Grand Challenge in Psychopharmacology: Setting Priorities to Shape a Bright Future

[No abstract available

MT-7716, a potent NOP receptor agonist, preferentially reduces ethanol seeking and reinforcement in post-dependent rats

Dysregulation of the nociceptin (N/OFQ) system has been implicated in alcohol abuse and alcoholism, and growing evidence suggests that targeting this system may be beneficial for treating alcoholism. To further explore the treatment target potential of the N/OFQ system, the novel non-peptide, small-molecule N/OFQ (NOP) agonist MT-7716, (R)-2-3-[1-(Acenaphthen-1-yl)piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl-N-methylacetamide hydrochloride hydrate, was examined for its effects on ethanol self-administration and stress-induced reinstatement of alcohol seeking in non-dependent and post-dependent rats. Male Wistar rats were trained to self-administer ethanol and then made ethanol dependent via repeated intragastric ethanol intubation. The effects of MT-7716 (0.3 and 1 mg/kg; PO) on alcohol self-administration were determined 2 weeks following dependence induction, when baseline self-administration was restored. Effects of MT-7716 on stress-induced reinstatement were tested in separate cohorts of rats, 1 and 3 weeks post-withdrawal. MT-7716 reduced alcohol self-administration and stress-induced reinstatement of alcohol seeking in post-dependent rats, but was ineffective in non-dependent animals. Moreover, the prevention of stress-induced reinstatement by MT-7716 was more pronounced at 3 weeks post-dependence. The results further confirm treatment target potential for the NOP receptor and identify non-peptide NOP agonists as promising potential treatment drugs for alcohol abuse and relapse prevention. The findings also support dysregulation of the N/OFQ system as a factor in alcohol seeking and reinforcement

The Role of Nonsexual Exclusivity Ideals in College Dating Relationships: Relationship Quality, Attachment, and Aggression

This study explored the associations between nonsexual exclusivity ideals and relationship quality, adult attachment, and aggression in college students' dating relationships. Nonsexual exclusivity ideals were defined as the desired amount of time, emotional support, and self-disclosure engaged in exclusively with one's romantic partner. It was predicted that the discrepancy between nonsexual exclusivity ideals and perceptions would be a significant predictor of relationship quality, trust, and love, and relationship aggression; such that individuals whose perception of exclusivity in their current relationship met or exceeded their ideals would perceive significantly higher relationship quality, trust, and love for their partner and would be less likely to use aggression against their partner than those whose perception of exclusivity did not meet their ideal. Nonsexual exclusivity ideal-perception discrepancy and attachment anxiety were also expected to interact in the prediction of physical and psychological aggression in the relationship. A survey was administered to 400 undergraduates in order to test these predictions. Results supported hypotheses for the prediction of relationship quality, trust, love, and psychological aggression in the participant's current relationship. Implications of these results as well as suggestions for future research are discussed

Glutamatergic transmission in the central nucleus of the amygdala is selectively altered in Marchigian Sardinian alcohol-preferring rats: Alcohol and CRF effects

The CRF system of the central nucleus of the amygdala (CeA) is important for the processing of anxiety, stress, and effects of acute and chronic ethanol. We previously reported that ethanol decreases evoked glutamate transmission in the CeA of Sprague Dawley rats and that ethanol dependence alters glutamate release in the CeA. Here, we examined the effects of ethanol, CRF and a CRF1 receptor antagonist on spontaneous and evoked glutamatergic transmission in CeA neurons from Wistar and Marchigian Sardinian Preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and characterized by heightened activity of the CRF1 system. Basal spontaneous and evoked glutamate transmission in CeA neurons from msP rats was increased compared to Wistar rats. Ethanol had divergent effects, either increasing or decreasing spontaneous glutamate release in the CeA of Wistar rats. This bidirectional effect was retained in msP rats, but the magnitude of the ethanol-induced increase in glutamate release was significantly smaller. The inhibitory effect of ethanol on evoked glutamatergic transmission was similar in both strains. CRF also either increased or decreased spontaneous glutamate release in CeA neurons of Wistar rats, however, in msP rats CRF only increased glutamate release. The inhibitory effect of CRF on evoked glutamatergic transmission was also lost in neurons from msP rats. A CRF1 antagonist produced only minor effects on spontaneous glutamate transmission, which were consistent across strains, and no effects on evoked glutamate transmission. These results demonstrate that the genetically altered CRF system of msP rats results in alterations in spontaneous and stimulated glutamate signaling in the CeA that may contribute to both the anxiety and drinking behavioral phenotypes

Cebranopadol, a Mixed Opioid Agonist, Reduces Cocaine Self-administration through Nociceptin Opioid and Mu Opioid Receptors

Cocaine addiction is a widespread psychiatric condition still waiting for approved efficacious medications. Previous studies suggested that simultaneous activation of nociceptin opioid (NOP) and mu opioid (MOP) receptors could be a successful strategy to treat cocaine addiction, but the paucity of molecules co-activating both receptors with comparable potency has hampered this line of research. Cebranopadol is a non-selective opioid agonist that at nanomolar concentration activates both NOP and MOP receptors and that recently reached phase-III clinical trials for cancer pain treatment. Here, we tested the effect of cebranopadol on cocaine self-administration (SA) in the rat. We found that under a fixed-ratio-5 schedule of reinforcement, cebranopadol (25 and 50 µg/kg) decreased cocaine but not saccharin SA, indicating a specific inhibition of psychostimulant consumption. In addition, cebranopadol (50 µg/kg) decreased the motivation for cocaine as detected by reduction of the break point measured in a progressive-ratio paradigm. Next, we found that cebranopadol retains its effect on cocaine consumption throughout a 7-day chronic treatment, suggesting a lack of tolerance development toward its effect. Finally, we found that only simultaneous blockade of NOP and MOP receptors by concomitant administration of the NOP antagonist SB-612111 (30 mg/kg) and naltrexone (2.5 mg/kg) reversed cebranopadol-induced decrease of cocaine SA, demonstrating that cebranopadol activates both NOP and classical opioid receptors to exert its effect. Our data, together with the fairly advanced clinical development of cebranopadol and its good tolerability profile in humans, indicate that cebranopadol is an appealing candidate for cocaine addiction treatment

Distribuzione spazio-temporale della specie Caretta caretta nell'arcipelago delle Isole Pelagie.

La Caretta caretta è la tartaruga marina più comune nel Mediterraneo, i principali siti di nidificazione si trovano lungo le coste della Turchia, Libia, Grecia e Israele. Considerando esclusivamente l’Italia la presenza dei nidi è limitata alle coste della Calabria, Sicilia, Campania, Puglia e dell’ arcipelago delle Isole Pelagie. La sopravvivenza di tale specie, tuttavia, è fortemente a rischio in tutto il bacino e le principali responsabilità sono state individuate nell'inquinamento marino, nella riduzione dei siti di nidificazione, nelle collisioni con le imbarcazioni e, non ultimo, nelle catture accidentali causate dagli attrezzi da pesca. Questo studio si inserisce in una più ampia ricerca multidisciplinare, che si occupa dell’individuazione di rotte migratorie, degli habitat sfruttati e delle aree maggiormente frequentate, non senza difficoltà, dipese dall’utilizzo di tecnologie e strumenti costosi (telemetria satellitare) e dalla scarsità di dati riguardanti gli individui maschi. In particolare, il presente lavoro prende in esame la distribuzione spazio-temporale della specie Caretta caretta nell’arcipelago delle Isole Pelagie, basandosi sugli avvistamenti da parte di diportisti e simili. Le Isole Pelagie (Lampedusa, Linosa e Lampione), per la loro posizione geografica al centro del Mediterraneo, sono un punto di unione delle acque del bacino orientale, più calde, e di quelle del bacino occidentale, influenzate dalle correnti atlantiche. Si tratta quindi di un sito "sentinella" per il monitoraggio dell'ambiente marino e dei suoi cambiamenti ecologici in atto. In particolare l’isola di Lampedusa è situata al margine settentrionale della piattaforma continentale tra la Sicilia e Tunisia-Libia e l’area marina circostante, oggetto dello studio, rappresenta una zona ad elevato passaggio di questi esemplari in quanto area di foraggiamento e di deposizione delle uova. La raccolta delle informazioni sugli avvistamenti è avvenuta mediante la compilazione di 75 interviste effettuate a diportisti, turisti e scuole diving in due differenti periodi, settembre-ottobre 2012 e maggio-ottobre 2013. I dati così ottenuti sono stati rielaborati attraverso il programma ArcGIS in modo da ottenere la localizzazione spaziale degli avvistamenti. La distribuzione spaziale e temporale così ottenuta fornisce indicazioni sulla presenza stagionale delle tartarughe comuni nell'area di studio e sulle zone maggiormente frequentate, rendendo così possibile l’identificazione di una eventuale relazione con le minacce presenti, in particolare con l’attività di pesca

Varenicline decreases nicotine but not alcohol self-administration in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats

Background: Alcohol and nicotine are largely co-abused. Here, we investigated whether concurrent exposure to both addictive drugs influences each other's consumption and whether varenicline attenuates alcohol consumption in the presence of nicotine. Methods: Marchigian Sardinian alcohol-preferring (msP) rats trained to simultaneously self-administer oral alcohol (10% v/v) and intravenous nicotine (30. μg/kg/inf) were used. Additional groups of rats were trained to self-administer either alcohol or nicotine. Further, msP rats were also trained to self-administer nicotine followed by 22-h/day access to alcohol and water in a two bottle free choice paradigm or water alone. The effects of varenicline (0.0, 0.3, 1.0, 3.0. mg/kg, p.o.) on alcohol and nicotine consumption were tested. Results: In a self-administration paradigm, msP rats showed a significantly high level of alcohol and nicotine intake when the drugs were administered alone. However, when access to both drugs occurred concomitantly, the number of nicotine infusions self-administered was significantly decreased. Nicotine self-administration was markedly reduced by varenicline regardless of whether it was self-administered alone or concurrently with alcohol. In a two bottle choice test, varenicline significantly decreased nicotine self-administration but had no influence on alcohol consumption. Conclusion: Varenicline is highly efficacious in decreasing nicotine self-administration either alone or in combination with alcohol. However, varenicline failed to influence both operant responding for alcohol and home-cage alcohol drinking in msP animals. Taken together, our findings suggest that the effects of varenicline could be specific to nicotine under conditions where excessive alcohol drinking is facilitated by genetic factors as in msP rats

Not Bad, For a Man: Shifting Standards in the Provision of Emotional Support Within Romantic Relationships

Previous research has found mixed results in terms of gender differences in the provision of emotional support to a relationship partner. Some studies support the popular stereotype that women are more emotionally supportive than men, while others find no gender differences in the amount of emotional support men and women provide to one another in a romantic relationship. These conflicting findings may be the result of shifting standards for men and women in terms of the amount of emotional support that is expected to be provided by each within a relationship. Since women are stereotypically assumed to be more nurturing and emotionally supportive than men, more emotional support will be expected of them in comparison with men who are assumed to be unemotional and largely unsupportive of their partners. Therefore, women will be held to a higher standard than men with regard to the provision of emotional support. The purpose of the current study was to test this shifting standards effect as it relates to the provision of emotional support within dating relationships. Heterosexual male and female undergraduates currently involved in a dating relationship were asked to rate their partners’ provision of emotional support using either an objective scale or a subjective scale. It was predicted that objective ratings of emotional support provision would reflect stereotypical gender differences with women being rated as providing more support than men. However, subjective ratings, which are subject to shifting standards, would not display gender differences in the provision of emotional support. These results were predicted to be associated with within-gender social comparison and adherence to gender stereotypes. Contrary to predictions, women rated their partners as providing significantly more emotional support than men on both the objective and subjective scales. Despite this fact, analyses of items measuring within-gender and between-gender comparisons revealed that participants adhered to the stereotype that women typically provide more emotional support than men. Ratings of emotional support provision were related to adherence to benevolent stereotypes about men and women, especially for men. The implications of these surprising results and suggestions for future research are discussed

The Link Among Neurological Diseases: Extracellular Vesicles as a Possible Brain Injury Footprint

Extracellular vesicles (EVs), referred as membranous vesicles released into body fluids from all cell types, represent a novel model to explain some aspects of the inter-cellular cross talk. It has been demonstrated that the EVs modify the phenotype of target cells, acting through a large spectrum of mechanisms. In the central nervous system, the EVs are responsible of the wide range of physiological processes required for normal brain function and neuronal support, such as immune signaling, cellular proliferation, differentiation, and senescence. Growing evidences link the EV functions to the pathogenic machinery of the neurological diseases, contributing to the disease progression and spreading. Extracellular vesicles are involved in the brain injury by multimodal ways; they propagate inflammation across the blood brain barrier (BBB), mediate neuroprotection and modulate regenerative processes. For these reasons, extracellular vesicles represent a promising biomarker in neurological disorders as well as an interesting starting point for the development of novel therapeutic strategies. Herein, we review the role of the EVs in the pathogenesis of neurological disease, discussing their potential clinical applications

Neurokinin 1 receptor blockade in the medial amygdala attenuates alcohol drinking in rats with innate anxiety but not in Wistar rats

Background and Purpose: Substance P and its preferred neurokinin receptor NK1 have been implicated in stress and anxiety and have been proposed as possible therapeutic targets for the treatment of anxiety/depression. Attention is also being focused on the role this neuropeptide system may play in drug addiction, because stress-related mechanisms promote drug abuse. Experimental Approach: The effects of the rat-specific NK1 receptor antagonist, L822429, on alcohol intake and seeking behaviour was investigated in genetically selected Marchigian Sardinian alcohol preferring rats. These rats demonstrate an anxious phenotype and are highly sensitive to stress and stress-induced drinking. Key Results: Systemic administration of L822429 significantly reduced operant alcohol self-administration in Marchigian Sardinian alcohol preferring rats, but did not reduce alcohol self-administration in stock Wistar rats. NK1 receptor antagonism also attenuated yohimbine-induced reinstatement of alcohol seeking at all doses tested but had no effect on cue-induced reinstatement of alcohol seeking. L822429 reduced operant alcohol self-administration when injected into the lateral cerebroventricles or the medial amygdala. L822429 injected into the medial amygdala also significantly reduced anxiety-like behaviour in the elevated plus maze test. No effects on alcohol intake were observed following injection of L822429 into the dorsal or the ventral hippocampus. Conclusions and Implications Our results suggest that NK1 receptor antagonists may be useful for the treatment of alcohol addiction associated with stress or comorbid anxiety disorders. The medial amygdala appears to be an important brain site of action of NK1 receptor antagonism