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The Orexin-1 Receptor Antagonist SB-334867 Reduces Alcohol Relapse Drinking, but not Alcohol-Seeking, in Alcohol-Preferring (P) Rats

Dhaher, Ronnie PhD; Hauser, Sheketha R. PhD; Getachew, Bruk PhD; Bell, Richard L. PhD; McBride, William J. PhD; McKinzie, David L. PhD; Rodd, Zachary A. PhD

doi: 10.1097/ADM.0b013e3181bd893f
Original Article

Principle: The orexin system has been hypothesized to regulate drug-seeking and drug self-administration behaviors, including ethanol (EtOH) seeking and consumption. However, studies on the effects of orexin receptor antagonists have not been conducted on robust alcohol-relapse behavior.

Objectives: This study assessed the effects of the orexin-1 receptor antagonist, SB-334867, on alcohol-seeking behavior and responding for alcohol under relapse conditions.

Methods: Adult alcohol-preferring (P) rats self-trained in 2-lever operant chambers to administer 15% EtOH (vol/vol) on a fixed-ratio-5 and water on a fixed-ratio-1 schedule of reinforcement. After 10 weeks, rats underwent extinction training for 7 sessions. Animals were then maintained in their home cages for 2 weeks before being tested for Pavlovian Spontaneous Recovery (PSR; a measure of alcohol seeking) for 4 sessions. Rats were then allowed a week in their home cages before being returned to the operant chamber with access to EtOH and water (relapse). Thirty minutes before the PSR and relapse test sessions, rats received 0, 10, or 20 mg/kg SB-334867.

Results: Responses on the EtOH lever during the first PSR test session were ∼70 presses/session (3-fold higher than baseline); SB-334867 did not alter responses on the EtOH lever. Under relapse conditions, P rats increased responding on the EtOH lever from 250 (at baseline) to 350 responses/session; both doses of SD-334867 prevented this increase.

Conclusions: The results of this study suggest that activation of orexin-1 receptors is not involved in intrinsically initiated EtOH seeking, but may regulate the consummatory behavior of EtOH consumption.

From the Department of Psychiatry (RD, SRH, BG, RLB, WJM, ZAR), Institute of Psychiatric Research, Indiana University School of Medicine, Indiana University-Purdue University at Indianapolis, Indianapolis, IN; and Neuroscience Discovery Research (DLM), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN.

Received for publication October 1, 2008; accepted August 21, 2009.

Send correspondence and reprint requests to Dr Zachary A. Rodd, Indiana University School of Medicine, Institute of Psychiatric Research, 791 Union Drive, Indianapolis, IN 46202-4887. e-mail:

Supported by AA07611, AA10717, AA10021, AA07462, and Eli Lilly & Co.

© 2010 American Society of Addiction Medicine