and responsibly manage climate change information and applied research. This book provides invaluable material for Blue Growth Management, theory and application, at all levels. This first edition includes up-to-date data, statistics, references, case material and figures of the 12 islands case studies. ¨Downscaling climate change impacts, socio-economic implications and alternative adaptation pathways for Islands and Outermost Regions¨ is a must-read book, given the accessible style and breadth and depth with which the topic is dealt. The book is an up-to-date synthesis of key knowledge on this area, written by a multidisciplinary group of experts on climate and economic modelling, and policy design

Electrophysiological properties of dopamine neurons in the ventral tegmental area of Sardinian alcohol-preferring rats

Rationale: Sardinian alcohol-preferring (sP) or -nonpreferring (sNP) rats are one of the few pairs of lines of rats selectively bred for their voluntary alcohol preference or aversion, respectively. Ventral tegmental area (VTA) dopamine (DA) neurons have long been implicated in many drug-related behaviors, including alcohol self-administration. However, the electrophysiological properties of these cells in sP and sNP rats remain unknown. Objectives: This study was designed to examine the properties of posterior VTA DA neurons and to unveil functional differences between sP and sNP rats. Materials and methods: The electrophysiological properties of DA cells were examined performing either single-cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. Results: Extracellular single-unit recordings revealed an increased spontaneous activity in sP rats. However, a corresponding difference was not found in vitro. Moreover, DA cells of sP and sNP rats showed similar intrinsic properties, suggesting changes at synaptic level. Therefore, inhibitory- and excitatory-mediated currents were studied. A decreased probability of GABA release was found in sP rats. Additionally, sP rats showed a reduced depolarization-induced suppression of inhibition, which is an endocannabinoid-mediated form of short-term plasticity. Additionally, the effect of cannabinoid-type 1 (CB1) receptor agonist WIN55,212-2 on GABAA IPSCs was smaller in sP rats, suggesting either a reduced number or functionality of CB1 receptors in the VTA. Conclusions: Our findings suggest that both decreased GABA release and endocannabinoid transmission in the VTA play a role in the increased impulse activity of DA cells and, ultimately, in alcohol preference displayed by sP rats

Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons

Background Recent studies have raised concerns about subtle long-lasting neurobiological changes that might be triggered by exposure to Cannabis derivatives, especially in a critical phase of brain maturation, such as puberty. The mesolimbic dopamine (DA) system, involved in the processing of drug-induced reward, is a locus of action of cannabinoids and endocannabinoids. Thus, we compared the effects of repeated cannabinoid administration in adolescent and adult rats on DA neuronal functions and responses to drugs of abuse. Methods Single-unit extracellular recordings from antidromically identified mesoaccumbens DA neurons and from their target cells in the nucleus accumbens were carried out in urethane-anesthetized rats. Animals were pretreated during adolescence or adulthood, for 3 days, with the cannabinoid agonist WIN55212.2 (WIN) or vehicle and allowed a 2-week interval. Results In cannabinoid-administered rats, DA neurons were significantly less responsive to the stimulating action of WIN, regardless of the age of pretreatment; however, in the adolescent group, but not in the adult, long-lasting cross-tolerance developed to morphine, cocaine, and amphetamine. Conclusions Our study suggests that an enduring form of neuronal adaptation occurs in DA neurons after subchronic cannabinoid intake at a young age, affecting subsequent responses to drugs of abuse

Gamma-hydroxybutyric acid (GHB) and the mesoaccumbens reward circuit: Evidence for GABAB receptor-mediated effects

γ-Hydroxybutyric acid (GHB) is a short-chain fatty acid naturally occurring in the mammalian brain, which recently emerged as a major recreational drug of abuse. GHB has multiple neuronal mechanisms including activation of both the GABAB receptor, and a distinct GHB-specific receptor. This complex GHB-GABAB receptor interaction is probably responsible for the multifaceted pharmacological, behavioral and toxicological profile of GHB. Drugs of abuse exert remarkably similar effects upon reward-related circuits, in particular the mesolimbic dopaminergic system and the nucleus accumbens (NAc). We used single unit recordings in vivo from urethane-anesthetized rats to characterize the effects of GHB on evoked firing in NAc "shell" neurons and on spontaneous activity of antidromically identified dopamine (DA) cells located in the ventral tegmental area. GHB was studied in comparison with the GABAB receptor agonist baclofen and antagonist (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911). Additionally, we utilized a GHB analog, γ-(p-methoxybenzil)-γ-hydroxybutyric acid (NCS-435), devoid of GABAB binding properties, but with high affinity for specific GHB binding sites. In common with other drugs of abuse, GHB depressed firing in NAc neurons evoked by the stimulation of the basolateral amygdala. On DA neurons, GHB exerted heterogeneous effects, which were correlated to the baseline firing rate of the cells but led to a moderate stimulation of the DA system. All GHB actions were mediated by GABAB receptors, since they were blocked by SCH50911 and were not mimicked by NCS-435. Our study indicates that the electrophysiological profile of GHB is close to typical drugs of abuse: both inhibition of NAc neurons and moderate to strong stimulation of DA transmission are distinctive features of diverse classes of abused drugs. Moreover, it is concluded that addictive and rewarding properties of GHB do not necessarily involve a putative high affinity GHB receptor