Psychopharmacology (2002) 160:371–380 DOI 10.1007/s00213-001-0994-x

O R I G I N A L I N V E S T I G AT I O N

J.D. Salamone · M.N. Arizzi · M.D. Sandoval K.M. Cervone · J.E. Aberman

Dopamine antagonists alter response allocation but do not suppress appetite for food in rats: contrast between the effects of SKF 83566, raclopride, and fenfluramine on a concurrent choice task Received: 1 June 2001 / Accepted: 1 December 2001 / Published online: 14 February 2002 © Springer-Verlag 2002

Abstract Rationale: Dopamine is important for enabling organisms to overcome work-related response costs. One way of investigating this function has been with concurrent choice procedures using food reinforcement. In the present study, rats were given a choice between pressing a lever for preferred Bioserve pellets, or approaching and consuming a less-preferred laboratory chow that was concurrently available. In previous work with this task, dopamine antagonists and accumbens dopamine depletions decreased lever pressing but increased chow consumption. Objective: The present study assessed three drugs (two dopamine antagonists and one appetite suppressant) using the lever pressing/chow feeding task. Results: Under baseline conditions, rats pressed the lever at high rates (1,300–1,500 responses) to obtain the preferred food, and little of the laboratory chow was eaten (1–2 g). Selective D1 and D2 antagonists (SKF 83566 and raclopride) reduced fixed ratio 5 lever pressing, but substantially increased chow consumption. In contrast, the serotonergic appetite suppressant fenfluramine reduced both lever pressing and chow consumption. With the dopamine antagonists, lever pressing and chow consumption were inversely correlated across treatments, while these two measures were unrelated in the fenfluramine experiment. Conclusions: Dopamine antagonists and accumbens dopamine depletions do not simply reduce appetite. Rats with accumbens dopamine depletions, or rats treated with low doses of selective or non-selective dopamine antagonists, remain directed toward the acquisition and consumption of food. These results demonstrate that fundamental aspects of food reinforcement are left intact after treatment with low doses of dopamine antagonists.

J.D. Salamone (✉) · M.N. Arizzi · M.D. Sandoval · K.M. Cervone J.E. Aberman Department of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA e-mail: [email protected] Tel.: +1-860-4864302

Keywords Operant · Instrumental · Behavior · Reinforcement · Motivation · Dopamine · Behavioral economics · Reward

Introduction For several decades, it has been suggested that dopamine (DA), especially in nucleus accumbens, mediates the primary reinforcing characteristics of natural stimuli such as food (Wise et al. 1978a, b; Wise 1982, 1985; Wise and Colle 1984; Hoebel 1988; Smith 1995; Wang et al. 2001). Advocates of the DA/reward hypothesis have emphasized that low-to-moderate doses of DA antagonists impair instrumental behaviors reinforced by food, and have attributed these effects to actions on food reward, motivation, or appetite (Wise et al. 1978a, b; Hoebel 1988; Smith 1995; Cheeta et al. 1995). More recently, it has been suggested that forebrain DA mediates incentive salience (i.e., “wanting”) for food, which includes components of appetite and aspects of food attraction and intake (Berridge and Robinson 1998; Berridge 2000; Wyvell and Berridge 2001). Nevertheless, it has not been conclusively demonstrated that DA systems in general, or accumbens DA in particular, directly mediate primary food reinforcement or motivation. Systemic and intraaccumbens injections of DA antagonists have been shown to suppress sucrose intake, and it has been claimed that this provides “proof” for the reward hypothesis of DA function (see Table 4 and related discussion in Smith 1995). Yet numerous studies have shown that the impairments in sucrose intake that result from DA antagonism are accompanied by deficits in oral motor functions such as lick efficiency, lick duration, lick force, lap volume, and tongue extension (Jones and Mogenson 1979; Gramling and Fowler 1985; Fowler and Mortell 1992; Das and Fowler 1996). The effects of DA antagonists on sucrose drinking have been interpreted as reflecting a diminished effort for obtaining the sucrose (Hsiao and Chen 1995), and as a lack of sensorimotor responsiveness to a gustatory stimulus (Muscat and

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Willner 1989). Although feeding behavior is suppressed by higher doses of DA antagonists, it is not at all clear that this effect results from a loss of appetite. In a recent study, the feeding impairments and locomotor suppression produced by flupenthixol showed strikingly similar patterns (Pitts and Horvitz 2000). The feeding suppression produced by high doses of DA antagonists is generally characterized by a substantial reduction in feeding efficiency (Blundell 1987; Salamone et al. 1990; Clifton et al. 1991). The alterations in parameters of feeding produced by haloperidol differed substantially from those produced by prefeeding to reduce food motivation (Salamone et al. 1990), and DA antagonists generally produce different patterns of feeding impairments than appetite suppressants such as fenfluramine (Blundell 1987; Clifton et al. 1991). If low doses of DA antagonists reduce food-reinforced lever pressing by producing a broad or general reduction in appetite or food motivation, then one would expect to see reductions of food intake that occur in the same dose range as the suppression of lever pressing. Yet, it has been demonstrated several times that DA antagonists suppress food-reinforced lever pressing at doses lower than those that suppress food intake or simple instrumental approach responses for food (Rolls et al. 1974; Fibiger et al. 1976; Salamone 1986; Rusk and Cooper 1994). A similar pattern has been observed for water-reinforced behavior as well (Ljungberg 1987, 1988, 1990; Horvitz et al. 1993). More recently, Ikemoto and Panksepp (1996) demonstrated that doses of flupenthixol up to 25 µg, injected directly into nucleus accumbens, impaired run speed in a sucrose-reinforced runway task, but did not impair sucrose consumption. The dissociable effects of DA antagonists on lever pressing and food intake have been demonstrated clearly in studies that offer animals concurrent access to both activities. A number of studies have employed a concurrent choice task in which rats can lever press to receive a more preferred food (Bioserve pellets), or can approach and consume a less preferred food (laboratory chow) that is concurrently available (Salamone et al. 1991, 1996; Cousins et al. 1993, 1994; Cousins and Salamone 1994; Sokolowski and Salamone 1998; Nowend et al. 2001). Typically, rats pressing on a continuous or fixed ratio 5 (FR5) schedule under non-drug conditions will get most of their food by lever pressing, and they consume only small amounts of chow. With rats performing on this task, prefeeding to reduce food motivation suppressed both lever pressing and chow consumption (Salamone et al. 1991). In contrast, low-to-moderate doses of DA antagonists, injected systemically or directly into the accumbens, produced a very different pattern of effects. The DA antagonists cis-flupenthixol, haloperidol, and SCH 23390 all decreased lever pressing for food but substantially increased consumption of the concurrently available chow (Salamone et al. 1991, 1996; Cousins et al. 1994; Koch et al. 2000). The low dose of haloperidol that produced this shift in behavior (0.1 mg/kg) did not alter consumption of the preferred or non-preferred

foods, nor did DA antagonism change food preferences in free-feeding choice tests (Salamone et al. 1991). Striatal DA depletions that produced severe motor impairments did not shift behavior from lever pressing to chow consumption, and instead only decreased both types of behavior (Cousins et al. 1993). Decreases in lever pressing and increases in chow intake on the concurrent choice task did result from accumbens DA depletions, as well as from intra-accumbens injections of DA antagonists (Salamone et al. 1991; Cousins et al. 1993; Cousins and Salamone 1994; Sokolowski and Salamone 1998; Koch et al. 2000; Nowend et al. 2001). The present experiments were designed to study the effects of systemic injections of highly selective DA antagonists, and to compare these effects with the actions of fenfluramine, a drug that has been shown reliably to suppress food intake. Previous work has shown that the D1 antagonist SCH 23390 decreases lever pressing and increases chow intake on the concurrent choice task (Cousins et al. 1994; Nowend et al. 2001). In order to broaden the pharmacological research in this area by investigating the effects of a different D1 antagonist, the first experiment studied the effects of the selective D1 antagonist, SKF 83566. This drug has been used in a variety of biochemical and physiological studies to characterize the effects of D1 blockade (O’Boyle et al. 1989; VieraCoelho and Soares-da-Silva 2000). SKF 83566 suppresses motor activity and induces catalepsy (Meyer et al. 1992, 1993; Fritts et al. 1997, 1998), and reduces scheduleinduced polydipsia (Mittleman et al. 1994), but this drug has not been well characterized in terms of its effect upon operant behavior. Haloperidol is a D2 antagonist that has been used in previous studies in this area (Salamone et al. 1991, 1996), but the effects of systemic injections of raclopride, which is a highly selective D2 antagonist (Andersen 1988), have not been evaluated using the concurrent choice task. Therefore, the effects of the highly selective D2 antagonist raclopride were assessed in the second experiment. Previous work with this task has demonstrated that both lever pressing and feeding were reduced by prefeeding to reduce food motivation, and by amphetamine (Salamone et al. 1991; Cousins et al. 1994). Although amphetamine has appetite suppressant effects, this drug also is a powerful motor stimulant, so the specific nature of the actions of amphetamine on the concurrent choice task are unclear. For these reasons, the third experiment studied the effects of the serotonergic appetite suppressant fenfluramine. This drug has been used for several decades both clinically and experimentally to suppress food intake, and has been described variously as an anorectic agent, an appetite suppressant, or a drug that induces satiety (Blundel 1987; Francis et al. 1997; Halford et al. 1998; Clifton et al. 2000; Voigt et al. 2000; Foltin 2001). It was hypothesized that the two highly selective DA antagonists would decrease lever pressing and increase chow consumption. In contrast, it was expected that the appetite suppressant fenfluramine would reduce lever pressing, but that this effect would not be accompanied by an increase in chow intake.

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Materials and methods Subjects A total of 36 adult male Sprague-Dawley rats (Harlan SpragueDawley, Indianapolis, Ind., USA) were used in this experiment. Rats were housed in a colony maintained at a constant temperature (23°C) with a 12-h light/dark cycle (lights on at 0600, 0700, or 0800 hours depending on the colony room). All rats weighed between 290 and 330 g at the beginning of the study. Prior to the lever pressing sessions, animals were food deprived to 85% of their free feeding body weight, and were maintained on this schedule throughout the experiments. Water was available ad libitum in the home cages at all times. Animal protocols were approved by the institutional animal care committee, and the methods were in accordance with the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, National Academy Press (1996). Behavioral procedures Testing sessions were conducted in operant conditioning chambers (28×23×23 cm; Med Associates). Animals were trained to lever press beginning with 1 day of magazine training followed by training on a continuous reinforcement schedule for an additional 4 days (30-min sessions, 45 mg reinforcement pellets; Bioserve, Frenchtown, N.J., USA). Rats were then changed to an FR5 schedule (30-min sessions, 5 days per week), and were trained on the FR5 schedule alone for 4 weeks. During the 5th week, rats were trained on the concurrent FR5/chow feeding procedure. For this procedure, weighed amounts of laboratory chow (typically 15–20 g, three large pieces) were concurrently available on the floor of the operant conditioning chamber during the 30-min FR5 sessions. At the end of the session, rats were immediately removed from the chamber. Food intake was determined by weighing the remaining food, including spillage, while lever pressing was recorded by a computer program.

Statistical analyses In each drug study, the total number of lever presses and gram quantity of chow intake were analyzed with repeated measures analysis of variance (ANOVA). Non-orthogonal planned comparisons using the overall error term were used to identify which doses were significantly different from vehicle (Keppel 1982). In addition, correlational analyses were used to measure the relation between lever pressing and chow consumption for each drug study, with the data collapsed across injection treatments within each study.

Results Effects of SKF 83566 The effects of injections of the D1 antagonist SKF 83566 on lever pressing and chow consumption are illustrated in Fig. 1. Repeated measures ANOVA revealed a significant effect on lever pressing [F(3,21)=119.6, P