Dysregulation of Nociceptin/Orphanin FQ Activity in the Amygdala Is Linked to Excessive Alcohol Drinking in the Rat

Department of Experimental Medicine & Public Health, University of Camerino, Camerino (MC), Italy.
Biological psychiatry (Impact Factor: 10.26). 09/2008; 64(3):211-8. DOI: 10.1016/j.biopsych.2008.02.004
Source: PubMed


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]).
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.
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 [(35)S]GTPgammaS 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.
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.

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    • "hol intoxication . For instance , both animal models are characterized by dysregulation of stress - mechanisms , upregula - tion of corticotropin releasing factor 1 receptors ( CRF1 receptor ) , altered response to the anxiolytic peptide nociception / orphanin FQ and enhanced emotional reactivity ( Hansson et al . , 2006 ; Heilig and Koob , 2007 ; Economidou et al . , 2008 ) . Based upon these con - siderations it is tempting to speculate that altered expression , composition or function of nAChRs could contribute to shape the post - dependent state and possibly alter the innate predisposition to excessive drinking in msP rats , while simultaneously causing reduced sensitivity to the effect of varenicline"
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    ABSTRACT: 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 (30μg/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, 3.0mg/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.
    Drug and Alcohol Dependence 09/2015; DOI:10.1016/j.drugalcdep.2015.09.002 · 3.42 Impact Factor
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    • "Considering the importance of relapse prevention in postdependent individuals, it would be important to determine whether the effects of pharmacological tools (e.g., Hcrt-r antagonists) change in postdependent individuals, as described earlier for metabotropic glutamate receptors (Aujla et al., 2008; Hao et al., 2010; Sidhpura et al., 2010; Kufahl et al., 2011) and the nociceptin system (e.g., Economidou et al., 2008; Martin-Fardon et al., 2010; Aujla et al., 2013) and whether these effects are mediated by the PVT. The literature and data generated by our laboratory strongly support a previously unrecognized mechanism, namely the dysregulation of Orx/Hcrt-PVT transmission, in the etiology of drug dependence, which may help identify novel therapeutic targets for drug addiction. "
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    ABSTRACT: A major challenge for the successful treatment of drug addiction is the long-lasting susceptibility to relapse and multiple processes that have been implicated in the compulsion to resume drug intake during abstinence. Recently, the orexin/hypocretin (Orx/Hcrt) system has been shown to play a role in drug-seeking behavior. The Orx/Hcrt system regulates a wide range of physiological processes, including feeding, energy metabolism, and arousal. It has also been shown to be recruited by drugs of abuse. Orx/Hcrt neurons are predominantly located in the lateral hypothalamus that projects to the paraventricular nucleus of the thalamus (PVT), a region that has been identified as a "way-station" that processes information and then modulates the mesolimbic reward and extrahypothalamic stress systems. Although not thought to be part of the "drug addiction circuitry", recent evidence indicates that the PVT is involved in the modulation of reward function in general and drug-directed behavior in particular. Evidence indicates a role for Orx/Hcrt transmission in the PVT in the modulation of reward function in general and drug-directed behavior in particular. One hypothesis is that following repeated drug exposure, the Orx/Hcrt system acquires a preferential role in mediating the effects of drugs vs. natural rewards. The present review discusses recent findings that suggest maladaptive recruitment of the PVT by drugs of abuse, specifically Orx/Hcrt-PVT neurotransmission.
    Frontiers in Behavioral Neuroscience 04/2014; 8:117. DOI:10.3389/fnbeh.2014.00117 · 3.27 Impact Factor
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    • "Importantly, in CeA from ethanol-dependent rats the N/OFQinduced decrease in CeA GABAergic transmission is larger than that observed in naïve rats, suggesting that neuroadaptations occur at these synapses during chronic alcohol exposure (Roberto and Siggins, 2006). Notably, the CeA has been also identified as the putative brain site of action of N/OFQ for its inhibitory effects on ethanol drinking (Economidou et al., 2008). Jenck et al. (2000) developed the first nonpeptidergic brain-penetrant NOP receptor agonist, Ro 61-6198, that was tested on alcohol-related behaviors (Kuzmin et al., 2007) and (Economidou et al., 2006). "
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    ABSTRACT: The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. A large body of evidence shows that Nociceptin/Orphanin FQ (N/OFQ) regulates ethanol intake and anxiety-like behavior. In the rat, ethanol significantly augments CeA GABA release, whereas N/OFQ diminishes it. Using electrophysiological techniques in an in vitro slice preparation, in this study we investigated the effects of a nonpeptidergic NOP receptor 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], and its interaction with ethanol on GABAergic transmission in CeA slices of naïve rats. We found that MT-7716 dose-dependently (100-1000 nM) diminished evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) and increased paired-pulse facilitation (PPF) ratio of these evoked IPSPs, suggesting a presynaptic site of action of the MT-7716 by decreasing GABA release at CeA synapses. The presynaptic action of MT-7716 was also supported by the significant decrease in the frequency of miniature inhibitory postsynaptic currents (mIPSCs) induced by the nociceptin receptor (NOP) agonist. Interestingly, MT-7716 prevented the ethanol-induced augmentation of evoked IPSPs. A putative selective NOP antagonist, [Nphe1]Nociceptin(1-13)NH2, totally prevented the MT-7716-induced inhibition of IPSP amplitudes indicating that MT-7716 exerts its effect through NOPs. These data provide support for an interaction between the nociceptin and GABAergic systems in the CeA and for the anti-alcohol properties of the NOP activation. The development of a synthetic nonpeptidergic NOP receptor agonist such as MT-7716 may represent a useful therapeutic target for alcoholism.
    Frontiers in Integrative Neuroscience 02/2014; 8:18. DOI:10.3389/fnint.2014.00018
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