Research ReportsEffects of remifentanil/histamine mixtures in rats responding under a choice procedureMinervini, Vanessaa; Tye, Cooper B.a; Ghodrati, Sabaa; France, Charles P.a,,bAuthor Information aDepartments of Pharmacology bDepartments of Psychiatry, The Addiction Research, Treatment and Training Center of Excellence, University of Texas Health Science Center at San Antonio, Texas, USA Received 20 January 2020 Accepted as revised 6 October 2020 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.behaviouralpharm.com. Correspondence to Charles P. France, PhD, Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive (Mail Code 7764), San Antonio, TX 78229, USA, E-mail: [email protected] Behavioural Pharmacology: June 2021 - Volume 32 - Issue 4 - p 278-285 doi: 10.1097/FBP.0000000000000610 Buy SDC Metrics Abstract Intravenous drug self-administration remains the ‘gold standard’ for assessing abuse liability. Failure of a drug to maintain self-administration might indicate the absence of positive reinforcing effects but might also indicate the presence of aversive effects. Sensitivity to aversive and punishing effects of drugs (as well as nondrug stimuli) might collectively determine the likelihood of use, abuse and relapse. Using a choice procedure, this study compared the effects of remifentanil (mu opioid receptor agonist; 0.001–0.01 mg/kg/infusion) and histamine (H1-4 receptor agonist; 0.32–3.2 mg/kg/infusion), alone and in mixtures, to test the hypothesis that remifentanil/histamine mixtures are less reinforcing compared with remifentanil alone and less punishing compared with histamine alone. Male Sprague–Dawley rats (n = 10) chose between an intravenous infusion + a pellet and a pellet alone. Rats were indifferent to saline, chose remifentanil + a pellet over a pellet alone, and chose a pellet alone over histamine + a pellet. The effects of remifentanil/histamine mixtures generally were different from the constituent doses of histamine alone but not from remifentanil alone. A mixture containing 3.2 mg/kg/infusion histamine and either 0.001 or 0.0032 mg/kg/infusion remifentanil was not different from saline but was different from the effects of the constituent dose, insofar as choice increased compared with 3.2 mg/kg/infusion histamine alone and decreased compared with 0.001 or 0.0032 mg/kg/infusion remifentanil alone. Reinforcing doses of remifentanil combined with punishing doses of histamine can yield mixtures that are neither preferred nor avoided, offering ‘proof-of-principle’ for using drug mixtures to avoid adverse effects of opioid receptor agonists. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.