1,720,965 research outputs found
Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats.
No full textRationale: Nociceptin/orphanin FQ (N/OFQ),
the endogenous ligand of the opioid-like orphan receptor
NOP, was shown to reduce home-cage ethanol consumption,
ethanol-induced conditioned place preference and
stress-induced reinstatement of alcohol-seeking behaviour.
Objectives: The present study, using genetically
selected Marchigian Sardinian alcohol-preferring (msP)
rats, was designed to evaluate the effect of this opioid
peptide on 10% ethanol and 10% sucrose self-administration,
under a fixed-ratio 1 (FR 1) or a progressive-ratio
(PR) schedule of reinforcement. Furthermore, using an
experimental model of relapse in which rats were trained
to lever press for ethanol in the presence of the
discriminative stimulus of an orange odour (S+) and a
1-s cue light (CS+) or for water in the presence of anise
odour (S) and 1-s white noise (CS), the effect of N/oFQ
on cue-induced reinstatement of extinguished ethanol
responding was investigated.
Results: Sub-chronic (6 days) intracerebroventricular (i.c.v.) injection of 0.5 mg or 1.0 mg N/OFQ per rat significantly reduced alcohol self-administration under both the FR 1 and PR schedules of reinforcement. Conversely, i.c.v. administration of 0.5, 1.0 or 4.0 mg of the peptide per rat did not affect sucrose self-administration. In addition, i.c.v. N/
OFQ (1.0–2.0 mg per rat) significantly inhibited the
reinstatement of extinguished ethanol responding under
an S+/CS+ condition, whereas lever pressing under S/CS
was not altered.
Conclusions: The present study demonstrates
that the reinforcing effects of ethanol are markedly
blunted by activation of the opioidergic N/OFQ receptor
system. Moreover, the data provide evidence of the
efficacy of N/OFQ to prevent reinstatement of ethanolseeking
behaviour elicited by environmental conditioned stimuli
Persistent increase of alcohol-seeking evoked by Neuropetide S: An effect mediated by the hypothalamic hypocretin system
No full textThe association of ethanol’s reinforcing effects with specific environmental stimuli is thought to be a critical factor for relapse risk in alcoholism. This study examined in rats the effects of a newly deorphanized neuropeptide receptor and its cognate ligand, Neuropeptide S (NPS), on ethanol consumption and reinstatement of ethanol-seeking by environmental cues previously associated with ethanol
availability. In the self-administration experiments, the stable response rates observed for ethanol reinforcement were not modified by intracerebroventricular (ICV) injection of NPS (1.0 and 2.0 nmol per rat). In the reinstatement experiments, ethanol-associated cues induced robust rates of ethanol seeking, which were highly resistant to extinction over repeated sessions of reinstatement testing. ICV
NPS treatment (1.0, 2.0 and 4.0 nmol per rat) resulted in a significant increase of ethanol seeking elicited by ethanol-associated cues. In contrast, NPS did not affect the reinstatement of responding to water-paired stimuli. Site-specific NPS injection (0.1 and 0.5 nmol per rat)
into the lateral hypothalamus also reinstated extinguished responding to ethanol. This effect was selectively blocked by pre-treatment with the hypocretin-1/orexin-A antagonist SB-334867 (10 mg/kg, i.p.). At the dose tested, SB-334867 did not modify alcohol reinstatement per se. These results provide the first demonstration that activation of NPS receptors in the LH intensifies relapse to
ethanol-seeking elicited by environmental conditioning factors. This effect is selective, and is mediated by activation of LH hypocretin neurones. Based on the present findings, we also predict that antagonism at NPS receptors could represent a novel pharmacological approach to alcohol relapse treatment
Buprenorphine reduces alcohol drinking through activation of the nociceptin/orphanin FQ-NOP receptor system.
No full textBackground: Activation of the NOP receptor by its endogenous ligand nociceptin/orphanin FQ reduces ethanol intake in genetically selected alcohol preferring Marchigian Sardinian alcohol preferring (msP) rats. Here we evaluated whether buprenorphine, a partial u-agonist at opioid and NOP receptors, would reduce ethanol consumption in msP rats via activation of NOP receptors.
Methods: Marchigian Sardinian alcohol preferring rats trained to drink 10% alcohol 2 hours/day were injected with buprenorphine (.03, .3, 3.0, or 6.0 mg/kg intraperitoneally [IP]) 90 min before access to ethanol.
Results: Similar to prototypical u-agonists, the two lowest doses of buprenorphine significantly increased ethanol consumption (p < .01); in contrast, the two highest doses reduced it (p < .05). Pretreatment with naltrexone (.25 mg/kg IP) prevented the increase of ethanol intake induced by .03 mg/kg of buprenorphine (p < .001) but did not affect the inhibition of ethanol drinking induced by 3.0 mg/kg of buprenorphine. Conversely, pretreatment with the selective NOP receptor antagonist UFP-101 (10.0 or 20.0 ug/rat)
abolished the suppression of ethanol drinking by 3.0 mg/kg of buprenorphine.
Conclusions: Buprenorphine has dualistic effects on ethanol drinking; low doses increase alcohol intake via stimulation of classic opioid receptors, whereas higher doses reduce it via activation of NOP receptors. We suggest that NOP agonistic properties of buprenorphine might be useful in the treatment of alcoholism
The NOP receptor as a target in the treatment of alcohol abuse
No full textAlcohol is the second most commonly abused psychotropic drug after caffeine in the world today (Samson & Harris, 1992), and alcoholism has emerged as a major social and health problem (Royal College of Psychiatrists, 1986). In the United States 19% of men and 8% of women have been diagnosed, at some time in their lives, with alcohol dependence as defined in the American Psychiatric Association’s (1994) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Grant et al., 1994). In Australia, in 1977 it was estimated that one in five hospital beds were occupied by those suffering the effects of alcohol (Commonwealth Department of Community Services and Health, 1987).\ud
In addition to causing numerous serious medical disorders (e.g., liver and heart disease), alcohol dependence is associated with costly, adverse social consequences such as disruption of families, crime, traumatic accidents, and lost productivity. As a result, the annual costs related to alcohol dependence in the United States for 1998 have been estimated at $185 billion (Harwood, 1998, 2000).\ud
Unfortunately, heavy alcohol use and alcohol dependence has been also increasing among younger people (Windle, 1990; Sobeck et al., 2000), indicating that alcohol dependence may become an ever more prominent public health problem. In fact, 31% of 12th graders in the United States reported getting drunk in the past month and 6–10% of teens meet diagnostic criteria for an alcohol use disorder (Rohde et al., 1996; Clark et al., 2002)....
Chronic treatment with novel brain-penetrating selective NOP receptor agonist MT-7716 reduces alcohol drinking and seeking in the rat
No full textSince its discovery, the nociceptin/orphanin FQ (N/OFQ)-NOP receptor system has been extensively investigated as a promising target to treat alcoholism. Encouraging results obtained with the endogenous ligand N/OFQ stimulated research towards the development of novel brain-penetrating NOP receptor agonists with a pharmacological and toxicological profile compatible with clinical development. Here we describe the biochemical and alcohol-related behavioral effects of the novel NOP receptor agonist MT-7716. MT-7716 has high affinity for human NOP receptors expressed in HEK293 cells with a Ki value of 0.21 nM. MT-7716 concentration-dependently stimulated GTPγ(35)S binding with an EC50 value of 0.30 nM and its efficacy was similar to N/OFQ, suggesting that MT7716 is a full agonist at NOP receptors. In the two bottle choice test MT-7716 (0, 0.3, 1, and 3 mg/kg, bid) given orally for 14 days dose-dependently decreased voluntary alcohol intake in Marchigian Sardinian rats. The effect became gradually stronger following repeated administration, and was still significant 1 week after discontinuation of the drug. Oral naltrexone (30 mg/kg, bid) for 14 days also reduced ethanol intake; however, the effect decreased over the treatment period and rapidly disappeared when drug treatment was discontinued. MT-7716 is also effective for preventing reinstatement caused by both ethanol-associated environmental stimuli and stress. Finally, to investigate the effect of MT-7716 on alcohol withdrawal symptoms, Wistar rats were withdrawn from a 7-day alcohol liquid diet. MT-7716 significantly attenuated somatic alcohol withdrawal symptoms. Together these findings indicate that MT-7716 is a promising candidate for alcoholism treatment remaining effective with chronic administration
Dysregulation of nociceptin/orphanin FQ activity in the amygdala is linked to excessive alcohol drinking in the rat
No full textBackground: Alcoholism is a complex behavioral disorder in which interactions between stressful life events and heritable susceptibility factors contribute to the initiation and progression of disease. Neural substrates of these interactions remain largely unknown. Here, we
examined the role of the nociceptin/orphanin FQ (N/OFQ) system, with an animal model in which genetic selection for high alcohol preference has led to co-segregation of elevated behavioral sensitivity to stress (Marchigian Sardinian alcohol-preferring [msP]).
Methods: The msP and Wistar rats trained to self-administer alcohol received central injections of N/OFQ. In situ hybridization and receptor binding assays were also performed to evaluate N/OFQ receptor (NOP) function in naïve msP and Wistar rats.
Results: Intracerebroventricular (ICV) injection of N/OFQ significantly inhibited alcohol self-administration in msP but not in nonselected Wistar rats. The NOP receptor messenger RNA expression and binding was upregulated across most brain regions in msP compared with Wistar rats. However, in msP rats [35S]GTPS binding revealed a selective impairment of NOP receptor signaling in the central amygdala
(CeA). Ethanol self-administration in msP rats was suppressed after N/OFQ microinjection into the CeA but not into the bed nucleus of the stria terminalis or the basolateral amygdala.
Conclusions: These findings indicate that dysregulation of N/OFQ-NOP receptor signaling in the CeA contributes to excessive alcohol intake in msP rats and that this phenotype can be rescued by local administration of pharmacological doses of exogenous N/OFQ. Data are
interpreted on the basis of the anti– corticotropin releasing factor (CRF) actions of N/OFQ and the significance of the CRF system in promoting excessive alcohol drinking in msP rats
Role of cannabinoidergic mechanisms in ethanol self-administration and ethanol seeking in rat adult offspring following perinatal exposure to Delta9-tetrahydrocannabinol
No full textThe present study evaluated the consequences of perinatal Delta(9)-tetrahydrocannabinol (Delta(9)-THC) treatment (5 mg/kg/day by gavage), either alone or combined with ethanol (3% v/v as the only fluid available), on ethanol self-administration and alcohol-seeking behavior in rat adult offspring. Furthermore, the effect of the selective cannabinoid CB(1) receptor antagonist, SR-141716A, on ethanol self-administration and on reinstatement of ethanol-seeking behavior induced either by stress or conditioned drug-paired cues was evaluated in adult offspring of rats exposed to the same perinatal treatment. Lastly, microarray experiments were conducted to evaluate if perinatal treatment with Delta(9)-tetrahydrocannabinol, ethanol or their combination causes long-term changes in brain gene expression profile in rats. The results of microarray data analysis showed that 139, 112 and 170 genes were differentially expressed in the EtOH, Delta(9)-THC, or EtOH+Delta(9)-THC group, respectively. No differences in alcohol self-administration and alcohol seeking were observed between rat groups. Intraperitoneal (IP) administration of SR-141716A (0.3-3.0 mg/kg) significantly reduced lever pressing for ethanol and blocked conditioned reinstatement of alcohol seeking. At the same doses SR-141716A failed to block foot-shock stress-induced reinstatement of alcohol seeking. The results reveal that perinatal exposure to Delta(9)-THC ethanol or their combination results in evident changes in gene expression patterns. However, these treatments do not significantly affect vulnerability to ethanol abuse in adult offspring. On the other hand, the results obtained with SR-141716A emphasize that endocannabinoid mechanisms play a major role in ethanol self-administration, as well as in the reinstatement of ethanol-seeking behavior induced by conditioned cues, supporting the idea that cannabinoid CB(1) receptor antagonists may represent interesting agents for the pharmacotherapy of alcoholism
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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