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Cippitelli A, Rezvani AH, Robinson JE, Eisenberg L, Levin ED, Bonaventure P et al. The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety. Alcohol 45: 567-576

Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Alcohol (Fayetteville, N.Y.) (Impact Factor: 2.04). 12/2010; 45(6):567-76. DOI: 10.1016/j.alcohol.2010.09.003
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ABSTRACT Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood-brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal.

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Available from: J. Elliott Robinson, Jun 17, 2014
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    • "Antagonism of Y2R systemically (Cippitelli et al. 2011) or in CeA (present study) reduces anxiety-like behavior in alcohol-naïve rats and also during acute withdrawal, without affecting operant alcohol self-administration, suggesting that NPY in CeA modulates alcohol drinking and anxiety-like behavior via different actions of presynaptic Y2Rs. In this study, antagonism of Y2Rs in CeA reduced anxiety-like behavior in alcohol-naïve and alcohol-dependent rats, confirming prior results that withdrawal-induced anxiety-like behavior is reversed by systemic JNJ-31020028 (Cippitelli et al. 2011), ablation of the Y2R gene in CeA produces a low-anxiety phenotype (Tasan et al. 2010), and pharmacological activation of Y2Rs in basolateral amygdala increases anxiety-like behavior in rats in the social interaction test (Sajdyk et al. 2002). The likely mechanism for this effect is that Y2R antagonists facilitate presynaptic release of NPY that activates postsynaptic Y1Rs to produce anxiolytic effects (Heilig et al. 1993). "
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    ABSTRACT: Electrophysiological data suggest a dual role of Y2 receptors (Y2 Rs) as autoreceptors regulating neuropeptide Y release and heteroceptors regulating gamma-aminobutyric acid release in the central amygdala (CeA). Here, we report that neither systemic (JNJ-31020028) nor intra-CeA (BIIE0246) Y2 R antagonism altered operant alcohol responding by alcohol-dependent or non-dependent rats. Conversely, BIIE0246 in the CeA reduced anxiety-like behavior in alcohol-dependent and alcohol-naïve rats. The finding that Y2 R antagonism reduces anxiety-like behavior but not alcohol drinking suggests that these two effects may occur via different functions of the Y2 R (e.g. autoreceptor versus heteroceptor function).
    Addiction Biology 05/2013; 19(5). DOI:10.1111/adb.12059 · 5.93 Impact Factor
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    • "Unfortunately, neither systemic nor intra-ventricular injection of this Y 2 R antagonist affects basal or post-stress anxiety-like behavior or alcohol consumption in a reliable way (Cippitelli et al., 2011; Shoblock et al., 2009). That said, the antagonist dose-dependently reverses stress-induced increases in corticosterone levels (Shoblock et al., 2009) and increases in anxiety-like behavior produced by hangover/withdrawal from a single bolus injection of alcohol (Cippitelli et al., 2011), suggesting that NPY systems are recruited following a challenge to the system. This idea is consistent with augmented effects of NPY in CeA on alcohol consumption in alcohol-dependent rats (Gilpin et al., 2008a), and the ability of NPY to reverse dependence-induced increases in GABA release in CeA, likely via actions at presynaptic Y 2 Rs (Gilpin et al., 2011). "
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    ABSTRACT: The central amygdala (CeA) is uniquely situated to function as an interface between stress- and addiction-related processes. This brain region has long been attributed an important role in aversive (e.g., fear) conditioning, as well as the negative emotional states that define alcohol dependence and withdrawal. The CeA is the major output region of the amygdala and receives complex inputs from other amygdaloid nuclei as well as regions that integrate sensory information from the external environment (e.g., thalamus, cortex). The CeA is functionally and anatomically divided into lateral and medial subdivisions that themselves are interconnected and populated by inhibitory interneurons and projections neurons. Neuropeptides are highly expressed in the CeA, particularly in the lateral subdivision, and the role of many of these peptides in regulating anxiety- and alcohol-related behaviors has been localized to the CeA. This review focuses on two of these peptides, corticotropin-releasing factor (CRF) and neuropeptide Y (NPY), that exhibit a high degree of neuroanatomical overlap (e.g., in CeA) and largely opposite behavioral profiles (e.g., in regulating anxiety- and alcohol-related behavior). CRF and NPY systems in the CeA appear to be recruited and/or up-regulated during the transition to alcohol dependence. These and other neuropeptides may converge on GABA synapses in CeA to control projection neurons and downstream effector regions, thereby translating negative affective states into anxiety-like behavior and excessive alcohol consumption.
    Alcohol (Fayetteville, N.Y.) 05/2012; 46(4):329-37. DOI:10.1016/j.alcohol.2011.11.009 · 2.04 Impact Factor
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    • "This experiment was conducted as described previously (Cippitelli et al., 2011). The apparatus was elevated 50 cm above the floor and consisted of two black plastic open arms (50 × 10 cm) and two enclosed arms (50 × 10 × 45 cm), which were arranged so that the similar arms were opposite to each other. "
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    ABSTRACT: A dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking. We compared intermittent and continuous access to 20% (v/v) alcohol in a two-bottle free choice drinking paradigm. Following a total of twenty 24-hour exposures for every experimental group, we assessed signs of alcohol withdrawal, including anxiety-like behavior and sensitivity to stress. The selective CRH1 receptor (CRH1R) antagonist antalarmin (0, 10, 20 mg/kg, i.p.) was tested on alcohol consumption. Intermittent access to 20% alcohol led non-selected Wistar rats to escalate their voluntary intake to a high and stable level, whereas continuously exposed animals maintained a lower consumption. These groups did not differ in physical withdrawal signs. In addition, no differences were found when anxiogenic-like behavior was studied, neither under basal conditions or following restraint stress. Nevertheless, sensitivity to the treatment with the CRH1R antalarmin was observed since a reduction of 20% alcohol intake was found in both groups of animals regardless of the regimen of alcohol exposure. In addition, antalarmin was effective when injected to animals exposed to intermittent 10% (v/v) alcohol whereas it failed to suppress 10% continuous alcohol intake. Pharmacological blockade of CRH1R reduced alcohol drinking when sustained high levels of intake were achieved suggesting that the CRH system plays a key role when high doses of ethanol are consumed by non-dependent subjects. This supports the notion that CRH system not only maintains the dependent state but also engages the transition to dependence.
    Pharmacology Biochemistry and Behavior 01/2012; 100(3):522-9. DOI:10.1016/j.pbb.2011.10.016 · 2.82 Impact Factor
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