Serum calcium levels are associated with cognitive function in hypoparathyroidism: a neuropsychological and biochemical study in an Italian cohort of patients with chronic post-surgical hypoparathyroidism.

PURPOSE: Hypoparathyroidism (HypoPT) is a rare endocrine disease and conventional therapy is based on calcium and vitamin D analogues. Conventional therapy does not restore calcium homeostasis and patients complain with neuropsychological symptoms, which have been evaluated with nonspecific self-administered questionnaires. This study aims to evaluate cognitive functions of patients with chronic post-surgical (PS)-HypoPT compared to a control population, using a standardized neuropsychological approach and evaluating the relationship with serum calcium (Alb-Ca). METHODS: Observational, monocentric study on 33 patients with PS-HypoPT and 24 controls, in whom biochemical testing and a standardized neuropsychological assessment by a trained psychologist were performed. RESULTS: In patients with PS-HypoPT, low Alb-Ca correlated with a worse performance on semantic memory abilities and executive function, as suggested by a significant inverse correlation between Alb-Ca and Trail Making Test A (TMT-A) scores (r = - 0.423; p = 0.014) and by a positive correlation with Semantic Fluency Test scores (SF)(r = 0.510; p = 0.002). PS-HypoPT patients with Alb-Ca ≤ 8.9 mg/dl had a significantly lower test performance compared with PS-HypoPT patients with Alb-Ca > 8.9 mg/dl, both at the TMT-A test (mean score: 34.53-18.55; p < 0.0001) and at SF test (mean score: 41.94-48.68; p = 0.01) and also a significantly lower test performance compared with control patients' group at TMT-A (mean score: 34.53-25.5; p = 0.0057). CONCLUSIONS: Patients with chronic PS-HypoPT in conventional therapy do not show a severe cognitive impairment; however, cognitive functions namely visuo-spatial attention, executive function and semantic memory appear to be modulated by Alb-Ca and impaired by its low levels.

The neurophysiological basis of excessive daytime sleepiness: suggestions of an altered state of consciousness.

Excessive daytime sleepiness (EDS) is characterized by difficulty staying awake during daytime, though additional features may be present. EDS is a significant problem for clinical and non-clinical populations, being associated with a range of negative outcomes that also represent a burden for society. Extreme EDS is associated with sleep disorders, most notably the central hypersomnias such as narcolepsy, Kleine-Levin syndrome, and idiopathic hypersomnia (IH). Although investigation of these conditions indicates that EDS results from diminished sleep quality, the underlying cause for this impairment remains uncertain. One possibility could be that previous research has been too narrow in scope with insufficient attention paid to non-sleep-related aspects. Here, we offer a broader perspective in which findings concerning the impact of EDS on cortical functioning are interpreted in relation to current understanding about the neural basis of consciousness. Alterations in the spatial distribution of cortical activity, in particular reduced connectivity of frontal cortex, suggest that EDS is associated with an altered state of consciousness.

The effect of single and repeated tDCS sessions on motor symptoms in Parkinson's disease: a systematic review.

OBJECTIVES: to update understanding of the effectiveness of transcranial direct current stimulation (tDCS) on motor dysfunction in Parkinson's disease, since the last review was published in 2016. METHODS: in order to identify suitable publications for inclusion, an online search of the Pubmed, Scopus and Cochrane databases was carried out. Searches of relevant full-text articles were performed through specific keywords. The final database check was performed in July 2019. Papers were restricted to studies investigating motor rehabilitative effects of tDCS in adult patients with Parkinson's disease. Studies involving either single or repeated tDCS sessions with a sham or controlled trial type design (which incorporated outcomes on motor performance measures) were considered. As studies varied widely in terms of methodology, a qualitative analysis of the selected studies was performed using the Newcastle-Ottawa Quality Assessment Scale or the Delphi list (depending on the study design). RESULTS: twenty-nine studies were retained in this systematic review. Of the studies included, fifteen involved single tDCS session (patients = 256) and fourteen involved repeated tDCS sessions (patients = 294). Eight investigations of single tDCS and ten investigations of repeated tDCS demonstrated significant results. Studies involving multi- target stimulation demonstrated significant improvements on mobility (p=0.006), balance (by 50.9%), gait velocity (by 29%), fall reduction (p0.05) compared to mono-target stimulations. CONCLUSIONS: despite increasing evidence that tDCS may improve motor symptoms, the results showed that fully optimized tDCS protocols are not yet established.

Brain connectivity is altered by extreme physical exercise during non-REM sleep and wakefulness: indications from EEG and fMRI studies.

Brain connectivity is associated to behavioral states (e.g. wake, sleep) and modified by physical activity although, to date, it is not clear which components (e.g. hypothalamus-pituitary-adrenal axis hormones, cytokines) associated to the exercise are involved. In this pilot study, we used extreme exercise (UltraTriathlon) as a model to investigate physical-activity-related changes of brain connectivity. We studied post-race brain synchronization during wakefulness and sleep as well as possible correlations between exercise-related cytokines/hormones and synchronization features. For wakefulness, global synchronization was evaluated by estimating from fMRI data (12 athletes) the brain global connectivity (GC). GC increased in several brain regions, mainly related to sensory-motor activity, emotional modulation and response to stress that may foster rapid exchange of information across regions, and reflect post-race internally-focused mental activity or disengagement from previous motor programs. No significant correlations between cytokines/hormones and GC were found. For sleep (8 athletes), synchronization was evaluated by estimating the local-(cortical) and global-related (thalamo- cortical) EEG features associated to the phenomenon of Sleep Slow Oscillations (SSO) of NREM sleep. Results showed that: power of fast rhythms in the baseline preceding the SSO increased in midline and parietal regions; amplitude and duration of SSOs increased, mainly in posterior areas; sigma modulation in the SSO up state decreased. In the post race, IL-10 positively correlated with fast rhythms baseline, SSO rate and positive slope; IL-1ra and cortisol inversely correlated with SSO duration; TNF-α and C-reactive protein positively correlated with fast rhythm modulation in the SSO up state. Sleep results suggest that: arousal during sleep, estimated by baseline fast rhythms, is increased; SSO may be sustained by cortical excitability, linked to anti-inflammatory markers (IL-10); thalamo-cortical entrainment, (sigma modulation), is impaired in athletes with higher inflammatory markers.

Sleep disorders and systemic lupus erythematosus.

OBJECTIVE: Sleep disturbances are often seen in rheumatic diseases, including systemic lupus erythematosus (SLE). However, the prevalence of sleep disorders in SLE as well as the contributing factors to their occurrence remain poorly understood. The aim of this paper is to review the clinical and psychobiological data on the relationship between sleep disturbances and SLE. METHOD: We performed a systematic search of MEDLINE, EMBASE and PsychINFO, using MeSH headings and keywords for "sleep disorders" and "SLE." RESULTS: Nine studies reporting the relationship between sleep disorders and SLE were found. Prevalence rates of sleep disorders ranged between 55% and 85%; differences in assessment techniques appeared to be a major source of this variability. In the majority of the studies an association between sleep disorders and disease activity, pain and fatigue has been reported. Psychosocial variables, depression, steroid use, and the role that sleep disruption has on pain, inflammation and cytokines, have been hypothesized as possible psychobiological factors. CONCLUSIONS: Sleep disorders appear to occur in more than half of patients with SLE and appear to be associated with disease activity. Pain and fatigue are also related to sleep disorders. Among the hypotheses on the possible mechanisms underlining the association between sleep disorders and SLE, psychosocial/psychological factors, especially depression, were the most frequently reported.

Poor sleep quality in systemic lupus erythematosus: does it depend on depressive symptoms?

OBJECTIVES: Sleep disturbances are frequently observed in rheumatic diseases including systemic lupus erythematosus (SLE). This study aimed at evaluating the prevalence of insomnia, poor sleep quality and their determinants in a cohort of SLE patients. METHODS: Eighty-one consecutive SLE female patients were evaluated in a cross-sectional study. The Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), the Beck Depression Inventory (BDI) and the Self-rating Anxiety Scale (SAS) were administered. Patients with previous diagnosis of obstructive sleep apnea or restless legs syndrome were excluded. Fifty-three women with hypertension (without SLE) were enrolled as control group (H). RESULTS: In the SLE cohort poor sleep quality (65.4% vs 39.6%, p < 0.01) and difficulty in maintaining sleep and/or early morning awakening (65.4% vs 22.6%, p < 0.001), but not insomnia (33.3% vs 22.6%, p = ns), were more prevalent than in H. Depressive symptoms were present in 34.6% of SLE vs 13.2% H patients (p < 0.001) while state anxiety was more common in H patients (H 35.8% vs SLE 17.3%, p < 0.005). SLE was associated with a 2.5-times higher probability of presenting poor sleep quality in comparison to H (OR 2.5 [CI 1.21-5.16]). After adjusting for confounders, both depressive symptoms (OR 4.4, [1.4-14.3]) and use of immunosuppressive drugs (OR 4.3 [CI 1.3-14.8]) were significantly associated with poor sleep quality in SLE patients. Furthermore, poor sleep quality was not associated either with disease duration or activity. CONCLUSIONS: In a cohort of SLE women, insomnia and poor sleep quality, especially difficulties in maintaining sleep, were common. Depressive symptoms might be responsible for the higher prevalence of poor sleep quality in SLE.

Depression and systemic lupus erythematosus: a systematic review.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic, relapsing-remitting autoimmune disorder that involves multiple organ systems including the central nervous system. Among the items included in the nomenclature for neuropsychiatric SLE, mood disorders have been identified. The aim of this paper is to review the clinical and psychobiological relationship between depression and SLE. METHOD: We performed a systematic search of MEDLINE, EMBASE, PsychINFO, using MeSH headings and keywords for 'depression' and 'SLE'. RESULTS: Seventeen studies reported depressive disorders, with prevalence rates in the range 17-75%. Three studies reported the most frequent symptoms, which may be represented by fatigue, weakness, somatic disorders and sleep disorders. Suicide ideation was much higher than in the general population. Nine studies analysed the relationship to SLE disease activity. The results of the available literature are contradictory. Psychobiological hypotheses have been considered in 13 studies. Among the psychobiological hypotheses which might underline the plausibility of their relationship, 'psychosocial factors' were the most frequently reported. CONCLUSIONS: Differences in assessment techniques appear to be the main explanation for the variability in findings and important methodological limitations are present in the available literature to definitively point to the prevalence of depression, type of depression and most prevalent symptoms. To date, the relationship between depression and SLE disease activity also appears controversial. Methodological limitations are present in the available literature and it would be necessary to develop evidence-based guidelines to improve the diagnosis of depression in SLE. Identification of SLE-specific biomarkers of depression also has high priority.

Minimal changes of thyroid axis activity influence brain functions in young females affected by subclinical hypothyroidism.

There is evidence of an association between thyroid hormones (TH) alterations and mental dysfunctions related to procedural and working memory functions, but the physiological link between these domains is still under debate, also for the presence of age as a confounding factor. Thus, we investigated the TH tuning of cerebral functions in young females affected by the borderline condition of subclinical hypothyroidism (SH) and in euthyroid females of the same age. The experiment consisted in the characterization of the affective state and cognitive abilities of the subjects by means of specific neuropsychological questionnaires, and of brain activity (EEG) in resting state and during the passive viewing of emotional video-clips. We found that SH had i) increased anxiety for Physical Danger; ii) better scores for both Mental Control and no-working-memory-related functions; iii) association between anxiety for Physical Danger and fT4 levels. Thus, in young adults, SH increases inward attention and paradoxically improves some cognitive functions. In addition, self-assessed questionnaires showed that SH had a greater susceptibility to unpleasant emotional stimulation. As for EEG data, SH compared to controls showed: i) reduction of alpha activity and of gamma left lateralization in resting state; ii) increased, and lateralized to the right, beta2 activity during stimulations. Both results indicated that SH have higher levels of arousal and greater susceptibility to negative emotion than controls. In conclusion, our study indicates that minimal changes in TH levels produce subtle but well-defined mental changes, thus encouraging further studies for the prediction of pathology evolution.

Objective selection of EEG late potentials through residual dependence estimation of independent components.

This paper presents a novel method to objectively select electroencephalographic (EEG) cortical sources estimated by independent component analysis (ICA) in event-related potential (ERP) studies. A proximity measure based on mutual information is employed to estimate residual dependences of the components that are then hierarchically clustered based on these residual dependences. Next, the properties of each group of components are evaluated at each level of the hierarchical tree by two indices that aim to assess both cluster tightness and physiological reliability through a template matching process. These two indices are combined in three different approaches to bring to light the hierarchical structure of the cluster organizations. Our method is tested on a set of experiments with the purpose of enhancing late positive ERPs elicited by emotional picture stimuli. Results suggest that the best way to look for physiologically plausible late positive potential (LPP) sources is to explore in depth the tightness of those clusters that, taken together, best resemble the template. According to our results, after brain sources clustering, LPPs are always identified more accurately than from ensemble-averaged raw data. Since the late components of an ERP involve the same associative areas, regardless of the modality of stimulation or specific tasks administered, the proposed method can be simply adapted to other ERP studies, and extended from psychophysiological studies to pathological or sport training evaluation support.

Be(a)ware of spider! An attentional blink study on fear detection.

We investigated whether detection of fearful stimuli is independent from attention by using an iconic version of the Attentional Blink Task in arachnophobic individuals. A colored animal icon (Target) and a black spider or butterfly icon (Probe) appeared in close temporal proximity within a stream of distractors, at one of 4 possible time lags. In one task, Probe detection was required; in another one, Target identification was also requested. In this case, competition for attentional resources produces the so-called AB effect, that is the decrease of Probe perception as a function of lag. During spider-Probe detection, arachnophobics showed a reduced AB effect with respect to the butterfly-Probe session. Their spider detection scores were also greater than ratings obtained by non-phobic controls with both Probe types. Thus, fear appears to enhance the probability of consciously perceiving the stimulus even when attention is engaged by a previous demanding event. One may assume that spider-Probe is scarcely attention demanding because detection of threat in arachnophobics is increased by rapid amygdala activation of visual areas and/or facilitated by a strong arousal-induced noradrenergic cortical input. Alternatively, an attention capturing mechanism involuntary triggered by the phobic meaning of the stimulus could be hypothesized.

Ultra-slow mechanical stimulation of olfactory epithelium modulates consciousness by slowing cerebral rhythms in humans.

The coupling between respiration and neural activity within olfactory areas and hippocampus has recently been unambiguously demonstrated, its neurophysiological basis sustained by the well-assessed mechanical sensitivity of the olfactory epithelium. We herein hypothesize that this coupling reverberates to the whole brain, possibly modulating the subject's behavior and state of consciousness. The olfactory epithelium of 12 healthy subjects was stimulated with periodical odorless air-delivery (frequency 0.05 Hz, 8 s on, 12 off). Cortical electrical activity (High Density-EEG) and perceived state of consciousness have been studied. The stimulation induced i) an enhancement of delta-theta EEG activity over the whole cortex mainly involving the Limbic System and Default Mode Network structures, ii) a reversal of the overall information flow directionality from wake-like postero-anterior to NREM sleep-like antero-posterior, iii) the perception of having experienced an Altered State of Consciousness. These findings could shed further light via a neurophenomenological approach on the links between respiration, cerebral activity and subjective experience, suggesting a plausible neurophysiological basis for interpreting altered states of consciousness induced by respiration-based meditative practices.

Combining electroencephalographic activity and instantaneous heart rate for assessing brain-heart dynamics during visual emotional elicitation in healthy subjects.

Emotion perception, occurring in brain areas such as the prefrontal cortex and amygdala, involves autonomic responses affecting cardiovascular dynamics. However, how such brain-heart dynamics is further modulated by emotional valence (pleasantness/unpleasantness), also considering different arousing levels (the intensity of the emotional stimuli), is still unknown. To this extent, we combined electroencephalographic (EEG) dynamics and instantaneous heart rate estimates to study emotional processing in healthy subjects. Twenty-two healthy volunteers were elicited through affective pictures gathered from the International Affective Picture System. The experimental protocol foresaw 110 pictures, each of which lasted 10 s, associated to 25 different combinations of arousal and valence levels, including neutral elicitations. EEG data were processed using short-time Fourier transforms to obtain time-varying maps of cortical activation, whereas the associated instantaneous cardiovascular dynamics was estimated in the time and frequency domains through inhomogeneous point-process models. Brain-heart linear and nonlinear coupling was estimated through the maximal information coefficient (MIC). Considering EEG oscillations in theθband (4-8 Hz), MIC highlighted significant arousal-dependent changes between positive and negative stimuli, especially occurring at intermediate arousing levels through the prefrontal cortex interplay. Moreover, high arousing elicitations seem to mitigate changes in brain-heart dynamics in response to pleasant/unpleasant visual elicitation.

Brain-heart linear and nonlinear dynamics during visual emotional elicitation in healthy subjects.

This study investigates brain-heart dynamics during visual emotional elicitation in healthy subjects through linear and nonlinear coupling measures of EEG spectrogram and instantaneous heart rate estimates. To this extent, affective pictures including different combinations of arousal and valence levels, gathered from the International Affective Picture System, were administered to twenty-two healthy subjects. Time-varying maps of cortical activation were obtained through EEG spectral analysis, whereas the associated instantaneous heartbeat dynamics was estimated using inhomogeneous point-process linear models. Brain-Heart linear and nonlinear coupling was estimated through the Maximal Information Coefficient (MIC), considering EEG time-varying spectra and point-process estimates defined in the time and frequency domains. As a proof of concept, we here show preliminary results considering EEG oscillations in the θ band (4-8 Hz). This band, indeed, is known in the literature to be involved in emotional processes. MIC highlighted significant arousal-dependent changes, mediated by the prefrontal cortex interplay especially occurring at intermediate arousing levels. Furthermore, lower and higher arousing elicitations were associated to not significant brain-heart coupling changes in response to pleasant/unpleasant elicitations.

Relaxation as a cognitive task.

In the present experiment the instruction to relax was given to awake highly (Highs) and non hypnotizable subjects (Lows), while their heart rate, respirogram and skin resistance were recorded together with electroencephalogram, electroculogram and corrugator electromiogram. At the beginning of the experiment, Highs exhibited no significant difference in heart rate (HR), respiratory frequency (RF) and heart rate variability (HRV) with respect to Lows, but showed a higher EEG alpha and theta1 power. During the session, both groups decreased their heart rate, but changes were significant only in Lows, which increased significantly also the parasympathetic component of their HRV (high frequency, HF). In both groups, EEG showed alpha, beta2 and theta2 power decrements; theta1 activity decreased only in Lows, while gamma power increased in Highs and decreased in Lows. Results suggest that Highs and Lows used different cognitive strategies in the elaboration of the relaxation request and that Highs performed the task through a higher integrative activity.

Slow wave and rem sleep mechanisms are differently altered in hereditary pick disease associated with the TAU G389R mutation.

Sleep disturbances are found in the course of most dementing syndromes. We report a longitudinal polysomnographic and 18FDG-PET study in a 38-year-old male with FTDP17 carrying the Tau gene mutation G389R. All-night sleep EEG and wake cerebral glucose metabolism at rest (eyes/ears covered) of the preceding day were studied twice, eight months (Night 1; PET 1) and sixteen months (Night 2; PET 2) after the initial neurological evaluation. The Night 1 study showed sleep fragmentation associated to a short REM latency and a severe reduction of slow wave sleep, with relatively preserved NREM-REM sleep cycles; daytime PET 1 revealed severe cerebral glucose metabolic reductions in frontal and temporal areas, with relative preservation of remaining cortical regions and subcortical structures. On Night 2, the total sleep time was less than 5 hours, delta sleep and REM latency remained shortened and only two sleep cycles could be identified; daytime PET 2 exam revealed a greater cortical metabolic impairment and an involvement of subcortical brain regions as compared to PET 1. Post-mortem neuropathological data showed severe neuronal loss, spongiosis and gliosis that were mostly marked in cortical layers I, II, V and VI. In vivo, neurometabolic and post-mortem neuropathological data are consistent with and indicative of a severe dysfunction of intra- and trans-hemispheric regional connectivity and of cortico-thalamic circuits. These findings suggest that the decreased cortical and subcortical connectivity may have been the main pathophysiological mechanism responsible for delta sleep reduction and the cognitive decline.

A Classification method for eye movements direction during REM sleep trained on wake electro-oculographic recordings.

Rapid eye movements (REMs) are a peculiar and intriguing aspect of REM sleep, even if their physiological function still remains unclear. During this work, a new automatic tool was developed, aimed at a complete description of REMs activity during the night, both in terms of their timing of occurrence that in term of their directional properties. A classification stage of each singular movement detected during the night according to its main direction, was in fact added to our procedure of REMs detection and ocular artifact removal. A supervised classifier was constructed, using as training and validation set EOG data recorded during voluntary saccades of five healthy volunteers. Different classification methods were tested and compared. The further information about REMs directional characteristic provided by the procedure would represent a valuable tool for a deeper investigation into REMs physiological origin and functional meaning.

Immunological alterations in adult obsessive-compulsive disorder.

BACKGROUND: Some recent findings suggest the involvement of autoimmune mechanisms in childhood onset of obsessive-compulsive disorder (OCD), on the basis of a parallel drawn with Sydenham's chorea, a manifestation of rheumatic fever. A monoclonal antibody called D8/D17 characterizing a B-lymphocyte antigen, present in almost all patients with rheumatic fever, has been found also in children affected by OCD, Tourette syndrome, and chronic tics to a greater degree than in healthy control subjects. The few observations of disturbances of some immunologic parameters in adult OCD patients, prompted the authors to investigate and compare subsets of peripheral immunological cells for differences in adult patients with OCD and healthy control subjects. METHODS: Twenty patients suffering from OCD, with no comorbidity for other psychiatric disorders, were compared with a similar group of healthy control subjects. The immune subsets were measured by flow cytometry. RESULTS: The CD8+ lymphocytes were significantly increased and CD4+ lymphocytes significantly decreased in OCD patients, while the other cells did not differ between the two groups. No correlation was found between immunologic and clinical parameters. CONCLUSIONS: These data indicate that patients with adult OCD showed increased CD8+, i.e., suppressor T lymphocytes, and decreased CD4+, which identify helper T lymphocytes, as compared with a similar group of healthy control subjects. The findings appear peculiar to patients with OCD and are suggestive of an immunologic imbalance, which might be related to the stress deriving from the frustrating situation determined by the disorder itself.

Potentiation of NMDA receptor function through somatostatin release: a possible mechanism for the cognition-enhancing activity of GABA(B) receptor antagonists.

CGP 36742 is a weak GABA(B) receptor antagonist. However, it improves cognitive performances at low doses; it blocks GABA(B) receptors potently and selectively on somatostatinergic terminals; it prevents kynurenate from antagonising NMDA-induced release of noradrenaline from rat brain slices potently. We here investigated whether and how somatostatin plays a role in the CGP 36742 activity. CGP 36742 increased the somatostatin-like immunoreactivity (SRIF-LI) release from hippocampal slices exposed to NMDA. In the kynurenate test with rat hippocampal slices SRIF-14 mimicked the effect of CGP 36742. CGP 36742 lost its activity in rats whose somatostatin content had been depleted with cysteamine. Exogenous SRIF-14 reverted kynurenate antagonism in somatostatin-depleted slices. L362855, an sst(5) receptor agonist, but not the selective sst(1)-sst(4) agonists, L797591, L779976, L796778 and L803087, displayed activity in the kynurenate test. The effects of CGP 36742, SRIF-14 and L362855 were antagonised by the sst(5)-preferring antagonist BIM-23056. The protein kinase C inhibitor GF 109203X prevented the reversal of the kynurenate antagonism by CGP 36742 or SRIF-14. In conclusion, by selectively blocking GABA(B) receptors on somatostatinergic terminals, CGP 36742 may disinhibit somatostatin release; the consequent activation of sst(5) receptors would potentiate the function of NMDA receptors coexisting with sst(5) receptors on noradrenergic neurons.

Neuropeptide Y release from cultured hippocampal neurons: stimulation by glutamate acting at N-methyl-D-aspartate and AMPA receptors.

L-Glutamate, N-methyl-D-aspartate, DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate increased the release of neuropeptide Y-like immunoreactivity from primary cultures of rat hippocampal neurons incubated in Mg2+(1.2 mM)-containing medium. The neuropeptide Y-like immunoreactivity released by 100 microM glutamate was mainly accounted for by neuropeptide Y (1-36), but consisted in part (about 20%) of peptide YY. The effect of 100 microM glutamate on neuropeptide Y-like immunoreactivity release was largely (about 70%) prevented by the N-methyl-D-aspartate receptor antagonist dizocilpine maleate (10 microM), while the remainder (about 30%) was sensitive to the AMPA/ kainate receptor antagonist 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2-3-dione (10 microM). The AMPA(100 microM)-evoked release of neuropeptide Y-like immunoreactivity was strongly antagonized by 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2-3-dione and by 1-aminophenyl-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine, but it was in part (15-20%) sensitive to dizocilpine. The releases of neuropeptide Y-like immunoreactivity elicited by glutamate, N-methyl-D-aspartate, AMPA and kainate were all strongly Ca(2+)-dependent. Tetrodotoxin (1 microM) abrogated the N-methyl-D-aspartate-evoked release and partly inhibited the release caused by glutamate, but did not modify significantly AMPA- or kainate-evoked release. Removal of Mg2+ from the medium caused increase of neuropeptide Y-like immunoreactivity release, an effect prevented by dizocilpine maleate or 7-Cl-kynurenate. Cyclothiazide (10 microM), a drug known to prevent AMPA receptor desensitization, enhanced the neuropeptide Y-like immunoreactivity release elicited by 100 microM AMPA, but not that caused by 100 microM kainate. However, when used at a lower concentration (50 microM), kainate elicited a response that was potentiated significantly by cyclothiazide. It is concluded that glutamate can stimulate Ca(2+)-dependent release of neuropeptide Y from hippocampal neurons mainly through N-methyl-D-aspartate receptors and, less so, by activating cyclothiazide-sensitive receptors of the AMPA-preferring type.

Human brain somatostatin release from isolated cortical nerve endings and its modulation through GABAB receptors.

UNLABELLED: 1. The release of somatostatin-like immunoreactivity (SRIF-LI) in the human brain was studied in synaptosomal preparations from fresh neocortical specimens obtained from patients undergoing neurosurgery to remove deeply sited tumours. 2. The basal outflow of SRIF-LI from superfused synaptosomes was increased about 3 fold during exposure to a depolarizing medium containing 15 mM KCl. The K(+)-evoked overflow of SRIF-LI was almost totally dependent on the presence of Ca2+ in the superfusion medium. 3. The GABAB receptor agonist, (-)-baclofen (0.3 - 100 microM), inhibited the overflow of SRIF-LI in a concentration-dependent manner (EC50 = 1.84 +/- 0.20 microM; maximal effect: about 50%). The novel GABAB receptor ligand, 3-aminopropyl(difluoromethyl)phosphinic acid (CGP 47656) mimicked (-)-baclofen in inhibiting the SRIF-LI overflow (EC50 = 3.06 +/- 0.52 microM; maximal effect: about 50%), whereas the GABAA receptor agonist, muscimol, was ineffective up to 100 microM. 4. The inhibition by 10 microM (-)-baclofen of the K(+)-evoked SRIF-LI overflow was concentration-dependently prevented by two selective GABAB receptor antagonists, 3-amino-propyl (diethoxymethyl)-phosphinic acid (CGP 35348) (IC50 = 24.40 +/- 2.52 microM) and [3-[[(3,4-dichlorophenyl) methyl]amino]propyl] (diethoxymethyl) phosphinic acid (CGP 52432) (IC50 = 0.06 +/- 0.005 microM). 5. The inhibition of SRIF-LI overflow caused by 10 microM CGP 47656 was abolished by 1 microM CGP 52432. 6. When human synaptosomes were labelled with [3H]-GABA and depolarized in superfusion with 15 mM KCl, the inhibition by 10 microM (-)-baclofen of the depolarization-evoked [3H]-GABA overflow was largely prevented by 10 microM CGP 47656 which therefore behaved as an autoreceptor antagonist. 7. IN CONCLUSION: (a) the characteristics of SRIF-LI release from synaptosomal preparations of human neocortex are compatible with a neuronal origin; (b) the nerve terminals releasing the neuropeptide possess inhibitory receptors of the GABAB type; (c) these receptors differ pharmacologically from the GABAB autoreceptors present on human neocortex nerve terminals since the latter have been shown to be CGP 35348-insensitive but can be blocked by CGP 47656.