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NEW PHARMACOLOGICAL TOOLS FOR AUTISM RESEARCH: OXYTOCIN RECEPTOR MUTANT MICE AND ZEBRAFISH AS NEUROBEHAVIOURAL MODELS
Full text linkAutism is a neurodevelopmental disorder which is characterized by severe and pervasive impairment in reciprocal socialization, qualitative impairment in communication and repetitive or stereotyped behaviour associated to resistance to change. Oxytocin (OT) is a peptidic hormone best known for its role in lactation and parturition. Recently, it has been also shown by several studies involving different lines of knock-out mice to play an important role in the central nervous system (CNS) by acting on the regulation of social, emotional, aggressive behaviour and on learning and memory. Furthermore, prosocial effects following OT administration in humans have been shown. The link between OT and autism has already been traced in preliminary clinical studies as autism affected patients received a beneficial outcome from treatment with OT. Pharmacokinetic (very short half-life), pharmacodynamic (unspecific binding to vasopressin (AVP) receptors) properties and the presence of peripheral side effects of OT, though, make this peptide an unsuitable target for a future clinical use. It is important, in this perspective, to characterize specific animal models in order to validate the use of OT analogs with more suitable characteristics for preclinical research.
To this end, a characterization of the behavioural phenotype of OTR knock-out mice (OTR-/-) and heterozygous littermates (OTR+/-) in comparison with their wild type counterparts (OTR+/+) has been carried out. General home cage behaviour, sensory, motor abilities and emotional behaviour were not affected by the altered genotype. Interestingly, both and OTR+/- and OTR-/- mice exhibited a significant social impairment as quantified in both the sociability and social novelty tests. Furthermore, OTR-/- mice displayed much higher levels of aggression when facing a stranger mouse as a higher number of attacks and tail rattlings has been registered in the neutral cage paradigm. Moreover, when tested in the reversal phase of a T-maze task for their cognitive flexibility, OTR-/- showed a profound impairment in responding to the changes applied in their established routine. All in all, the OTR mutant mouse model provides full range autism-related aberrant behaviours, displaying social impairments, altered aggressive behaviour, a strong resistance to change and stereotyped behaviour. Mechanisms underlying the aberrant phenotype revealed by mutant mice were investigated through autoradiographic binding experiments for both OTR and vasopressin 1A receptor (V1aR) distribution. In addition, pharmacological treatments with OT, AVP and V1aR antagonist SR49059 were done. Binding experiments were carried out in specific brain areas known to exert a key role in integrating the processing of olfactory information that is crucial to regulate social and emotional behaviour in rodents. OTR-/- animals displayed an almost undetectable OTR binding in all tested areas. Furthermore, a slight compensatory up-regulation of V1aR in the hippocampus and a significant down-regulation of the V1aR expression in the anterior olfactory nucleus, amygdala, ventral pallidum and lateral septum were found. As for heterozygous mutants their phenotype appeared as halfway between the wild type and knock out counterparts for OTR binding sites and V1aR binding has been subjected to a slight reduction in ventral pallidum and anterior olfactory nucleus only. Hence, the previously mentioned aberrant behavioural phenotype displayed by OTR mutant mice could be due to an altered OT/AVP receptors concentration in crucial brain areas. Interestingly, intracerebroventicular treatment with both OT and AVP (0.5ng/mouse) in mutant mice was able to rescue the impairment shown in all behavioural tasks. Furthermore, pre-treatment with V1aR antagonist SR49059 (0.5 ng/mouse), which per se did not exert any effect, in association with OT, blocked the social, aggressive and cognitive enhancing effects of the neuropeptide. Our results suggest a strong involvement of AVP, alongside OT, and in particular the subtype 1A of the AVP receptor, in the modulation of social abilities and cognitive flexibility of OTR mutant mice.
Finally, as an increasing interest for the use of zebrafish for social behavioural analyses to study the genetic basis of behaviour is rising, we also evaluated zebrafish potential as a screening tool for neuropsychiatric diseases involving deficits in social behaviour. To this end, we analyzed the effect of OT, AVP but most importantly isotocin (ISO) and vasotocin (AVT) (zebrafish homologues of OT and AVP, respectively) using the shoaling preference test as social paradigm. Dose-response parabolic curves were obtained and all neuropeptides showed significant efficacy in enhancing social interaction, suggesting the involvement of the oxytocin/vasopressin systems and their analogs in the modulation of zebrafish social behaviour.
In conclusion, our findings indicate that OTR-/- and in part OTR+/- mice display autistic-like symptoms rescued by administration of AVP and OT to young adult animals. The OTR mutant mouse is thus instrumental to investigate the neurochemical and synaptic abnormalities underlying autistic-like disturbances and to test new strategies of pharmacological intervention. We also suggest the use of zebrafish as an alternative animal model for the study of social behaviour, especially as a screening tool: future studies involving new molecules acting on OT and AVP systems will be carried out, taking advantage of this new promising model
Involvement of the cannabinoid receptor type-1 (CB1) on Salvinorin-A-induced emotional response in rats
No full textSalvinorin A, a potent kappa-opioid receptor agonist (1) is the major active ingredient of Salvia divinorum,a hallucinogenic herb, usually smoked or buccally absorbed by chewing. Recently, salvinorin A has been shown to produce reinforcing effects in the zebrafish when given at low doses (2). About emotional reactivity, salvinorin A induces in humans both positive and negative effects. Until now, only a pro-depressant like-response in the forced swimming test (3), has been reported in rats. Thus, the aim of the present work was to investigate salvinorin A on emotional reactivity in male Sprague-Dawley rats using the elevated plus-maze (EPM) and the forced swimming test (FST) at doses not affecting motor activity. Salvinorin A (0.001-1000 mg/kg), was studied in EPM apparatus The test length was 5 min, the total time spent in each arm and the number of arm entries were scored, 20 min after treatment. The FST test, consisted in two swimming sessions where the time of immobility during the 2nd 5-min session was an indicator of antidepressant activity. Salvinorin A showed a dose-dependent increase in the mean number of entries and time spent in the open arms and a decrease of the mean time spent in immobility. Pre-treatment with the k opioid antagonist, nor-binaltorphimine (10 mg/kg i.p.), and with the CB1 cannabinoid receptor antagonist AM 251 (3 mg/kg i.p.), given 2 h and 40 min before salvinorin A respectively, significantly blocked the anxiolytic and antidepressant effect. These findings support for the first time the demonstration of the emotional response induced by salvinorin A through a mechanism cannabinoid CB1 receptor mediated
Delta9-tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors
No full textBACKGROUND AND PURPOSE: It has been suggested that the endocannabinoid system elicits neuroprotection against excitotoxic brain damage. In the present study the therapeutic potential of AM 404 on ischaemia-induced neuronal injury was investigated in vivo and compared with that of the classical cannabinoid receptor type 1 (CB1) agonist, delta 9-tetraydrocannabinol (THC), using a model of transient global cerebral ischaemia in the gerbil. EXPERIMENTAL APPROACH: The effects of AM 404 (0.015-2 mg kg(-1)) and THC (0.05-2 mg kg(-1)), given 5 min after ischaemia, were measured from 1 h to 7 days in terms of electroencephalographic (EEG) total spectral power, spontaneous motor activity, memory function, rectal temperature and hippocampal CA1 neuronal count. KEY RESULTS: Over the dose range tested, AM 404 (2 mg kg(-1)) and THC (1 mg kg(-1)) completely reversed the ischaemia-induced behavioural, EEG and histological damage. Only THC (1 and 2 mg kg(-1)) induced a decrease of body temperature. Pretreatment with the selective CB1 receptor antagonist, AM 251 (1 mg kg(-1)) and the opioid antagonist, naloxone (2 mg kg(-1)) reversed the protective effect induced by both AM 404 and THC while the TRPV1 vanilloid antagonist, capsazepine (0.01 mg kg(-1)), was ineffective. CONCLUSIONS AND IMPLICATIONS: Our findings demonstrate that AM 404 and THC reduce neuronal damage caused by bilateral carotid occlusion in gerbils and that this protection is mediated through an interaction with CB1 and opioid receptors. Endocannabinoids might form the basis for the development of new neuroprotective drugs useful for the treatment of stroke and other neurodegenerative pathologies
Emotional response induced by salvinorin A and D9–tetrahydrocannabinol (THC) is mediated by k-opioid and CB1 cannabinoid receptor in rats
No full textSalvinorin A, a potent k-opioid receptor agonist (Roth et al., 2002), is the major active ingredient of Salvia divinorum, the abuse of which has greatly increased in recent years for its hallucinogenic effects. Recently, salvinorin A has been shown to produce, in the zebrafish, CB1 cannabinoid receptor mediated-reinforcing effects (Braida et al., 2007). Furthermore, salvinorin A, like THC, induced in humans both positive and negative emotional responses, depending on the dose and route of administration (Porter and Felder, 2001; Gonzalez et al., 2006).
The aim of the present work was to investigate salvinorin A, in comparison with THC, on emotional reactivity in male Sprague-Dawley rats (150-200 g) using the elevated plus-maze (EPM) and the forced swimming test (FST) apparatus at doses not affecting motor activity. Animals, divided in groups of 10 each, were acutely treated with Salvinorin A (0.001-1000 mg kg-1 s.c.) or THC (1.5-1500 mg kg-1 i.p.). Anxiety-like response was studied in EPM apparatus according to Pellow et al. (1985). The test length was 5 min. The total time spent in each arm and the number of arm entries were scored 20 min after salvinorin A and 30 min after THC treatment. Depression was evaluated in the FST (Porsolt, 1979) consisting in two swimming sessions where the time of immobility, during the 2nd 5-min session, was an indicator of antidepressant activity. The obtained results were expressed as mean (± SEM) and statistically analysed by one-way ANOVA or Kruskal-Wallis test followed by appropriate post-hoc test.
Salvinorin A and THC showed a significant dose-dependent increase in the mean number of entries and time spent in the open arms and a decrease of the mean time spent in immobility. The maximal anxiolytic effect was obtained with the dose of 0.1 mg kg-1 of salvinorin A and 750 mg kg-1 of THC, while the maximal antidepressant effect was obtained with 10 mg kg-1 of salvinorin A and 75 mg kg-1 of THC. Pre-treatment with the CB1 cannabinoid receptor antagonist, AM 251 (3 mg kg-1 i.p. -40 min), and the k-opioid antagonist, nor-binaltorphimine (10 mg kg-1 i.p. –120 min), significantly blocked both the anxiolytic and antidepressant effects induced by salvinorin A and THC.
The present findings support the demonstration of a mechanism which is CB1 cannabinoid and k-opioid receptor-mediated for the emotional response induced by both salvinorin A and THC
Effetto della salvinorina A, una nuova sostanza d’abuso, sui processi cognitivi nel ratto
No full textBehavioural characterization of oxytocin mutant mice: implications for autism
No full textThere is a growing interest in the neuropeptide oxytocin (OT) and its receptor (OTR) in the pathogenesis of autism. OT controls the ability to remember individuals previously encountered, a form of social recognition that is essential for the establishment of all complex relationships (Hollander et al., 2003) , suggesting that the OT system is involved in the normal processing of socially relevant cues. The crucial role of OT in regulating the social brain has been recently confirmed in knockout OTR-/- mice, an animal model characterized by marked defects in maternal and social behaviour (Takayanagi et al., 2005).
Aim of the present study was to examine the behavioural phenotype of heterozygous OTR+/- and knockout OTR-/- mice in comparison to wild type OTR+/+ mice with particular attention for more specialized behavioural tasks relevant for autism such as the social approach to stranger mouse, the preference for social novelty and reversal of a position habit in an appetitive T-maze task (Crawley, 2007).
Preliminary results indicate that both OTR+/- and knockout OTR-/- mice have a good general health and normal neurological reflexes. However, they are severely impaired in : social recognition and social novelty test, reversal learning in the T-maze task.
These findings further confirm that the OTR may play a role in core symptoms characterizing autistic disorders. Furthermore, the deficit found in the heterozygous OTR+/- mice makes these animals an interesting model for the in vivo screening of new pharmacological compounds targeting the OT/OTR system
Profilo elettroencefalografico della salvinorina A e del D9tetraidrocannabinolo (THC) nel ratto
No full textLa Salvia divinorum è una sostanza ricreazionale che induce potenti stati allucinatori di breve durata (1) e che spesso viene consumata in sostituzione della marijuana (2). Studi recenti condotti nel nostro laboratorio hanno dimostrato un profilo comportamentale del tutto sovrapponibile tra la salvinorina A, agonista k-oppioide e principale ingrediente della Salvia divinorum, e il D9 tetraidrocannabinolo (THC), agonista per il recettore cannabinoide CB1 e principale costituente della marijuana. Infatti ambedue le sostanze, che tra l’altro condividono una struttura diterpenica molto simile, esibiscono effetti ansiolitici, antidepressivi e rinforzanti (3), che sono bloccati sia dall’antagonista per il recettore cannabinoide CB1, l’AM251, che da quello selettivo per il recettore k-oppiode , la nor-binaltorfimina (nor-BNI).
Scopo del presente studio è stato quello di studiare in ratti Wistar il profilo elettroencefalografico dei due composti, al fine di individuarne eventuali similitudini e di indagarne il meccanismo d’azione. A tal fine, differenti gruppi di ratti sono stati sottoposti, previa anestesia (cloralio idrato 450 mg/kg i.p.), ad intervento chirurgico per il posizionamento di 4 elettrodi a livello della corteccia cerebrale parieto-occipitale. Dopo una settimana di recupero, durante la quale gli animali sono stati quotidianamente abituati all’ambiente della gabbia di Faraday, sono state effettuate due registrazioni basali della durata di un’ora ciascuna. Successivamente gli animali sono stati sottoposti al trattamento e la loro attività elettrica cerebrale è stata registrata per le 2 ore seguenti. Il segnale elettrico, proveniente da ciascun animale, è stato analizzato, mediante il sistema software PowerLab, per calcolare l’analisi spettrale totale (0.5 e 25.0 Hz) e quella relativa alle singole bande di frequenza (0.2–4.0 Hz d, 4.2–8.0 Hz q, 8.2–13 Hz a, 13.2–25 Hz b) con una risoluzione di 0.2 Hz. Differenti gruppi di ratti hanno ricevuto una somministrazione acuta di veicolo, salvinorina A (40-1600 mg/kg s.c.) o THC (0.75-10 mg/kg i.p.).
I risultati ottenuti indicano che sia la salvinorina A che il THC non inducono cambiamenti significativi della potenza spettrale totale ma incrementano significativamente le bande di frequenza a e b, tipiche dello stato di veglia. Tali effetti sono stati ottenuti alle dosi di 40 mg/kg di salvinorina A e 0.75 mg/kg di THC, risultate attive nell’indurre effetti rinforzanti nella Conditioned Place Preference e nell’autosomministrazione intracerebroventricolare. Studi preliminari, condotti per indagare il meccanismo d’azione, indicano che il pretrattamento con AM 251 (3 mg/kg i.p.), effettuato 30 minuti prima della salvinorina A , riduce significantemente l’incremento della banda a indotto dalla sola salvinorina A.
In conclusione, si dimostra che la salvinorina A e il THC condividono un simile profilo elettroencefalografico e comportamentale attraverso il sistema endocannabinoide. Questi risultati rendono conto del fatto che nell’uomo la Salvia Divinorum viene spesso utilizzata come sostituto della marijuana
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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