Tobacco use in first-episode psychosis, a multinational EU-GEI study.

BACKGROUND: Tobacco is a highly prevalent substance of abuse in patients with psychosis. Previous studies have reported an association between tobacco use and schizophrenia. The aim of this study was to analyze the relationship between tobacco use and first-episode psychosis (FEP), age at onset of psychosis, and specific diagnosis of psychosis. METHODS: The sample consisted of 1105 FEP patients and 1355 controls from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We assessed substance use with the Tobacco and Alcohol Questionnaire and performed a series of regression analyses using case-control status, age of onset of psychosis, and diagnosis as outcomes and tobacco use and frequency of tobacco use as predictors. Analyses were adjusted for sociodemographic characteristics, alcohol, and cannabis use. RESULTS: After controlling for cannabis use, FEP patients were 2.6 times more likely to use tobacco [p ⩽ 0.001; adjusted odds ratio (AOR) 2.6; 95% confidence interval (CI) [2.1-3.2]] and 1.7 times more likely to smoke 20 or more cigarettes a day (p = 0.003; AOR 1.7; 95% CI [1.2-2.4]) than controls. Tobacco use was associated with an earlier age at psychosis onset (ß = -2.3; p ⩽ 0.001; 95% CI [-3.7 to -0.9]) and was 1.3 times more frequent in FEP patients with a diagnosis of schizophrenia than in other diagnoses of psychosis (AOR 1.3; 95% CI [1.0-1.8]); however, these results were no longer significant after controlling for cannabis use. CONCLUSIONS: Tobacco and heavy-tobacco use are associated with increased odds of FEP. These findings further support the relevance of tobacco prevention in young populations.

Low incidence of psychosis in Italy: confirmation from the first epidemiological study in Sicily.

PURPOSE: The incidence of psychotic disorders varies in different geographical areas. As there have been no reports from Southern Italy, this study aimed to determine the incidence rate of first-episode psychosis in Palermo, Sicily. METHODS: All patients, aged 18-65 years, presenting with a first episode of psychosis (FEP) (ICD-10 F20-29, F30-33) to mental health services in Palermo, were recorded over a 3-year period. Incidence rates of psychotic disorders and their 95% confidence intervals (95% CI) were estimated. Poisson regression was applied to estimate the differences in incidence rate ratio (IRR) by age, sex and migrant status. RESULTS: Two hundred and four FEP participants were identified during the 3 years; 183 (89.7%, males n = 112) participants were native Italians and 21 were migrants (10.3%, males n = 14). The crude incidence of all psychoses was 15.9 (95% CI 13.7-18.1). As predicted, the risk of schizophrenia F20 was higher in males compared to females (adjusted IRR = 1.99, 95% CI 1.36-2.88) and in migrants compared to native Italians (adjusted IRR = 4.02, 95% CI 2.39-6.75). CONCLUSIONS: This study, the first from Sicily, confirms previous findings from Northern Italy that the risk of schizophrenia and other psychoses is much lower in Italian cities than those reported from cities in Northern Europe; the reasons for this disparity may provide important clues to the aetiology of psychosis.

Exploring the underwater life in transitional environments: Benthic foraminifera, ostracods, and dinoflagellate cysts - Biotic trends and EcoQS assessment in the Mar Piccolo of Taranto (Ionian sea, southern Italy).

Coastal areas have historically thrived as centers of human activities due to their resources, economic opportunities, and natural allure. The rapid growth of coastal populations has however brought forth a multitude of challenges to tackle, with pollution emerging as a significant and far-reaching issue. Our study focuses on the Mar Piccolo of Taranto (Ionian Sea, Southern Italy), a lagoon-like coastal basin (separated in two sub-basins) that, since decades, has been heavily affected by human activities and aquaculture, leading to environmental deterioration. Although past studies have looked at environmental conditions in the Mar Piccolo from a chemical perspective, the biological component (e.g., biological indicators) has been mostly neglected. In this study, we firstly aim to examine the distribution and diversity of foraminifera, ostracods, and dinoflagellate cysts in December 2016 and compare our findings with data collected in December 2011. Foraminiferal and ostracod communities exhibit similar patterns in the two sampling campaigns, while the communities of encysted dinoflagellates show differences concerning both densities and diversity. Then, we evaluate the Ecological Quality Status (EcoQS) using ecological indices. While the indices in the inner basin appear to reflect an actual ecological degradation, they yield conflicting results in the outer basin. In the outer basin, indeed, the indices overestimate the EcoQS. This study highlights the potential of these indices for characterizing the EcoQS but emphasizes the need for improvements in their reliability. This research also contributes to a more holistic understanding of environmental condition in the Mar Piccolo and underscores the importance of integrating biological quality elements into ecosystem management and remediation strategies.

Biological markers in cerebrospinal fluid for axonal impairment in multiple sclerosis: acetylcholinesterase activity cannot be considered a useful biomarker.

An impairment of the cholinergic system activity has been demonstrated in multiple sclerosis (MS). The correlation between the cholinergic system and the cognitive dysfunction in MS has led to studies on the use of acetylcholinesterase inhibitors (AChEI). The acetylcholinesterase (AChE), essential enzyme for the regulation of turnover of acetylcholine, can be considered the most important biochemical indicator of cholinergic signaling in the nervous system. Besides its catalytic properties, AChE has a crucial role in the regulation of the immune function. Based on the role of the AChe in the regulation of cholinergic signaling in the nervous system, the aim of the present study is to evaluate the activity of AChE in different pathological conditions: MS, other inflammatory neurological disorders (OIND) and non-inflammatory neurological disorders (NIND). We measured AChE activity in CSF samples obtained from 34 relapsing-remitting MS patients and, as controls, 40 patients with other inflammatory neurological disorders (OIND) and 40 subjects with other non-inflammatory neurological disorders (NIND). Fluorimetric detection of the AChE in MS patients and in the controls showed no statistically significant differences: 1.507 ± 0.403 nmol/ml/min in MS patients, 1.484 ± 0.496 nmol/ml/min in OIND and 1.305 ± 0.504 nmol/ml/min in NIND. Similar results were obtained in another recent study, using a different method. Further studies must be conducted on a larger number of patients, with different degrees of cognitive impairment. However, AChE measured in CSF can probably not be considered a useful biomarker for the assessment of the functional alterations of cholinergic system in pathological conditions.

A method for bivalve shells characterization by FT-IR photoacoustic spectroscopy as a tool for environmental studies.

Fourier Transform Infrared Spectroscopy has been employed to investigate the composition of the shells of two marine bivalves Mytilus galloprovincialis and Corbula gibba from four samples collected from the Mar Piccolo of Taranto (Ionian Sea, Southern Italy). Bivalve shells are composed of 95-99.9% calcium carbonate (CaCO3), while the remaining portion is constituted by organic matrix, which in some cases may incorporate pollutants from the surrounding environment. Recognizing the role of bivalves in the carbon biogeochemical cycle and their economic importance for aquaculture, we aimed to develop a methodology for shells powder samples preparation and analysis. The main objective of the study was to demonstrate the feasibility of Fourier Transform Infrared photoacoustic spectroscopy to perform a fast sample analysis in order to detect the possible presence of pollutants in the shells. The results revealed an unbiased differentiation between the shell compositions of the two bivalve selected species. Moreover, the spectra interpretation indicated that C. gibba specimens recorded a shell matrix contaminated by organic pollutants present in the surrounding environment. In conclusion, the described methodology including sample preparation tailored for photoacoustical investigations demonstrated to be a tool for the characterization of bivalve shells contamination enhancing environmental studies of polluted marine areas.•Bivalve species were collected from sampling stations located in the Mar Piccolo of Taranto (Ionian Sea, Southern Italy).•Samples preparation stages include: sonication, grinding and fractioning by sieving.•FT-IR PAS spectral region of interest is in the mid-infrared between 4000 and 400 cm-1.

The influence of risk factors on the onset and outcome of psychosis: What we learned from the GAP study.

The GAP multidisciplinary study carried out in South London, recruited 410 first episode of psychosis patients and 370 controls; the aim was to elucidate the multiple genetic and environmental factors influencing the onset and outcome of psychosis. The study demonstrated the risk increasing effect of adversity in childhood (especially parental loss, abuse, and bullying) on onset of psychosis especially positive symptoms. Adverse life events more proximal to onset, being from an ethnic minority, and cannabis use also played important roles; indeed, one quarter of new cases of psychosis could be attributed to use of high potency cannabis. The "jumping to conclusions" bias appeared to mediate the effect of lower IQ on vulnerability to psychosis. We confirmed that environmental factors operate on the background of polygenic risk, and that genetic and environment act together to push individuals over the threshold for manifesting the clinical disorder. The study demonstrated how biological pathways involved in the stress response (HPA axis and immune system) provide important mechanisms linking social risk factors to the development of psychotic symptoms. Further evidence implicating an immune/inflammatory component to psychosis came from our finding of complement dysregulation in FEP. Patients also showed an upregulation of the antimicrobial alpha-defensins, as well as differences in expression patterns of genes involved in NF-κB signaling and Cytokine Production. Being of African origin not only increased risk of onset but also of a more difficult course of illness. The malign effect of childhood adversity predicted a poorer outcome as did continued use of high potency cannabis.

Neurochemical changes in the striatum of dyskinetic rats after administration of the cannabinoid agonist WIN55,212-2.

Chronic use of levodopa, the most effective treatment for Parkinson's disease, causes abnormal involuntary movements named dyskinesias, which are linked to maladaptive changes in plasticity and disturbances of dopamine and glutamate neurotransmission in the basal ganglia. Dyskinesias can be modeled in rats with unilateral 6-hydroxydopamine lesions by repeated administration of low doses of levodopa (6 mg/kg, s.c.). Previous studies from our lab showed that sub-chronic treatment with the cannabinoid agonist WIN55,212-2 attenuates levodopa-induced dyskinesias at doses that do not interfere with physiological motor function. To investigate the neurochemical changes underlying WIN55,212-2 anti-dyskinetic effects, we used in vivo microdialysis to monitor extracellular dopamine and glutamate in the dorsal striatum of both the hemispheres of freely moving 6-hydroxydopamine-treated, SHAM-operated and intact rats receiving levodopa acutely or chronically (11 days), and studied how sub-chronic WIN55,212-2 (1 injection x 3 days, 20 min before levodopa) affected these neurochemical outputs. Our data indicate that: (1) the 6-hydroxydopamine lesion decreases dopamine turnover in the denervated striatum; (2) levodopa injection reduces extracellular glutamate in the side ipsilateral to the lesion of dyskinetic rats; (3) sub-chronic WIN55,212-2 prevents levodopa-induced glutamate volume transmission unbalances across the two hemispheres; and (4) levodopa-induced dyskinesias are inversely correlated with glutamate levels in the denervated striatum. These data indicate that the anti-dyskinetic properties of WIN55,212-2 are accompanied by changes of dopamine and glutamate outputs in the two brain hemispheres of 6-hydroxydopamine-treated rats.

Neurotensin receptor mechanisms and its modulation of glutamate transmission in the brain: relevance for neurodegenerative diseases and their treatment.

The extracellular accumulation of glutamate and the excessive activation of glutamate receptors, in particular N-methyl-D-aspartate (NMDA) receptors, have been postulated to contribute to the neuronal cell death associated with chronic neurodegenerative disorders such as Parkinson's disease. Findings are reviewed indicating that the tridecaptide neurotensin (NT) via activation of NT receptor subtype 1 (NTS1) promotes and reinforces endogenous glutamate signalling in discrete brain regions. The increase of striatal, nigral and cortical glutamate outflow by NT and the enhancement of NMDA receptor function by a NTS1/NMDA interaction that involves the activation of protein kinase C may favour the depolarization of NTS1 containing neurons and the entry of calcium. These results strengthen the hypothesis that NT may be involved in the amplification of glutamate-induced neurotoxicity in mesencephalic dopamine and cortical neurons. The mechanisms involved may include also antagonistic NTS1/D2 interactions in the cortico-striatal glutamate terminals and in the nigral DA cell bodies and dendrites as well as in the nigro-striatal DA terminals. The possible increase in NT levels in the basal ganglia under pathological conditions leading to the NTS1 enhancement of glutamate signalling may contribute to the neurodegeneration of the nigro-striatal dopaminergic neurons found in Parkinson's disease, especially in view of the high density of NTS1 receptors in these neurons. The use of selective NTS1 antagonists together with conventional drug treatments could provide a novel therapeutic approach for treatment of Parkinson's disease.

Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology.

Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson's disease, schizophrenia and drug addiction or drug dependence may substantially build on the existence of intramembrane receptor-receptor interactions within dopamine receptor containing receptor mosaics (RM; dimeric or high-order receptor oligomers) where it is believed that the dopamine D(2) receptor may operate as the 'hub receptor' within these complexes. The constitutive adenosine A(2A)/dopamine D(2) RM, located in the dorsal striato-pallidal GABA neurons, are of particular interest in view of the demonstrated antagonistic A(2A)/D(2) interaction within these heteromers; an interaction that led to the suggestion and later demonstration that A(2A) antagonists could be used as novel anti-Parkinsonian drugs. Based on the likely existence of A(2A)/D(2)/mGluR5 RM located both extrasynaptically on striato-pallidal GABA neurons and on cortico-striatal glutamate terminals, multiple receptor-receptor interactions within this RM involving synergism between A(2A)/mGluR5 to counteract D(2) signaling, has led to the proposal of using combined mGluR5 and A(2A) antagonists as a future anti-Parkinsonian treatment. Based on the same RM in the ventral striato-pallidal GABA pathways, novel strategies for the treatment of schizophrenia, building on the idea that A(2A) agonists and/or mGluR5 agonists will help reduce the increased dopaminergic signaling associated with this disease, have been suggested. Such treatment may ensure the proper glutamatergic drive from the mediodorsal thalamic nucleus to the prefrontal cortex, one which is believed to be reduced in schizophrenia due to a dominance of D(2)-like signaling in the ventral striatum. Recently, A(2A) receptors also have been shown to counteract the locomotor and sensitizing actions of cocaine and increases in A(2A) receptors have also been observed in the nucleus accumbens after extended cocaine self-administration, probably representing a compensatory up-regulation to counteract the cocaine-induced increases in dopamine D(2) and D(3) signaling. Therefore, A(2A) agonists, through antagonizing D(2) and D(3) signaling within A(2A)/D(2) and A(2A)/D(3) RM heteromers in the nucleus accumbens, may be found useful as a treatment for cocaine dependence. Furthermore, antagonistic cannabinoid CB(1)/D(2) interactions requiring A(2A) receptors have also been discovered and possibly operate in CB(1)/D(2)/A(2A) RM located principally on striatal glutamate terminals but also on some ventral striato-pallidal GABA neurons, thereby opening up a new mechanism for the integration of endocannabinoid, DA and adenosine mediated signals. Thus, A(2A), mGluR5 and/or CB(1) receptors can form integrative units with D(2) receptors within RM displaying different compositions, topography and localization. Also galaninR/5-HT(1A) RM probably participates in the transmission of the ascending 5-hydroxytryptamine neurons, where galanin receptors antagonize 5-HT(1A) recognition and signaling. Subtype specific galanin receptor antagonists may therefore represent novel antidepressant drugs. These results suggest the importance of a complete understanding of the function of these RM with regard to disease. Ultimately receptor-receptor interactions within RM that modify dopaminergic and serotonergic signaling may give new strategies for treatment of a wide range of diseases associated with altered dopaminergic and serotonergic signaling.

Acute exposure to methylmercury at two developmental windows: focus on neurobehavioral and neurochemical effects in rat offspring.

The neurobehavioral and neurochemical effects produced by prenatal methylmercury exposure (8 mg/kg, gestational-days 8 or 15), were investigated in rats. On postnatal day 40, animals exposed to methylmercury and tested in the open field arena, showed a reduction in the number of rearings, whereas the number of crossings and resting time was not altered with respect to the age-matched control rats. The methylmercury-exposed groups showed a lower level of exploratory behavior as well as an impairment in habituation and working memory when subjected to the novel object exploration task. The neophobia displayed by methylmercury-exposed rats is unlikely to be attributed to a higher degree of anxiety. Prenatal methylmercury exposure did not affect motor coordination or motor learning in 40-day-old rats subjected to the balance task on a rotating rod, and it did not impair the onset of reflexive behavior in pups screened for righting reflex, cliff aversion and negative geotaxis. In cortical cell cultures from pups exposed to methylmercury during gestation, basal extracellular glutamate levels were higher, whereas the KCl-evoked extracellular glutamate levels were lower than that measured in cultures from rats born to control mothers. In addition, a higher responsiveness of glutamate release to N-methyl-D-aspartic acid receptor activation was evident in cortical cell cultures from pups born from methylmercury-treated dams than in cultures obtained from control rats. The present results suggest that acute maternal methylmercury exposure induces, in rat offspring, subtle changes in short-term memory as well as in exploratory behavior. These impairments seem to be associated to alterations of cortical glutamatergic signaling.

Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 and carbon monoxide reduces extracellular glutamate levels in primary rat cerebral cortex cell cultures.

The effects of prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 (0.5 mg/kg s.c.), alone or in combination with carbon monoxide, on extracellular glutamate levels in primary rat cerebral cortical neuronal cultures, were investigated. Dam weight gain, pregnancy length and litter size at birth were not affected by prenatal treatment with WIN 55,212-2 and carbon monoxide alone or in combination. Basal and K(+)-evoked extracellular glutamate levels were reduced in cortical cultures from pups born to mothers exposed to WIN 55,212-2 and carbon monoxide alone or in combination compared to cultures from rats born to vehicle-treated mothers. In cultures obtained from rats exposed to vehicle or carbon monoxide alone during gestation, WIN 55,212-2 (0.01-100 nM) increased extracellular glutamate levels, displaying a bell-shaped concentration-response curve. In cultures from rats born to mothers exposed to WIN 55,212-2 alone or in combination with carbon monoxide the WIN 55,212-2 ( 1 nM)-induced increase in extracellular glutamate levels was lower than that observed in cultures from rats born to vehicle-treated mothers and similar at those observed at 10 and 100 nM concentrations. The selective CB1 receptor antagonist SR141716A (10 nM) counteracted the WIN 55,212-2-induced increase in extracellular glutamate levels in cultures exposed to vehicle or carbon monoxide during gestation, but failed to antagonise it in cultures from rats born to mothers exposed to WIN 55,212-2 alone or in combination with carbon monoxide. These findings provide evidence that prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 and carbon monoxide, alone or in combination, is associated with an impairment in cortical glutamatergic transmission. It could be speculated that such detrimental effects might be involved in the reported deficit in learning and memory associated with prenatal marijuana exposure.

Benthic foraminifera and heavy metals distribution: a case study from the Naples Harbour (Tyrrhenian Sea, Southern Italy).

The analysis of 90 surficial sediments from three docks of the Naples Harbour (Levante, Granili, and Diaz) permits to compare the distribution modes of heavy metals with grain sizes, total organic carbon content (TOC) and distribution patterns of benthic foraminifera. Foraminiferal density and species richness decrease with the increasing toxic elements concentrations from the Levante to the Diaz dock. Median concentrations of Ni, Pb, Zn, and Hg (medians of 21.43 mg/kg, 270.24 mg/kg, 489.65 mg/kg, and 1.18 mg/kg, respectively) were reported for the Diaz dock where foraminifera are absent, thus suggesting a possible impact of toxic elements on the benthic ecosystem balance. Compared to the unpolluted marine sediments of the Granili dock, the Levante area shows higher heavy metals levels and a quasi-oligotypic benthic assemblage. This is dominated by the tolerant species Ammonia tepida that may be used as bio-indicator of pollution of anthropised marine sediments.

CDKL5 knockout leads to altered inhibitory transmission in the cerebellum of adult mice.

Mutations in the X-linked cyclin-dependent kinase-like 5 gene (CDKL5) are associated to severe neurodevelopmental alterations including motor symptoms. In order to elucidate the neurobiological substrate of motor symptoms in CDKL5 syndrome, we investigated the motor function, GABA and glutamate pathways in the cerebellum of CDKL5 knockout female mice. Behavioural data indicate that CDKL5-KO mice displayed impaired motor coordination on the Rotarod test, and altered steps, as measured by the gait analysis using the CatWalk test. A higher reduction in spontaneous GABA efflux, than that in glutamate, was observed in CDKL5-KO mouse cerebellar synaptosomes, leading to a significant increase of spontaneous glutamate/GABA efflux ratio in these animals. On the contrary, there were no differences between groups in K(+) -evoked GABA and glutamate efflux. The anatomical analysis of cerebellar excitatory and inhibitory pathways showed a selective defect of the GABA-related marker GAD67 in the molecular layer in CDKL5-KO mice, while the glutamatergic marker VGLUT1 was unchanged in the same area. Fine cerebellar structural abnormalities such as a reduction of the inhibitory basket 'net' estimated volume and an increase of the pinceau estimated volume were also observed in CDKL5-KO mice. Finally, the BDNF mRNA expression level in the cerebellum, but not in the hippocampus, was reduced compared with WT animals. These data suggest that CDKL5 deletion during development more markedly impairs the establishment of a correct GABAergic cerebellar network than that of glutamatergic one, leading to the behavioural symptoms associated with CDKL5 mutation.

Synthetic cannabinoid JWH-018 and its halogenated derivatives JWH-018-Cl and JWH-018-Br impair Novel Object Recognition in mice: Behavioral, electrophysiological and neurochemical evidence.

It is well known that an impairment of learning and memory function is one of the major physiological effects caused by natural or synthetic cannabinoid consumption in rodents, nonhuman primates and in humans. JWH-018 and its halogenated derivatives (JWH-018-Cl and JWH-018-Br) are synthetic CB1/CB2 cannabinoid agonists, illegally marketed as "Spice" and "herbal blend" for their Cannabis-like psychoactive effects. In the present study the effects of acute exposure to JWH-018, JWH-018-Cl, JWH-018-Br (JWH-018-R compounds) and Δ(9)-THC (for comparison) on Novel Object Recognition test (NOR) has been investigated in mice. Moreover, to better characterize the effects of JWH-018-R compounds on memory function, in vitro electrophysiological and neurochemical studies in hippocampal preparations have been performed. JWH-018, JWH-018-Cl and JWH-018-Br dose-dependently impaired both short- and long-memory retention in mice (respectively 2 and 24 h after training session). Their effects resulted more potent respect to that evoked by Δ(9)-THC. Moreover, in vitro studies showed as JWH-018-R compounds negatively affected electrically evoked synaptic transmission, LTP and aminoacid (glutamate and GABA) release in hippocampal slices. Behavioral, electrophysiological and neurochemical effects were fully prevented by CB1 receptor antagonist AM251 pretreatment, suggesting a CB1 receptor involvement. These data support the hypothesis that synthetic JWH-018-R compounds, as Δ(9)-THC, impair cognitive function in mice by interfering with hippocampal synaptic transmission and memory mechanisms. This data outline the danger that the use and/or abuse of these synthetic cannabinoids may represent for the cognitive process in human consumer.

Behavioral and neurochemical studies on brain aging in galanin overexpressing mice.

To study possible involvement of galanin in brain aging quality, we have investigated behavioral, neurochemical and morphological parameters in aged mice overexpressing galanin under the platelet-derived growth factor B promoter (GalOE mice) compared to wild-type littermates (WT mice). The behavioral analysis in the forced swim test showed that old GalOE animals spent more time in immobility compared to WT. In the activity cage test, galanin overexpression counteracted the age-induced decrease in exploratory behavior. The neurochemical analysis showed a 30% decrease in noradrenaline overflow in the cerebral cortex of WT old mice that was not present in age-matched GalOE mice. Our results indicate that overexpression of galanin can influence several behavioral and neurochemical parameters in old mice.

The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade.

The effects of modafinil on glutamatergic and GABAergic transmission in the rat medial preoptic area (MPA) and posterior hypothalamus (PH), are analysed. Modafinil (30-300 mg/kg) increased glutamate and decreased GABA levels in the MPA and PH. Local perfusion with the GABAA agonist muscimol (10 microM), reduced, while the GABAA antagonist bicuculline (1 microM and 10 microM) increased glutamate levels. The modafinil (100 mg/kg)-induced increase of glutamate levels was antagonized by local perfusion with bicuculline (1 microM). When glutamate levels were increased by the local perfusion with the glutamate uptake inhibitor L-trans-PDC (0.5 mM), modafinil produced an additional enhancement of glutamate levels. Modafinil (1-33 microM) failed to affect [3H]glutamate uptake in hypothalamic synaptosomes and slices. These findings show that modafinil increases glutamate and decreases GABA levels in MPA and PH. The evidence that bicuculline counteracts the modafinil-induced increase of glutamate levels strengthens the evidence for an inhibitory GABA/glutamate interaction in the above regions controlling the sleep-wakefulness cycle.

Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil.

The present in vitro and in vivo studies examined the effects of modafinil on serotonergic transmission in the rat frontal cortex. In the in vitro study modafinil (0.3-30 microM) increased electrically-evoked, but not spontaneous, serotonin ([(3)H]5-HT) efflux from cortical slices in a concentration-dependent manner while the indirect serotonin agonist dl-fenfluramine (1-15 microM) enhanced both spontaneous and evoked [(3)H]5-HT efflux. The effects of modafinil were more pronounced when the 5-HT reuptake was blocked by paroxetine. Contrary to paroxetine (0.3-3 microM) and dl-fenfluramine (1-5 microM), modafinil failed to influence the [(3)H]5-HT uptake. In the in vivo study modafinil (3-100 mg/kg i.p.) increased 5-HT dialysate levels, the maximal effect being already reached at the 30 mg/kg dose. dl-fenfluramine (5 mg/kg) induced an increase in 5-HT levels which was significantly higher than that displayed by modafinil at 30 mg/kg. In the presence of paroxetine (3 microM), the effect of modafinil at 30 mg/kg was higher than that observed in the absence of 5-HT reuptake inhibition. Finally, in the presence of the selective 5-HT(1A) receptor agonist 8-OH-DPAT, modafinil at 100 mg/kg failed to affect 5-HT dialysate levels. These results demonstrate that modafinil regulates cortical serotonergic transmission and suggest that the drug preferentially acts by amplifying the electro-neurosecretory coupling mechanisms and via mechanisms which do not involve the reuptake process.

Facilitation of GABA release by neurotensin is associated with a reduction of dopamine release in rat nucleus accumbens.

The main aim of the present study was to investigate the effects of local perfusion with the tridecapeptide neurotensin on extracellular GABA and dopamine levels in the nucleus accumbens of the halothane-anaesthetized rat, using in vivo microdialysis. In an initial set of characterization studies we examined the Na+ dependence of neurotransmitter release by local perfusion with ouabain, veratridine and tetrodotoxin. Local perfusion with the Na+ ATPase inhibitor ouabain (10 microM) or the Na+ channel agonist veratridine (20 microM) perfused into the nucleus accumbens increased both extracellular GABA and dopamine levels. The Na+ channel antagonist tetrodotoxin (1 microM) consistently decreased (24% of basal) dopamine levels, while even at 10 microM it did not affect GABA. However, tetrodotoxin (10 microM) abolished the veratridine-induced increase in both GABA and dopamine, demonstrating that Na(+)-dependent neuronal activity is involved in this release mechanism. In a second set of experiments a hypothesis for a functional link between neurotensin, dopamine and GABA in the medial nucleus accumbens was tested. Towards this aim, the effects of local perfusion with a high 1 microM concentration of neurotensin into the nucleus accumbens increased both GABA (210% of basal value) and dopamine (145% of basal) release. However, a low (10 nM) concentration of neurotensin again increased GABA release (160% of basal), but decreased that of dopamine (75% of basal value). Furthermore, the local perfusion with the GABAA receptor antagonist bicuculline abolished the neurotensin (10 nM) induced inhibition of dopamine release without affecting the increase in GABA release. These findings suggest that neurotensin modulates both GABA and dopamine neurotransmission in the nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects on cortical glutamate release induced by prenatal exposure to the cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone: an in vivo microdialysis study in the awake rat.

The aim of the present in vivo microdialysis study was to investigate whether prenatal exposure to the CB(1) receptor agonist WIN55,212-2 mesylate (WIN; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone), at a dose of 0.5 mg/kg (s.c. from the fifth to the 20th day of gestation), that causes neither malformations nor overt signs of toxicity, influences cortical glutamate extracellular levels in adult (90-day old) rats. Dam weight gain, pregnancy length and litter size at birth were not significantly affected by prenatal treatment with WIN. Basal and K(+)-evoked dialysate glutamate levels were lower in the cerebral cortex of adult rats exposed to WIN during gestation than in those born from vehicle-treated mothers. In both group of animals WIN (0.1 mg/kg, i.p.) increased dialysate glutamate levels. However, while the blockade of the CB1 receptors with the selective receptor antagonist SR141716A completely counteracted the WIN-induced increase in those rats exposed to vehicle during gestation, it failed to antagonise the increase in those born from WIN-treated dams. These findings suggest that prenatal exposure to the CB1 receptor agonist WIN, at a concentration which is not associated with gross malformations and/or overt signs of toxicity, induces permanent alterations in cortical glutamatergic function. The possibility that these effects might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users is discussed.

Evidence for a differential cholecystokinin-B and -A receptor regulation of GABA release in the rat nucleus accumbens mediated via dopaminergic and cholinergic mechanisms.

In the present study we characterized the cholecystokinin receptor regulation of (i) the dopamine D2 agonist binding sites in striatal sections including the nucleus accumbens and (ii) GABA and dopamine release in the central part of the rat nucleus accumbens, by combining the in vitro filter wipe-off and the in vivo microdialysis techniques. In the binding study we demonstrate that sulphated cholecystokinin octapeptide (1 nM) increased (219 +/- 30%) the KD value of the D2 agonist [3H]N-propylnorapomorphine binding sites in sections from the striatum including the accumbens. This effect was counteracted by the cholecystokinin-B antagonist PD134308 (50 nM). In a parallel study using microdialysis in the central nucleus accumbens, we found that local perfusion with sulphated cholecystokinin octapeptide (1 microM) induced an increase in GABA (135 +/- 7%) and dopamine (146 +/- 8%) release which was unaffected by the cholecystokinin-A antagonist L-364,718 (10 nM). In contrast, when the cholecystokinin-B antagonist PD134308 (10 nM) was co-perfused with the peptide it prevented the increase in dopamine and decreased GABA release (-24 +/- 2%). This reduction was counteracted by the addition to the perfusate medium of the cholecystokinin-A antagonist or the cholinergic muscarinic M2 receptor antagonist AF-DX 116 (0.1 microM). Taken together, these data demonstrate that the facilitation by sulphated cholecystokinin octapeptide of GABA and dopamine release in the central accumbens probably reflects an inhibitory effect of the peptide on both pre- and postsynaptic D2 receptors, mediated via cholecystokinin-B receptor activation. In addition, for the first time we provide evidence for a differential cholecystokinin-A and -B receptor-mediated regulation of GABA transmission in the central accumbens, where the cholecystokinin-B receptor exerts a dominant excitatory influence while the cholecystokinin-A receptor mediates an inhibition of GABA release via a local muscarinic M2 receptor.