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PurposeThe purpose of this paper is to assess the country-level drivers of managers' and executives' mobility. Both sub-groups play a fundamental role in entrepreneurship, innovation and ultimately on wealth creation in destination countries. The objective is to capture how the impact of economic, cultural and institutional factors differ for these sub-groups’ vis-a-vis the broad highly skilled group's mobility.Design/methodology/approachThe paper investigates the country-level drivers of managers' and executives' bilateral migration from 190 countries to 32 Organisation for Economic Co-operation and Development (OECD) countries. It builds a model on four macro-contextual attractiveness factors of destination countries: economic conditions, cultural affinity, institutions and quality of life. The authors use fixed-effects regressions and carry several model specifications comparing the impact of different attractiveness factors on the migration of lower skilled, highly skilled, managers and executives.FindingsThe authors find that economic incentives do not motivate managers' or executives' mobility. The quality of life is more significant in driving executives' mobility than economic measures are. Cultural affinity, institutions and quality of life are more important for managers. Ethnic relations are significant for the overall highly skilled sample.Practical implicationsThese results have implications for global companies interested in recruiting managers and executives and their recruitment strategies. International businesses attempting to maximize their access to international managers, for instance, can develop recruitment packages that capitalize on the particularities of the quality of life of the potential destination country. Such packages can contribute to streamlining the process and focusing on candidates' needs to increase the likelihood of relocation. The study’s results, in addition, have policy implications in terms of the “branding” of countries whose aim is to attract managers and other highly skilled talent. Officials can build an effective country-branding strategy on the existence of ethnic networks, effective institutions and quality of life to attract a particular segment of the talent pool. For instance, they can develop a strategy to attract executives by focusing on a specific cultural characteristic and elements of the quality of life such as the effectiveness of their country's healthcare and education systems.Social implicationsThe paper also points out to the issues that policymakers must resolve in the absence of an education system that guarantees the talent pool that the economy needs. For those countries that rely on foreign talent (such as Switzerland, Singapore and the USA), it is paramount to promote safety, quality of life and institutional development, in order to guarantee a sufficient inflow of talent.Originality/valueMost global studies focus on the complete migrant stock or on highly skilled workers in particular. The authors disaggregate the sample further to capture the drivers of managers' and executives' migration. The authors find that latter sub-groups respond to different country-level attractiveness factors compared to the broader highly skilled sample. In doing so, the authors contextualize the study of mobility through a positively global lens and incorporate the impact of some of the factors generally overlooked.

Opioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain) are actively sought. Among them, N-palmitoylethanolamide (PEA), an endogenous lipid neuromodulator with anti-inflammatory and neuroprotective properties, was shown to exert anti-hyperalgesic effects and to delay the emergence of morphine tolerance. A selective augmentation in endogenous PEA levels can be achieved by inhibiting N-acylethanolamine acid amidase (NAAA), one of its primary hydrolyzing enzymes. This study aimed to test the hypothesis that NAAA inhibition, with the novel brain permeable NAAA inhibitor AM11095, modulates morphine’s antinociceptive effects and attenuates the development of morphine tolerance in rats. We tested this hypothesis by measuring the pain threshold to noxious mechanical stimuli and, as a neural correlate, we conducted in vivo electrophysiological recordings from pain-sensitive locus coeruleus (LC) noradrenergic neurons in anesthetized rats. AM11095 dose-dependently (3–30 mg/kg) enhanced the antinociceptive effects of morphine and delayed the development of tolerance to chronic morphine in behaving rats. Consistently, AM11095 enhanced morphine-induced attenuation of the response of LC neurons to foot-shocks and prevented the attenuation of morphine effects following chronic treatment. Behavioral and electrophysiological effects of AM11095 on chronic morphine were paralleled by a decrease in glial activation in the spinal cord, an index of opioid-induced neuroinflammation. NAAA inhibition might represent a potential novel therapeutic approach to increase the analgesic effects of opioids and delay the development of tolerance. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01116-4.

Although endeavours to protect mental well-being during the COVID-19 pandemic were taken at national and regional levels, e.g., mental support in school, a COVID-19 emergency toll-free number for psychological support, these were sporadic conjunctural financing interventions. In this Communication, the authors conducted a systematic search for programmatic and policy documents and reports with a solid literature and policy analysis concerning the main objective, which is to analyse the appropriateness in implementing gender- and age-sensitive, integrated, youth-centred mental health services in Italy. The Italian National Action Plan for Mental Health reports a highly fragmented situation in the Child and Adolescent Neuropsychiatry services, in terms of an integrated and comprehensive regional network of services for the diagnosis, treatment, and rehabilitation of neuropsychological disorders in young people. Wide-ranging interventions, systemic actions should be implemented, funded, and included in an overall structural strengthening of the healthcare system, including those dedicated to transition support services. In this context, the National Recovery and Resilience Plan (NRRP), may represent an opportunity to leverage specific funds for mental health in general, and for youth in particular. Finally, mental health service governance should be harmonized at both national and regional EU levels—with the adoption of best practices implemented by other Member States. This includes, among others, health information system and data collection, which is critical for analysing epidemiological trends and for monitoring and evaluating services, to offer a public and integrated system for the care and protection of young people, in line with the Convention on the Rights of the Child.

Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition. We find both a potentiation of neurotransmission and coincident restoration of dendritic spines in the dorsal hippocampus, indicative of reinstatement of dopamine-induced synaptic plasticity in aging rodents. Treatment with (S,S)-CE-158 significantly improved behavioral flexibility in scopolamine-compromised animals and increased the number of spontaneously active prefrontal cortical neurons, both in young and aging rodents. In addition, (S,S)-CE-158 restored learning and memory recall in aging rats comparable to their young performance in a hippocampus-dependent hole board test. In sum, we present a well-tolerated, highly selective DAT inhibitor that normalizes the age-related decline in cognitive function at a synaptic level through increased dopamine signaling.

Background and Purpose Spice/K2 herbal mixtures, containing synthetic cannabinoids such as JWH-018, have been marketed as marijuana surrogates since 2004. JWH-018 has cannabinoid CB1 receptor-dependent reinforcing properties and acutely increases dopaminergic transmission selectively in the NAc shell. Here, we tested the hypothesis that repeated administration of JWH-018 (i) modulates behaviour, (ii) affects dopaminergic transmission and its responsiveness to motivational stimuli, and (iii) is associated with a neuroinflammatory phenotype. Experimental Approach Rats were administered with JWH-018 once a day for 14 consecutive days. We then performed behavioural, electrophysiological, and neurochemical evaluation at multiple time points after drug discontinuation. Key Results Repeated JWH-018 exposure (i) induced anxious and aversive behaviours, transitory attentional deficits, and withdrawal signs; (ii) decreased spontaneous activity and number of dopamine neurons in the VTA; and (iii) reduced stimulation of dopaminergic transmission in the NAc shell while potentiating that in the NAc core, in response to acute JWH-018 challenge. Moreover, (iv) we observed a decreased dopamine sensitivity in the NAc shell and core, but not in the mPFC, to a first chocolate exposure; conversely, after a second exposure, dialysate dopamine fully increased in the NAc shell and core but not in the mPFC. Finally, selected dopamine brain areas showed (v) astrogliosis (mPFC, NAc shell and core, VTA), microgliosis (NAc shell and core), and downregulation of CB1 receptors (mPFC, NAc shell and core). Conclusion and Implications Repeated exposure to JWH-018 may provide a useful model to clarify the detrimental effects of recurring use of Spice/K2 drugs. Drug Policies Department, Presidency of the Council of Ministers, Italy, project: "INSIDE-018"; Drug Policies Department, Presidency of the Council of Ministers, Italy, project: "Effects of NPS: development of a multicentre research for the information enhancement of the Early Warning System"; Drug Policies Department, Presidency of the Council of Ministers, Italy, project: RAS-FSC 2018 [RC_CRP_034, CUP RASSR03071]; Dipartimento Salute Mentale e Dipendenze (DSMD)-zona Sud-ATS Sardegna within the Convenzione sanitaria in materia di studio e ricerca tossicologica con il DiSB (UniCa) in oggetto al "PROGRAMMA REGIONALE PER L'ASSISTENZA SANITARIA DELLE PERSONE TOSSICODIPEN [121] Published version This research has been funded by the Drug Policies Department, Presidency of the Council of Ministers, Italy, projects: "INSIDE-018" (PI: Prof. De Luca, University of Cagliari) and "Effects of NPS: development of a multicentre research for the information enhancement of the Early Warning System" (PI: Prof. Marti, University of Ferrara) to M.A.D.L., and RAS-FSC 2018 (Codice intervento: RC_CRP_034; CUP RASSR03071; project: "Multidisciplinary preclinical study on NPS and evaluation of their behavioral and neurophysiological effects related to age and sex") to M.A.D.L., N.S., and L.F. Prof. De Luca would gratefully like to thank the Dipartimento Salute Mentale e Dipendenze (DSMD)-zona Sud-ATS Sardegna within the Convenzione sanitaria in materia di studio e ricerca tossicologica con il DiSB (UniCa) in oggetto al "PROGRAMMA REGIONALE PER L'ASSISTENZA SANITARIA DELLE PERSONE TOSSICODIPENDENTI NEGLI ISTITUTI PENITENZIARI DELLA SARDEGNA" (Resolution of the Special Commissioner ATS n. 121 of 21-02-2020).

Despite impressive progress, nearly two billion people worldwide have no access to essential medicines. The COVID-19 pandemic revealed Africa’s vulnerability due to its reliance on imports for most vaccines, medicines, and other health product needs. The vaccine manufacturing is complex and requires massive financial investments, with global, regional, and national regulatory structures introducing consistent and urgent reforms to assure the quality and safety of medicines. In 2020, there were approximately 600 pharmaceutical manufacturers in Africa, 80% of which were concentrated in eight countries: Egypt, Algeria, Morocco, Tunisia, Nigeria, Ghana, Kenya, and South Africa. Only 4 countries had more than 50 manufacturers, while 22 countries had no local production. Out of the 600, around 25% were multinational companies. Africa is equally affected by modest scaled capacities substantially engaging in packaging and labelling, and occasionally fill and finish steps, facing criticalities in terms of solvent domestic markets. This article discusses the challenges in the development of a local pharmaceutical manufacturing in Africa and reflects on the importance of the momentum for strengthening the local medical production capacity in the continent as a critical opportunity for advancing universal health coverage (UHC).

We evaluated whether maternal intake of conjugated linoleic acid (CLA) and docosahexaenoic acid (DHA) in the phospholipid (PL) form (CLA-DHA PL) affects maternal and fetal brain and liver fatty acids (FAs) profile and the biosynthesis of FA-derived bioactive lipid mediators

OBJECTIVES: Among the macronutrients provided by the mothers to fetuses free fatty acids (FFA), particularly palmitic acid and glycerol cross the placental barrier in smaller proportions respect to glucose and amino acids, due to a minor placental permeability. It has already been suggested that during advanced gestation, fetal FA are mainly derived from de novo lipogenesis (DNL) in the fetal liver. Therefore, the aim of this study was to evaluate DNL metabolic biomarkers in fetuses of rat dams at gestational day (GD) 16, which represent the beginning of the third stage of gestation. Peculiarly, besides the usual lipid biomarkers of DNL, increase of PA and POA and the ratio PA/LA, we also evaluated whether C16:0 ceramide biosynthesis was enhanced by DNL thereby representing a novel biomarker of DNL. METHODS: The profile of FA and ceramides was measured by using LC-DAD and MS/MS in line in liver of rat dams sacrificed at GD16 and their fetuses. Differences between rat dams and their fetuses were determined by an Mann-Whitney unpaired test. RESULTS: Our results show that lipid metabolism in the liver of fetuses, when compared to those of their mother, was characterized by profound differences in the fatty acid profile, i.e., increased levels of the palmitic acid (16:0) (1.24 fold; p = 0.04) and its desaturase product palmitoleic acid (16:1-n7) (2.5 fold; p = 0.002) indicating an overactive DNL. Peculiarly, we found striking higher levels (30 fold; p = 0.02) in fetal liver respect to rat dams liver of C16:0 ceramide, while the other ceramides species didn't increase significantly. CONCLUSIONS: Our data suggest that the 16:0 to form fetal C16:0 ceramide derives from DNL. C16:0 ceramide in adults is usually associated to impaired insulin signalling and energy homeostasis, and eventually to insulin resistance and type 2 diabetes. On the other hand, it has also been shown that C16:0 ceramide sustains lipogenesis, which may be functional to the increased fetal growth rate characteristic of the last gestational stage. FUNDING SOURCES: This study was supported by grant from the Ministry of University and Research (MUR) - Proof of Concept 2018.

Environmental tobacco smoke (ETS) exposure during brain development has been associated with several disorders, such as depression, anxiety, sudden infant death syndrome, and the predisposition to addiction. The endocannabinoid system plays an essential role in neuronal development. We investigated the effects of early postnatal ETS exposure on the endocannabinoid system in different brain regions. C57BL/6 J mice were exposed to ETS that was generated from 3R4F cigarettes from postnatal day 3 (P3) to P14. Receptors and enzymes of the endocannabinoid system were assessed in infancy, adolescence, and adulthood by Western blot. In the brainstem, ETS exposure decreased cannabinoid 1 (CB1) receptor, CB2 receptor, N-arachidonoyl phosphatidyl ethanol-specific phospholipase D (NAPE-PLD), and fatty acid amino hydrolase (FAAH) levels and increased in diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) levels during infancy and decreased CB2 and FAAH levels during adulthood. In the striatum, ETS decreased in the NAPE-PLD and MAGL levels and increased FAAH levels during infancy, increased FAAH levels during adolescence, and decreased NAPE-PLD levels during adulthood. The present findings indicate that exposure to ETS during a critical period of brain development can disturb the endocannabinoid system in the brainstem and striatum, regions that are involved in the pathogenesis of sudden infant death syndrome and the susceptibility to addiction.

Tobacco smoke is the leading preventable cause of death in the world and treatments aimed to increase success rate in smoking cessation by reducing nicotine dependence are sought. Activation of peroxisome proliferator-activated receptor-alpha (PPARα) by synthetic or endogenous agonists was shown to suppress nicotine-induced activation of mesolimbic dopamine system, one of the major neurobiological substrates of nicotine dependence, and nicotine-seeking behavior in rats and monkeys. An alternative indirect way to activate PPARα is inhibition of N-acylethanolamine acid amidase (NAAA), one of the major hydrolyzing enzyme for its endogenous agonists palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). We synthetized a novel specific brain permeable NAAA inhibitor, AM11095. We administered AM11095 to rats and carried out brain lipid analysis, a functional observational battery (FOB) to assess toxicity, in vivo electrophysiological recording from dopamine cells in the ventral tegmental area, brain microdialysis in the nucleus accumbens shell and behavioral experiments to assess its effect on nicotine -induced conditioned place preference (CPP). AM11095 (5 and 25 mg/kg, i.p.) was devoid of neurotoxic and behavioral effects and did not affect motor behavior and coordination. This NAAA inhibitor (5 mg/kg i.p.) increased OEA and PEA levels in the hippocampus and cortex, prevented nicotine-induced activation of mesolimbic dopamine neurons in the ventral tegmental area, nicotine-induced elevation of dopamine levels in the nucleus accumbens shell and decreased the expression of nicotine CPP. Our results indicate that NAAA inhibitors represent a new class of pharmacological tools to modulate brain PEA/PPARα signalling and show potential in the treatment of nicotine dependence.

Since the early stage of the current pandemic, digital contact tracing (DCT) through mobile phone apps, called “Immuni”, has been introduced to complement manual contact tracing in Italy. Until 31 December 2021, Immuni identified 44,880 COVID-19 cases, which corresponds to less than 1% of total COVID-19 cases reported in Italy in the same period (5,886,411). Overall, Immuni generated 143,956 notifications. Although the initial download of the Immuni app represented an early interest in the new tool, Immuni has had little adoption across the Italian population, and the recent increase in its download is likely to be related to the mandatory Green Pass certification for conducting most daily activities that can be obtained via the application. Therefore, Immuni failed as a support tool for the contact tracing system. Other European experiences seem to show similar limitations in the use of DTC, leaving open questions about its effectiveness, although in theory, contact tracing could allow useful means of “proximity tracking”.

Summary Aims Prenatal maternal immune activation (MIA) is associated with a risk to develop schizophrenia and affects dopamine systems in the ventral tegmental area (VTA), key region in the neurobiology of psychoses. Considering the well‐described sex differences in schizophrenia, we investigated whether sex affects MIA impact on dopamine system and on schizophrenia‐related behavioral phenotype. Furthermore, considering peroxisome proliferator‐activated receptor‐α (PPARα) expression in the CNS as well as its anti‐inflammatory and neuroprotective properties, we tested if PPARα activation by prenatal treatment with a clinically available fibrate (fenofibrate) may mitigate MIA‐related effects. Methods We induced MIA in rat dams with polyriboinosinic‐polyribocytidylic acid (Poly I:C) and assessed prepulse inhibition and dopamine neuron activity in the VTA by means of electrophysiological recordings in male and female preweaned and adult offspring. Results Poly I:C‐treated males displayed prepulse inhibition deficits, reduced number and firing rate of VTA dopamine neurons, and paired‐pulse facilitation of inhibitory and excitatory synapses. Prenatal fenofibrate administration attenuated detrimental effects induced by MIA on both the schizophrenia‐like behavioral phenotype and dopamine transmission in male offspring. Conclusion Our study confirms previous evidence that females are less susceptible to MIA and highlights PPARα as a potential target for treatments in schizophrenia.

In this paper, we report on the first project on the promotion of urban geoheritage in Cagliari, the capital of the Autonomous Region of Sardinia (Italy). We briefly address the history of geo-palaeontological research in the city area and outline the main phases of development in the history of Cagliari’s geo-palaeontological museum. Geotourism is an efficient method of bringing geosciences to a wider audience. For this project, we compiled a geoitinerary of the main lithotypes and fossils present within the urban territory. Miocene lithotypes are the most important materials in the edification of the Cagliari’s old town, and in the past, the quarrying activity favoured the geology knowledge of the area. The presence of abandoned quarries and natural outcrops in parks, public gardens, on the nearby coastline, and also of fossils exposed in ashlars of historic buildings, made Cagliari an excellent example to valorise the geo-palaeontological heritage using geotourism. This project showcases the importance of knowledge transfer and non-technical communication methods by converting highly technical aspects into accessible and engaging information dissemination to a wide range of audience types, including non-specialised ones.

The family of lipid neuromodulators has been rapidly growing, as the use of different -omics techniques led to the discovery of a large number of naturally occurring N-acylethanolamines (NAEs) and N-acyl amino acids belonging to the complex lipid signaling system termed endocannabinoidome. These molecules exert a variety of biological activities in the central nervous system, as they modulate physiological processes in neurons and glial cells and are involved in the pathophysiology of neurological and psychiatric disorders. Their effects on dopamine cells have attracted attention, as dysfunctions of dopamine systems characterize a range of psychiatric disorders, i.e., schizophrenia and substance use disorders (SUD). While canonical endocannabinoids are known to regulate excitatory and inhibitory synaptic inputs impinging on dopamine cells and modulate several dopamine-mediated behaviors, such as reward and addiction, the effects of other lipid neuromodulators are far less clear. Here, we review the emerging role of endocannabinoid-like neuromodulators in dopamine signaling, with a focus on non-cannabinoid N-acylethanolamines and their receptors. Mounting evidence suggests that these neuromodulators contribute to modulate synaptic transmission in dopamine regions and might represent a target for novel medications in alcohol and nicotine use disorder.

Study region The Lakes Basin is located in the Main Ethiopian Rift. It covers the northern part of the rift valley basin, the Upper Awash River basin, and some sub-basins from the Omo River basin. Due to the presence of high fluoride (F−) content, natural contamination of groundwater has long been recognized as a water-related health issue in the area. Study focus A multidisciplinary research effort, including geological, hydrogeological, hydro-chemical, and geophysical investigations, was adopted to understand the 3D hydrogeological conceptual model and to evaluate F− enrichment in groundwater. New hydrological insights for the region The 3D hydrogeological conceptual model shows a complex hydrogeological environment and a clear hydraulic interconnection between different aquifers. The geological setting has deeply influenced the geometry of the aquifers, recharge and discharge areas, and F− enrichment in groundwater. Two hydrogeological units, namely sedimentary and volcanic multi-aquifers, were identified. The analyses of groundwater circulation, flow paths, and distribution of F- concentrations in each aquifer were conducted. In groundwater, the concentration of fluoride varies from 0.1 to 68.9 mg L−1; in surface water, it ranges from 0.6 to 244.2 mg L−1. Fluoride concentration of 62 % of the water samples analyzed exceeded the 1.5 mg L−1 WHO threshold for fluoride concentration in drinking water. The proposed methodological approach has been demonstrated to be a powerful tool that could be applied in other similar areas.

The Chattian-Aquitanian carbonate system of Isili sub-basin (SE Sardinia, Italy) were studied to better understand the hydrodynamic processes controlling the formation of landward-downlapping, rhodolith-rich, giant clinoforms. The studied flat-topped platform was attached to an island (semi-isolated) and migrated onshore (landward) over a shallow marine, protected embayment. The depositional profile is characterized by four, sea to land, zones: seaward slope, flat-topped platform (submerged flat), landward slope and mixed siliciclastic-carbonate embayment. In particular, these zones record different levels, from high to moderate, of hydrodynamic energy and persistency. The paleodepth of the studied succession, based on T/D test on Amphistegina specimens, red-algal genera and geometric reconstruction of the overall system, ranges from − 10 to − 30 m for the platform up to around − 40 m for the landward slope base. Thus, the flat-topped platform was permanently submerged and an extensive carbonate (sea grass, algal and bryozoan-algal) factory along with oyster framestones developed. The widespread presence in the barren zones of rhodolith-to-shell rich small to very small compound dunes (high-energy zone) suggests that the flat-topped platform was periodically swept by unidirectional, landward-directed currents. These currents allow the formation of large-scale, rhodolith-rich clinobeds along the landward slope (washover fan-like system). The presence of rodolith pavements developed along the flat-topped platform at or slightly below the fairweather wave base suggests that clinobeds were formed in a nearshore, shallow subtidal setting. Finally, the shallow marine, protected embayment (moderate-energy zone) represents the widening distal reaches of the currents flowing or along the clinoforms or from the coast basinward (river floods and/or ebb tidal currents). Despite few tidal-related sedimentary structures such as bi-directional ripples and small compound dunes separated by finer-grained “drapes” or reactivation surfaces were observed, the prevailing processes acting over the platform are unidirectional, landward-directed currents possibly associated with longshore currents and/or wave actions. However, the resultant migration of the whole system onshore (landward) cannot be easily explained with storm or wind-related processes. Thus the studied flat-topped platform seems to be controlled by long term tidal regulation within a meso to macro tidal regime. In particular, such meso/macro tidal environments experience multiannual to multidecennial phases of stronger/weaker tidal range fluctuations resembling periods of relatively sea highs and lows with respect to the mean sea level (0 m). All the (wind, storm, wave and tidal) currents sweeping the flat-topped platform were maxima during phases of strong tidal fluctuations generating erosion and sediment transportation over the flat and accumulation on the landward slope (clinobeds). Conversely, during phases of weaker tidal range fluctuations overall currents were minima, clinoforms did not develop and factories widespread re-colonized the submerged flat. Therefore, the studied platform developed in a current-dominated and tidal modulated setting. Finally, the studied carbonates of Sardinia suggest that the Sardinian seaway and the incipient Provencal basin during the Chattian-Aquitanian were, locally, capable to generate meso to macro tidal conditions.

The Sardinian Graben System was a part of a NE-SW-oriented extensional basin, rotated counter-clockwise into a N-S-elongate basin, as consequence of the eastward migration of the Apennine orogenic front, in the western Mediterranean during the Neogene. Starting from the early Miocene, the Sardinian Graben was inundated by marine waters, turning progressively into a seaway, characterized by a tidal circulation as consequence of the connection between the Atlantic Ocean to the west and the Paratethys Ocean to the east. In this work, we investigate an area located marginally to the mid-seaway, whose well-exposed volcaniclastic deposits record the local expression of a tidal amplification occurring in a coastal peripheral embayment of the wider Sardinian Seaway. The studied succession is ca. 140 m thick and includes three main units: (i) the 20-m-thick lowermost unit consists of fluvio-lacustrine sandstones and conglomerates belonging to lower delta-plain and delta-platform environments; (ii) the second unit is 60–70 m thick and includes heterolithic sandstones and mudstones, exhibiting a variety of tidal sedimentary structures, and lies on the previous deposits through a tidal ravinement surface; these two units are mostly volcaniclastic in composition, reflecting the dominance of a magmatic source over other extrabasinal components; (iii) the uppermost unit is ca. 50 m thick, erosionally overlies the previous deposits and is made up of shoreface sandstones and open-shelf mudstones, whose composition indicates even less volcaniclastic elements and the prevalence of other clastic alongshore-derived components. Based on the results of the facies analysis, the study succession is interpreted as the infill of an incised valley along the southern flank of a structural high. The valley was excavated during a phase of relative sea-level lowstand (Aquitanian?) preceding a subsequent stage of major transgression (Burdigalian). Initially, a fluvial system impinged the valley from the west favoring the progradation of a deltaic system in a shallow-marine embayment. During an early stage of transgression, the isolation of a part of this coastal area generated by the building of a barrier island, produced the onset of a tidal-flat sedimentation over the previous deposits. A late transgression occurred through the inundation of this coastal area by marine waters and the consequent back-stepping of beach-barrier and open-shelf strata. The sedimentological features of this stratigraphic succession indicate as this valley was filled in a tectonic setting with a high rate of accommodation, where the tidal influence progressively increased during sediment accumulation, possibly due to the marginal position respect to a wider tide-dominated marine conduit. The present paper thus: (i) documents for the first time a tidal signature in the lower Miocene strata of Sardinia; (ii) indicates new possible relationships with other, coeval seaway successions of the western and northern Mediterranean area; (iii) suggests constrains for palaeogeographic reconstructions; (iv) and throws the basis for future researches on the Sardinian Seaway.

The combination of prenatal, such as maternal infections, and postnatal environmental insults (e.g., adolescent drug abuse) increases risks for psychosis, as predicted by the two-hit hypothesis of schizophrenia. Cannabis abuse during adolescence is widespread and is associated with increased risk of psychoses later in life. Here, we hypothesized that adolescent Δ9-tetrahydrocannabinol (THC) worsens the impact of prenatal maternal immune activation (MIA) on ventral tegmental area (VTA) dopamine cells in rat offspring. Additionally, since substance abuse disorder is particularly prevalent among schizophrenia patients, we also tested how VTA dopamine neurons in MIA offspring respond to acute nicotine and cocaine administration. We used a model of neurodevelopmental disruption based on prenatal administration of the polyriboinosinic-polyribocytidilic acid [poly (I:C)] in rats, which activates the maternal immune system by mimicking a viral infection and induces behavioral abnormalities and disruption of dopamine transmission relevant to psychiatric disorders in the offspring. Male offspring were administered THC (or vehicle) during adolescence (PND 45–55). Once adult (PND 70–90), we recorded the spontaneous activity of dopamine neurons in the VTA and their responses to nicotine and cocaine. MIA male offspring displayed reduced number, firing rate and altered activity pattern of VTA dopamine cells. Adolescent THC attenuated several MIA-induced effects. Both prenatal [poly (I:C)] and postnatal (THC) treatments affected the response to nicotine but not to cocaine. Contrary to our expectations, adolescent THC did not worsen MIA-induced deficits. Results indicate that the impact of cannabinoids in psychosis models is complex.

Animal studies of effort-based choice behavior are being used to model effort-related motivational dysfunctions in humans. With these procedures, animals are offered a choice between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/ low reward options. Several previous studies have shown that dopamine (DA) uptake inhibitors, including GBR12909, lisdexamfetamine, methylphenidate, and PRX-14040, can reverse the effort-related effects of the vesicular monoamine transport blocker tetrabenazine, which inhibits DA storage. Because many drugs that block DA transport act as major stimulants that also release DA, and produce a number of undesirable side effects, there is a need to develop and characterize novel atypical DA transport inhibitors. (S)-CE-123 ((S)-5-((benzhydrylsulfnyl) methyl)thiazole) is a recently developed analog of modafnil with the biochemical characteristics of an atypical DA transport blocker. The present paper describes the enantioselective synthesis and initial chemical characterization of (S)-CE-123, as well as behavioral experiments involving effort-based choice and microdialysis studies of extracellular DA. Rats were assessed using the fxed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior, decreasing lever pressing and increasing chow intake. (S)-CE-123 was coadministered at doses ranging from 6.0 to 24.0 mg/kg, and the highest dose partially but signifcantly reversed the effects of tetrabenazine, although this dose had no effect on fxed ratio responding when administered alone. Additional experiments showed that (S)-CE-123 signifcantly increased lever pressing on a progressive ratio/chow feeding choice task and that the effective dose (24.0 mg/kg) increased extracellular DA in nucleus accumbens core. In summary, (S)-CE-123 has the behavioral and neurochemical profle of a compound that can block DA transport, reverse the effort-related effects of tetrabenazine, and increase selection of high-effort progressive ratio responding. This suggests that (S)-CE- 123 or a similar compound could be useful as a treatment for effort-related motivational dysfunction in humans.

Appropriate behavioural strategies to cope with unexpected salient stimuli require synergistic neuronal responses in diverse brain regions. Among them, the epithalamic lateral habenula (LHb) plays a pivotal role in processing salient stimuli of aversive valence. Integrated in the complex motivational circuit, LHb neurons are indeed excited by aversive stimuli, including footshock (Fs). However, whether such excitation is a common feature represented throughout the LHb remains unclear. Here, we combined single-unit extracellular recordings in anaesthetized mice with juxtacellular labelling to describe the nature, location and pharmacological properties of Fs-driven responses within the LHb. We find that, along with Fs-excited cells, about 10% of LHb neurons display Fs-mediated inhibitory responses. Such inhibited neuronal population, in contrast to Fs-excited neurons, display regular and high frequency activity at baseline and is clustered in the medial portion of the LHb. Juxtacellular labelling of Fs-excited and inhibited neurons unravels that both populations are of glutamatergic type, as they co-localized with the EAAC1 glutamatergic transporter but not with the GAD67 GABAergic marker. Moreover, while the excitatory responses to Fs require both AMPA and NMDA receptors, the inhibitory responses rely instead on GABAA channels. Taken together, our results indicate that two functionally and partly segregated LHb neuronal ensembles encode Fs in an opposite fashion. This highlights the neuronal complexity in the LHb for processing aversive external stimuli.

Animal studies of effort-based choice behavior are being used to model effort-related motivational dysfunctions in humans. With these procedures, animals are offered a choice between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/low reward options. Several previous studies have shown that dopamine (DA) uptake inhibitors, including GBR12909, lisdexamfetamine, methylphenidate, and PRX-14040, can reverse the effort-related effects of the vesicular monoamine transport blocker tetrabenazine, which inhibits DA storage. Because many drugs that block DA transport act as major stimulants that also release DA, and produce a number of undesirable side effects, there is a need to develop and characterize novel atypical DA transport inhibitors. (S)-CE-123 ((S)-5-((benzhydrylsulfinyl) methyl)thiazole) is a recently developed analog of modafinil with the biochemical characteristics of an atypical DA transport blocker. The present paper describes the enantioselective synthesis and initial chemical characterization of (S)-CE-123, as well as behavioral experiments involving effort-based choice and microdialysis studies of extracellular DA. Rats were assessed using the fixed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior, decreasing lever pressing and increasing chow intake. (S)-CE-123 was coadministered at doses ranging from 6.0 to 24.0 mg/kg, and the highest dose partially but significantly reversed the effects of tetrabenazine, although this dose had no effect on fixed ratio responding when administered alone. Additional experiments showed that (S)-CE-123 significantly increased lever pressing on a progressive ratio/chow feeding choice task and that the effective dose (24.0 mg/kg) increased extracellular DA in nucleus accumbens core. In summary, (S)-CE-123 has the behavioral and neurochemical profile of a compound that can block DA transport, reverse the effort-related effects of tetrabenazine, and increase selection of high-effort progressive ratio responding. This suggests that (S)-CE-123 or a similar compound could be useful as a treatment for effort-related motivational dysfunction in humans.

The reinforcing effects of Δ(9)-tetrahydrocannabinol (THC) in rats and monkeys, and the reinforcement-related dopamine-releasing effects of THC in rats, can be attenuated by increasing endogenous levels of kynurenic acid (KYNA) through systemic administration of the kynurenine 3-monooxygenase inhibitor, Ro 61–8048. KYNA is a negative allosteric modulator of α7 nicotinic acetylcholine receptors (α7nAChRs) and is synthesized and released by astroglia, which express functional α7nAChRs and cannabinoid CB1 receptors (CB1Rs). Here, we tested whether these presumed KYNA autoreceptors α7nAChRs) and CB1Rs regulate glutamate release. We used in vivo microdialysis and electrophysiology in rats, RNAscope in situ hybridization in brain slices, and primary culture of rat cortical astrocytes. Acute systemic administration of THC increased extracellular levels of glutamate in the nucleus accumbens shell (NAcS), ventral tegmental area (VTA) and medial prefrontal cortex (mPFC). THC also reduced extracellular levels of KYNA in the NAcS. These THC effects were prevented by administration of Ro 61–8048 or the CB1R antagonist, rimonabant. THC increased the firing activity of glutamatergic pyramidal neurons projecting from the mPFC to the NAc or to the VTA in vivo. These effects were averted by pretreatment with Ro 61–8048. In vitro, THC elicited glutamate release from cortical astrocytes (on which we demonstrated co-localization of the CB1Rs and α7nAChRs mRNAs), and this effect was prevented by KYNA and rimonabant. These results suggest a key role of astrocytes in interactions between the endocannabinoid system, kynurenine pathway and glutamatergic neurotransmission, with ramifications for the pathophysiology and treatment of psychiatric and neurodegenerative diseases.