Abstract
Alcoholism and anxiety disorders have a huge impact on society and afflict 17.6 million and 40 million people in the United States, respectively. A strong comorbidity exists between alcoholism and anxiety disorders. Indeed, alcohol withdrawal-induced anxiety is a primary contributing factor for relapse, and anxiolytics are a common adjuvant therapy prescribed for treatment-seeking alcoholics. It is thought that the use of alcohol to self-medicate and relieve anxiety contributes to the development of addiction. Treatment for anxiety disorders and alcoholism exist but are not universally effective. The delta opioid receptor (DOR) plays a role in both alcohol consumption and anxiety, making it a very interesting clinical target. Two pharmacologically distinct DORs have been described: DOR1 and DOR2. We find here that the relative specificity of DOR agonists for DOR1 or DOR2 can greatly affect the effects they exert on ethanol consumption and anxiety. The DOR1 agonist 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,30g]isoquinoline (TAN-67), although not effective in decreasing anxiety-like behavior in naive mice, has anxiolytic-like properties in ethanol-withdrawn mice. In contrast, a less subtype-selective agonist, (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), while also reducing anxiety-like behavior, increases ethanol consumption. In addition, we found that the conical anxiolytic diazepam [DZ; 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one] is a less effective anxiolytic in ethanol-withdrawn mice than in naive mice. Together, our findings suggest that selective DOR agonists can decrease anxiety-like behavior and are more effective than diazepam at reducing ethanol consumption. We believe the dual efficacy of DOR1 agonists makes these receptors an interesting therapeutic target for treatment-seeking alcoholics.
Footnotes
This work was supported by the Department of Defense [Grant DAMD62-10-5-071] (to J.L.W.), the National Institute on Alcohol Abuse and Alcoholism [Grant AA017072-01] (to J.L.W.), National Institutes of Health National Institute on Drug Abuse [Grants DA015232, DA019958] (to J.L.W.), and funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (to J.L.W.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.170969.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- DOR
- delta opioid receptor
- DOR1
- DOR subtype 1
- DOR2
- DOR subtype 2
- KO
- knockout
- AD
- anxiety disorder
- SSRI
- selective serotonin reuptake inhibitor
- BZD
- benzodiazepine
- ANOVA
- analysis of variance
- WT
- wild type
- TAN-67 (SB-205607)
- 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,30g]isoquinoline
- SNC80
- (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide
- DZ
- 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one
- NTX
- 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one
- NTB
- 17-(cyclopropylmethyl)-6,7-didehydro-3,14β-dihydroxy-4,5α-epoxy-6,7–2,3′-benzo furanomorphinan
- LY686017
- (2-chloro-phenyl)-(2-(5-pyridin-4-yl-1-(3,5-bistrifluoromethyl-benzyl)-1H-(1,2,3)triazol-4-yl)pyridin-3-yl)methanone.
- Received June 2, 2010.
- Accepted July 2, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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