University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Faculty Publications, Department of Psychology Psychology, Department of July 2007 Nicotine as a Conditioned Stimulus: Impact of Attention-Deficit/ Hyperactivity Disorder Medications Carmela M. Reichel University of Nebraska-Lincoln Jessica D. Linkugel University of Nebraska-Lincoln, [email protected] Rick A. Bevins University of Nebraska-Lincoln, [email protected] Follow this and additional works at: https://digitalcommons.unl.edu/psychfacpub Part of the Psychiatry and Psychology Commons Reichel, Carmela M.; Linkugel, Jessica D.; and Bevins, Rick A., "Nicotine as a Conditioned Stimulus: Impact of Attention-Deficit/Hyperactivity Disorder Medications" (2007). Faculty Publications, Department of Psychology. 292. https://digitalcommons.unl.edu/psychfacpub/292 This Article is brought to you for free and open access by the Psychology, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Faculty Publications, Department of Psychology by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Published in Experimental and Clinical Psychopharmacology, 15:5 (2007), pp. 501–509; doi: 10.1037/1064-1297.15.5.501 Copyright © 2007 American Psychological Association. Used by permission. “This article may not exactly replicate the final version published in the APA journal. It is not the copy of record.” http://www.apa.org/journals/pha/ Submitted June 11, 2007; revised July 19, 2007; accepted July 24, 2007. Nicotine as a Conditioned Stimulus: Impact of Attention-Deficit/Hyperactivity Disorder Medications Carmela M. Reichel, Jessica D. Linkugel, and Rick A. Bevins Department of Psychology, University of Nebraska–Lincoln Abstract: People diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk to start smoking and have greater difficulty quitting. Nicotine, one of the principal addictive components of tobacco smoke, functioned as a conditioned stimu- lus (CS) for intermittent sucrose delivery in a Pavlovian drug discrimination task with rats. This study compared the ability of com- monly prescribed ADHD medications (i.e., methylphenidate, atomoxetine, and bupropion) and additional dopamine reuptake inhib- itors (i.e., cocaine and GBR 12909) to substitute for the CS effects of nicotine. Atomoxetine was also used to antagonize these CS effects. Rats acquired the discrimination as evidenced by increased dipper entries in nicotine (0.2 mg base/kg) sessions as compared with saline sessions. Nicotine generalization was dose dependent. Bupropion (10 and 20 mg/kg), methylphenidate (10 mg/kg), and cocaine (5 and 10 mg/kg) partially substituted for the 0.2 mg/kg nicotine CS. Atomoxetine did not substitute for the nicotine CS; however, atomoxetine (1 to 10 mg/kg) partially blocked nicotine’s CS effects. These results suggest that atomoxetine, bupropion, and/or methylphenidate may be effective treatments for people diagnosed with ADHD and addicted to nicotine. Keywords: dopamine, drug discrimination, interoceptive Pavlovian conditioning, nicotinic acetylcholine receptors, norepinephrine Nicotine is the primary psychoactive and addictive com- pathways (Ascher et al., 1995; Bymaster et al., 2002; Kuczen- ponent of tobacco smoke. It is interesting to note that higher ski & Segal, 1997; Nomikos, Damsma, Wenkstern, & Fibiger, incidences of tobacco dependence and difficulty quitting 1992). Bupropion has lower affinity for the dopamine trans- are reported in clinical populations (Morris, Giese, Turn- porter than methylphenidate and also blocks norepineph- bull, Dickinson, & Johnson-Nagel, 2006; Williams & Ziedo- rine reuptake (Ascher et al., 1995; Katz, Izenwasser, & Terry, nis, 2004). For example, tobacco dependence commonly co- 2000). Atomoxetine, on the other hand, acts primarily on the occurs in schizophrenic populations (de Leon & Diaz, 2005) noradrenergic system by blocking the reuptake of synaptic and is highly correlated with mood disorders (Glassman et norepinephrine (Bymaster et al., 2002). Drugs targeting the al., 1990; Pomerleau, Marks, & Pomerleau, 2000). Recent re- noradrenergic system may benefit patients with ADHD who ports show that people diagnosed with attention-deficit/hyper- are also smokers given that atomoxetine has impacted nico- activity disorder (ADHD) are twice as likely to become smok- tine-induced responding in prior research. Specifically, Gould, ers than their peers (Milberger, Biederman, Faraone, Chen, & Rukstalis, and Lewis (2005) demonstrated that an acute ad- Jones, 1997; A. S. Potter & Newhouse, 2004) and show more ministration of nicotine (0.125 mg/kg) or atomoxetine (2 mg/ severe withdrawal symptoms when trying to quit tobacco use kg) enhanced prepulse inhibition of the acoustic startle re- (Pomerleau et al., 2003). Thus, the abuse liability of nicotine sponse in mice. However, this enhancement was blocked appears exacerbated in ADHD patients. Therefore, pharmaco- when atomoxetine was administered before nicotine, probably therapies simultaneously targeting ADHD symptoms and nic- owing to overactivation of the noradrenergic system (Gould et otine addiction may have some treatment utility for this clini- al., 2005). Atomoxetine also alleviates attention deficits asso- cal subpopulation. ciated with nicotine withdrawal. For example, mice undergo- Three drugs commonly prescribed to treat ADHD are meth- ing nicotine withdrawal show impaired contextual fear condi- ylphenidate, bupropion, and atomoxetine (Ritalin, Wellbutrin, tioning in comparison to mice in a control condition (Davis & and Strattera, respectively). Of these drugs, bupropion and Gould, 2007; Davis, James, Siegel, & Gould, 2005). This im- methylphenidate increase dopamine release in brain reward pairment was reversed by an acute injection of atomoxetine (Davis & Gould, 2007). We thank Joyce Besheer for her thoughtful comments on an earlier ver- sion of this report. This research and Rick A. Bevins were partially supported Current theories of tobacco abuse attribute associative by U.S. Public Health Service Grant DA018114. All MED-PC programs used learning processes as having a prominent role in the acquisi- in the present article are available on request. tion, maintenance, and/or relapse of drug use and abuse (e.g., Corresponding author: Rick A. Bevins, Department of Psychology, 238 Bevins & Palmatier, 2004; Di Chiara, 1999; Geier, Mucha, Burnett Hall, University of Nebraska–Lincoln, Lincoln, NE 68588-0308; email: [email protected]. & Pauli, 2000; Lazev, Herzog, & Brandon, 1999; Pritchard, 501 502 REICHEL, LINKUGEL, & BEVINS IN EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY, 15 (2007) Robinson, Guy, Davis, & Stiles, 1996; Rose & Levin, 1991). vided in the home cage. Food access was restricted such that In the case of nicotine conditioning, environmental cues (con- rats’ body weights were maintained at 85% of their free-feed- ditioned stimulus, CS) presented in close temporal proxim- ing weight. Approximately every 30 days, this target weight ity with the physiological effects of the drug (unconditioned was increased by 2 g. All sessions were conducted during the stimulus, US) come to evoke behavioral and cognitive re- light portion of a 12-hr light–dark cycle. Experimental proto- sponses even in a non–drug state. From this framework, the cols were approved by the University of Nebraska—Lincoln interoceptive effects of nicotine are functioning as a US. In- Institutional Animal Care and Use Committee and followed deed, this framework is the most commonly used to study the the Guide for the Care and Use of Laboratory Animals (Na- potential conditioning processes contributing to nicotine use tional Research Council, 1996). (see Bevins & Palmatier, 2004, for a review). Research from our laboratory and others has extended this conceptualization Apparatus to include nicotine as an interoceptive CS (Besheer, Palma- Eight standard conditioning chambers (Med Associates, tier, Metschke, & Bevins, 2004; Bevins, Penrod, & Reichel, Georgia, VT) were used in this study. Each chamber was en- 2007; Clements, Glautier, Stolerman, White, & Taylor, 1996; closed in a light- and sound-attenuating polyvinyl chloride cu- Murray & Bevins, 2007; Troisi, 2006; Wilkinson et al., 2006). bicle fitted with a fan to provide airflow and mask noise. The In our research, to train nicotine as a CS, rats had intermit- conditioning chambers measured 30.5 × 24.1 × 21 cm (l × w × tent access to sucrose on nicotine sessions; on intermixed sa- h). The sidewalls were made of aluminum; the ceiling, front, line sessions no sucrose was present. Conditioned responding and back walls were clear polycarbonate. Each chamber con- to the nicotine CS was evidenced by more head entries into tained a recessed dipper receptacle (5.2 × 5.2 × 3.8 cm; l × the dipper receptacle before the first sucrose delivery on nico- w × d) in one of the aluminum sidewalls. When the dipper tine sessions (often termed goal tracking; Boakes, 1977; Far- arm was raised, it allowed access to 0.1 ml of 26% sucrose so- well & Ayres, 1979) than in a comparable time period on sa- lution (wt/vol) in the receptacle. An infrared emitter–detector line sessions (Besheer et al., 2004; Bevins et al., 2007; Murray unit located 1.2 cm inside the receptacle and 3 cm from the & Bevins, 2007; Wilkinson et al., 2006). floor recorded head entries. A second infrared emitter–detec- To date, bupropion is the only drug approved for the treat- tor unit bisected the chamber 14.5