Repeated heroin in rats produces locomotor sensitization and enhances appetitive Pavlovian and instrumental learning involving food reward Robert Ranaldi a, ⁎, Jonathan Egan a , Karen Kest a , Matthew Fein b , Andrew R. Delamater b a Department of Psychology, Queens College/City University of New York, Flushing, NY , USA b Department of Psychology, Brooklyn College/City University of New York, Brooklyn, NY, USA abstract article info Article history: Received 17 June 2008 Received in revised form 1 August 2008 Accepted 5 August 2008 Available online 8 August 2008 Keywords: Locomotor sensitization Conditioned reward Conditioned reinforcement Operant conditioning Pavlovian discrimination learning Reversal learning Motivation Reward value Reinforcement Heroin Drug addiction Locomotor activity We tested the hypothesis that sensitization to heroin enhances appetitive motivational processes involving food reward. In Experiment 1, sixteen rats were exposed to positive pairings of a light stimulus and food for 4 consecutive daily sessions. Then, the rats received either saline or heroin (2 mg/kg) injections before placement in activity monitors for 9 consecutive daily sessions. Rats were then tested in operant conditioning chambers where one lever produced the light stimulus previously paired with food and another lever produced a tone stimulus not paired with anything. Heroin produced both significant progressive increases in locomotor activity (sensitization) and significantly enhanced conditioned reinforcement of instrumental lever pressing by the food-associated stimulus. In Experiment 2, thirty-two rats were given Pavlovian discrimination training in a conditioned magazine approach task where one stimulus was associated with food and a second unpaired with food. Rats then received repeated saline or heroin injections as in Experiment 1, before being tested under extinction conditions with the two stimuli without the drug. Chronic heroin had no effect on performance in this test, but it facilitated learning of the reversed discrimination in a subsequent phase. These data suggest that sensitization to heroin enhances appetitive motivational processes involving food reward. © 2008 Elsevier Inc. All rights reserved. Chronic exposure to heroin produces neural and behavioral adapta- tions some of which occur in brain circuits that are important for learning and motivation. This raises the possibility that chronic exposure to heroin – specifically in the form of repeated intermittent doses as is experienced by heroin abusers – may result in changes in other more natural (i.e., non-drug) appetitive motivational processes. Investigating this possibility is important because not only would it provide insight into the changing motivational processes of heroin users but also into how these changes may contribute to the development and maintenance of addiction. The present study is an initial investigation of this possibility. Repeated intermittent exposure to opiates leads to sensitization to at least some of their behavioral effects. Sensitization refers to the progressive augmentation of a behavioral response, such as locomo- tion, to a drug with repeated intermittent exposure to the drug. Sensitized responses have been observed weeks and even months after the final treatment (Vanderschuren and Kalivas, 2000), suggest- ing that it results from long-term changes in neuronal function. Repeated injections of morphine in rats produces sensitization to its locomotor-stimulant effects (Babbini and Davis, 1972) and this sensitized response has been demonstrated to persist for at least 2 weeks after the last treatment (Ranaldi et al., 2000). Sensitization to the behavioral effects of heroin has been studied considerably less than that to morphine. Although sensitization to the locomotor- stimulant effects of heroin has been reported (Pontieri et al., 1997), the effect is not well-characterized. Given that heroin is one of the more abused substances in the opiate class, as well as in all classes of abused drugs in general, it is important to investigate the behavioral effects of heroin specifically. Thus, another aim of this study is to begin to characterize the locomotor sensitization profile to heroin specifically. Sensitization to opiates is associated with neural adaptations in the mesolimbic dopamine (DA) system (Vanderschuren and Kalivas, 2000). In animals treated repeatedly with morphine, a morphine challenge given after a short withdrawal period – a few days after the last treatment – is associated with greater extracellular levels of nucleus accumbens DA than in animals not treated repeatedly with morphine (Kalivas and Duffy, 1987). Functional investigations of the mesolimbic DA system after protracted periods of withdrawal – typically three or more weeks from the last morphine treatment – reveal hypersensitive nerve terminals (Spanagel et al., 1993; Nestby et al., 1997). At the level of the ventral tegmental area (VTA), the site of origin of the mesolimbic DA neurons, an increase in the number of GluR1 receptors is observed (Fitzgerald et al., 1996). Given that GluR1 receptors are located on DA Pharmacology, Biochemistry and Behavior 91 (2009) 351–357 ⁎ Corresponding author. Department of Psychology, Queens College, CUNY, 65-30 Kissena Boulevard, Flushing, NY 11367, USA. Tel.: +1718 997 3553; fax: +1718 997 3257. E-mail address: Robert.Ranaldi@qc.cuny.edu (R. Ranaldi). 0091-3057/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2008.08.006 Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh