3-(4-Chloro-2-Morpholin-4-yl-Thiazol-5-yl)-8-(1-Ethylpropyl)-2,6-Dimethyl-Imidazo[1,2-<i>b</i>]Pyridazine: A Novel Brain-Penetrant, Orally Available Corticotropin-Releasing Factor Receptor 1 Antagonist with Efficacy in Animal Models of Alcoholism

Gehlert, Donald R.; Cippitelli, Andrea; Thorsell, Annika; Lê, A. D.; Hipskind, Philip A.; Hamdouchi, Chafiq; Lu, Jian-Liang; Hembre, Erik J.; Cramer, Jeffrey W.; Song, Min; McKinzie, David L.; Morin, Mario; Ciccocioppo, Roberto; Heilig, Markus

doi:10.1523/jneurosci.4985-06.2007

Cited by 229 publications

(262 citation statements)

References 41 publications

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“…This level of increased ethanol consumption attained in the present series of experiments has been previously shown to result in significant elevation (two-to threefold increase) in blood ethanol levels and brain ethanol concentrations (Griffin et al, 2009b). These results (increased alcohol consumption) are congruent with those reported by others using similar procedures in mice (Finn et al, 2007;Dhaher et al, 2008) and rats (Gehlert et al, 2007;Roberts et al, 1996;Roberts et al, 2000;Sommer et al, 2008).…”

Section: Discussionsupporting

confidence: 93%

Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

Griffin

Haun

Hazelbaker

et al. 2013

Neuropsychopharmacol

129

112

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Using a well-established model of ethanol dependence and relapse, this study examined adaptations in glutamatergic transmission in the nucleus accumbens (NAc) and their role in regulating voluntary ethanol drinking. Mice were first trained to drink ethanol in a free-choice, limited access (2 h/day) paradigm. One group (EtOH mice) received repeated weekly cycles of chronic intermittent ethanol (CIE) exposure with intervening weeks of test drinking sessions, whereas the remaining mice (CTL mice) were similarly treated but did not receive CIE treatment. Over repeated cycles of CIE exposure, EtOH mice exhibited significant escalation in drinking (up to B3.5 g/kg), whereas drinking remained relatively stable at baseline levels (2-2.5 g/kg) in CTL mice. Using in vivo microdialysis procedures, extracellular glutamate (GLU EX ) levels in the NAc were increased approximately twofold in EtOH mice compared with CTL mice, and this difference was observed 7 days after final CIE exposure, indicating that this hyperglutamatergic state persisted beyond acute withdrawal. This finding prompted additional studies examining the effects of pharmacologically manipulating GLU EX in the NAc on ethanol drinking in the CIE model. The non-selective glutamate reuptake antagonist, threo-b-benzyloxyaspartate (TBOA), was bilaterally microinjected into the NAc and found to dose-dependently increase drinking in nondependent (CTL) mice to levels attained by dependent (EtOH) mice. TBOA also further increased drinking in EtOH mice. In contrast, reducing glutamatergic transmission in the NAc via bilateral injections of the metabotropic glutamate receptor-2/3 agonist LY379268 reduced drinking in dependent (EtOH) mice to nondependent (CTL) levels, whereas having a more modest effect in decreasing ethanol consumption in CTL mice. Taken together, these data support an important role of glutamatergic transmission in the NAc in regulating ethanol drinking. Additionally, these results indicate that ethanol dependence produces adaptations that favor elevated glutamate activity in the NAc which, in turn, promote excessive levels of ethanol consumption associated with dependence.

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Section: Discussionsupporting

confidence: 93%

Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

Griffin

Haun

Hazelbaker

et al. 2013

Neuropsychopharmacol

129

112

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“…2 [6,23]. As predicted from the allostatic concept of addiction (Box 1) we found upregulated CRH activity in the central amygdala of postdependent animals during acute withdrawal and many weeks thereafter, contributing to increased ethanol intake, anxiety, and ethanol-seeking behavior, all of which can be alleviated by blockade of CRH 1 receptors [6,[23][24][25][26]. In fact, the excessive ethanol consumption appears to be a means to downregulate amygdala CRH 1 receptors [27].…”

Section: Introductionsupporting

confidence: 51%

“…In summary, inhibition of the CRH 1 receptor subtype has been proposed as an attractive target for medication development in anxiety, depression, and addiction [23,30,31] and promising compounds are in development [6,25,32]. On the other hand, a wide variety of safe and effective RAS-targeting medications exist, but their potential as adjuvant medications for these disorders is largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders

Sommer

Saavedra

2008

J Mol Med

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The brain renin-angiotensin system (RAS) participates importantly in the regulation of endocrine, autonomic, and behavioral response to stress. Recent data indicate that central action of AT 1 receptor antagonists can reduce anxiety symptoms in experimental animals. Furthermore, central inhibition of RAS activity decreases ethanol intake in an animal model of alcoholism. Pathological anxiety responses and the development of substance dependence are both critically mediated through corticotrophin-releasing hormone (CRH) systems, and the RAS is positioned to interact both with hypothalamic as well as extrahypothalamic CRH systems. The thesis of this paper is that the RAS is part of the neurochemical dysregulation underlying negative affective states, anxiety disorders, and ethanol dependence and that medications targeting the RAS should be considered to augment the treatment of these disorders.

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“…The percent of time spent in open arms and the percent of open arm entries were used as measures of anxiety-like behaviour, while the number of entries into the closed arms was used as an indicator of general motor activity (Cruz et al 1994). As previously described by Gehlert et al (2007), alcoholinduced anxiety was measured by treating rats (N=32) IP with 3.0 g/kg of 20% alcohol or vehicle (saline) and 12 h later running the elevated plus-maze (EPM) test. Rats (N= 9/group) were treated with URB597 (0.3, 1.0 mg/kg) or its vehicle 30 min prior to the EPM.…”

Section: Alcohol-induced Anxietymentioning

confidence: 99%

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

et al. 2008

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Rationale A major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuserelated behaviours. As an alternative approach, CB1-receptor-mediated activity can be facilitated by increasing anandamide levels with the use of hydrolase fatty acid amide hydrolase (FAAH) inhibitors. Objective Using the selective FAAH inhibitor URB597, we investigated whether activation of the endogenous cannabinoid tone increases alcohol abuse liability, as what happens with the CB1 receptor direct agonists.Materials and methods URB597 was tested on alcohol self-administration in Wistar rats and on homecage alcohol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. In Wistar rats, URB597 effects on alcohol-induced anxiety and on stress-, yohimbineand cue-induced reinstatement of alcohol seeking were also evaluated. For comparison, the effect of the CB1 receptor antagonist rimonabant on ethanol self-administration was also tested. Results Under our experimental condition, intraperitoneal (IP) administration of URB597 (0.0, 0.3 and 1.0 mg/kg) neither increased voluntary homecage alcohol drinking in msP rats nor facilitated fixed ratio 1 and progressive ratio alcohol self-administration in nonselected Wistars. In the reinstatement tests, the compound did not have effects on cue-, footshock stress-and yohimbine-induced relapse. Conversely, URB597 completely abolished the anxiogenic response measured during withdrawal after an acute IP administration of alcohol (3.0 g/kg). Rimonabant (0.0, 0.3, 1.0 and 3.0 mg/kg) significantly reduced ethanol self-administration. Conclusions Results demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of FAAH does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal. We thus can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct CB1 receptor activators.

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3-(4-Chloro-2-Morpholin-4-yl-Thiazol-5-yl)-8-(1-Ethylpropyl)-2,6-Dimethyl-Imidazo[1,2-b]Pyridazine: A Novel Brain-Penetrant, Orally Available Corticotropin-Releasing Factor Receptor 1 Antagonist with Efficacy in Animal Models of Alcoholism

Cited by 229 publications

References 41 publications

Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

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