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. Author manuscript; available in PMC: 2010 Feb 9.
Published in final edited form as: Appetite. 2009 Jul 25;53(3):422. doi: 10.1016/j.appet.2009.07.018

Dopamine/adenosine interactions involved in effort-related aspects of food motivation

John D Salamone a,*, Merce Correa a,b
PMCID: PMC2817982  NIHMSID: NIHMS173095  PMID: 19635514

Abstract

Nucleus accumbens dopamine (DA) is involved in effort-related aspects of food motivation. Accumbens DA depletions reduce the tendency of rats to work for food, and alter effort-related choice, but leave other aspects of food motivation and appetite intact. DA and adenosine receptors interact to regulate effort-related processes. Adenosine A2A antagonists can reverse the effects of DA D2 antagonists on effort-related choice, and intra-accumbens injections of a adenosine A2A agonist produce effects that are similar to those produced by accumbens DA depletion or antagonism. These studies have implications for understanding the neurochemical interactions that underlie activational aspects of motivation.

Keywords: Operant, Reinforcement, Motivation, Behavioral economics, Reward, Decision making, Activation

Dopaminergic involvement in activational aspects of food motivation

Food motivation is a complex process, comprising several interacting but dissociable components. For several decades, research and theory in motivation has emphasized that there are both directional and activational aspects of motivation (Salamone, 1988). Directional aspects refer to the observation of that behavior is directed towards or away from particular motivational stimuli. In addition, it also is evident that motivated behavior can be characterized by persistence, vigor and high levels of work output. These activational aspects of motivation are adaptive because they enable organisms to overcome obstacles or work-related response costs that separate them from significant stimuli such as food (Salamone & Correa, 2002; Salamone, Correa, Farrar, & Mingote, 2007). Animals can forage in the wild, covering large areas of space and investing considerable amounts of time, in order to gain access to food or other primary motivational stimuli. In the laboratory, animals can perform in mazes, climb barriers, or vigorously press levers, to receive food reinforcement.

One of the brain systems that has been most vigorously studied in relation to aspects of motivation is the mesolimbic dopamine (DA) system. Though it is most commonly linked to drug reinforcement, nucleus accumbens DA also has been implicated in features of food motivation. In fact, there is little doubt that nucleus accumbens DA is involved in some aspects of food motivation. The difficult question is—which aspects? Reports indicating that nucleus accumbens DA release can be increased during presentation of food or food-related stimuli do not identify the specific aspects of motivation or learning in which DA is participating. Although it is generally recognized that whole forebrain DA depletions can produce aphagia (i.e., lack of eating), this effect has been conclusively linked to depletions of DA in the lateral or ventrolateral caudate/putamen, but not the nucleus accumbens (Dunnett & Iversen, 1982; Salamone, Kurth, McCullough, Sokolowski, & Cousins, 1993). Accumbens DA depletions do not substantially impair appetite for food, or produce a general disruption of all aspects of primary food motivation (Koob, Riley, Smith, & Robbins, 1978; Kelley, Baldo, Pratt, and Will, 2005; Salamone et al., 1993). Accumbens DA depletions did not reduce food intake or feeding rate, nor did they impair food handling, although similar depletions of ventrolateral neostriatum affected these parameters (Salamone et al., 1993). Based upon their observations that injections of DA D1 or D2 family antagonists into either core or shell subregions of nucleus accumbens impaired locomotion and rearing, but did not suppress food intake, Baldo, Sadeghian, Basso, and Kelley (2002) emphasized that DA receptor blockade “did not abolish the primary motivation to eat” (p. 176).

Although nucleus accumbens DA has not been strongly implicated in food consumption or appetite, considerable evidence indicates that accumbens DA is involved in behavioral activation, and, more specifically, in effort-related aspects of food motivation. Nucleus accumbens DA depletions have been shown to reduce spontaneous and novelty-induced locomotor activity and rearing, as well as stimulant-induced activity (Correa, Carlson, Wisniecki, & Salamone, 2002; Cousins, Sokolowski, & Salamone, 1993; Koob et al., 1978). Activities such as excessive drinking, wheel-running or locomotor activity that are induced by scheduled presentation of food pellets were reduced by accumbens DA depletions (McCullough & Salamone, 1992; Robbins & Koob, 1980). In addition, the effects of accumbens DA depletions on food-reinforced behavior vary greatly depending upon the specific task requirements of the schedule of food reinforcement. If the primary effects of accumbens DA depletions were related to a reduction in appetite for food, then the fixed ratio 1 (FR1) schedule should be highly sensitive to DA depletion. In fact, this schedule is one of the tasks that is least sensitive to the effects of compromised DA transmission in nucleus accumbens (Aberman & Salamone, 1999; McCullough, Cousins, & Salamone, 1993; Salamone, Kurth, McCullough, & Sokolowski, 1995). If time intervals without reinforcement were the most significant factor yielding sensitivity to the effects of impaired accumbens DA transmission, then one would expect that variable interval schedules would be easily disrupted by the effects of accumbens DA depletions or antagonism. Yet, these schedules are among the least sensitive (Correa et al., 2002; Mingote, Weber, Ishiwari, Correa, & Salamone, 2005; Sokolowski & Salamone, 1998). Several years of research has demonstrated that a critical factor yielding sensitivity to the effects of accumbens DA depletions on food reinforced behavior is the size of the ratio requirement; as ratio requirements get higher, rats become more sensitive to the response suppressing effects of accumbens DA depletions (Aberman & Salamone, 1999; Correa et al., 2002; Ishiwari, Weber, Mingote, Correa, & Salamone, 2004; Mingote et al., 2005). This pattern of results suggests that accumbens DA depletions leave fundamental aspects of appetite or primary food motivation intact, but reduce the tendency of the animals to work for food reinforcement.

Accumbens DA and effort-related choice behavior

Nucleus accumbens DA also is involved in effort-related choice behavior. In a complex environment there may be several sources of food available, which can vary in terms of quantity or quality. Furthermore, there can be multiple paths for obtaining access to each food location, and each path can require different responses that vary in terms of time, work, and other parameters. In order to generate adaptive behavior, animals must select between these alternatives, making effort-related decisions and allocating resources based upon cost/benefit analyses. Several behavioral paradigms have been developed that assess effort-based choice behavior. An operant concurrent choice task has been used that offers rats a choice between lever pressing to obtain a preferred food (high carbohydrate pellets), vs. approaching and consuming a less preferred food (lab chow) that is concurrently available. Under non-drug conditions, rats pressing on an FR5 schedule typically get most of their food by lever pressing, and eat only small amounts of chow. Pre-feeding to reduce food motivation was shown to suppress both lever pressing and chow intake (Salamone et al., 1991). In contrast, the DA antagonists cis-flupenthixol, haloperidol, raclopride, eticlopride, ecopipam, SCH 23390, and SKF83566 all decreased lever pressing for food but substantially increased intake of the concurrently available chow (Salamone et al., 1991, 2007; Salamone, Arizzi, Sandoval, Cervone, & Aberman, 2002; Sink, Vemuri, Olszewska, Makriyannis, & Salamone, 2008; Worden et al., 2009). The low dose of haloperidol (0.1 mg/kg) that produced this effect did not alter food intake or preference in free-feeding choice tests (Salamone et al., 1991). Appetite suppressants such as fenfluramine and cannabinoid CB1 antagonists showed a very different pattern of effects from DA antagonists (Salamone et al., 2002; Sink et al., 2008), and did not increase chow intake at doses that suppress lever pressing. Together with the findings reviewed above, these results demonstrate that interference with DA transmission does not simply reduce appetite for food.

Nucleus accumbens, and not neostriatum, is the DA terminal region s most closely associated with these effects. Ventrolateral striatal DA depletions produced severe motor impairments that decreased both types of behavior (Cousins et al., 1993). Decreases in lever pressing and increases in chow intake result from accumbens DA depletions, as well as from intra-accumbens injections of D1 or D2 antagonists (Cousins & Salamone, 1994; Cousins et al., 1993; Koch, Schmid, & Schnitzler, 2000; Nowend, Arizzi, Carlson, & Salamone, 2001; Salamone et al., 1991; Sokolowski & Salamone, 1998). The shift from lever pressing to chow intake on this task has been shown to occur in rats if injections of a D1 or D2 family antagonist are given into various core or shell subregions of the accumbens (Nowend et al., 2001; Salamone et al., 1991). Thus, although lever pressing is decreased by accumbens DA antagonism or depletions, the rats show a compensatory reallocation of behavior and select a new path to an alternative food source.

A T-maze procedure also was developed to assess the effects of accumbens DA depletions on effort-related choice (Salamone, Cousins, & Bucher, 1994). The two choice arms of the maze can have different reinforcement densities (e.g. 4 food pellets vs. 2 food pellets, or 4 vs. 0), and under some conditions a 44 cm barrier can be placed in the arm with the higher density of food reinforcement to vary task difficulty. When no barrier is present in the arm with the high reinforcement density, rats mostly choose that arm, and neither haloperidol nor accumbens DA depletion alters their response choice (Salamone et al., 1994). When the arm with the barrier contained 4 pellets, but the other arm contained no pellets, DA depleted rats were relatively slow, but still chose the high density arm, climbed the barrier, and consumed the pellets (Cousins, Atherton, Turner, & Salamone, 1996). Yet, accumbens DA depletions dramatically altered choice when the high density arm (4 pellets) had the barrier in place, and the arm without the barrier contained an alternative food source (2 pellets). In this case, DA depleted rats showed decreased choice for the high density arm that contained the barrier, and increased choice for the arm with less food that did not have a barrier (Cousins et al., 1996; Salamone et al., 1994). These studies, together with the results of the operant concurrent choice studies, indicate that accumbens DA depletions cause animals to reallocate their instrumental response selection based upon the response requirements of the task (Salamone & Correa, 2002; Salamone et al., 2007).

In summary, rats with accumbens DA depletion or antagonism remain directed towards approaching and consuming food. Nevertheless, they have a reduced tendency to work for food, and their choice behavior is altered such that they become biased towards obtaining food through responses that have lower work-related costs. Thus, rats with impaired accumbens DA transmission switch from lever pressing for preferred food pellets to approaching and consuming the less preferred chow, and they switch from climbing the barrier to obtain the higher density of food reinforcement towards the other arm of the maze, which has less food that can be obtained with a lower degree of effort.

DA and adenosine interact in the Regulation of behavioral activation and effort

As discussed above, substantial evidence indicates that DA antagonists and accumbens DA depletions are altering behavioral activation, instrumental response output, response allocation, effort-related processes (Floresco, Tse, & Ghods-Sharifi, 2008; Phillips, Walton, & Jhou, 2007; Robbins & Everitt, 2007; Salamone & Correa, 2002; Salamone et al., 1991, 2007). Of course, DA does not participate in effort-related processes in isolation, and for that reason it is important to review how other brain areas and neurotransmitters interact with dopaminergic mechanisms. Several studies have shown that basolateral amygdala, anterior cingulate cortex, and ventral pallidum also are involved (Farrar et al., 2008; Floresco & Ghods-Sharifi, 2007; Hauber & Sommer, in press; Mingote et al., 2008; Walton, Kennerley, Bannerman, Phillips, & Rushworth, 2006). Much recent work also has focused upon interactions between DA and adenosine.

Non-selective adenosine antagonists, such as caffeine and other methylxanthines, act as minor stimulants (Ferré et al., 2008). Within the last few years, there has been a rapid expansion of research on adenosine receptor pharmacology and neurochemistry, with particular emphasis on the A2A receptor subtype. Striatal areas, including caudate/putamen (neostriatum) and also nucleus accumbens, are very rich in adenosine A2A receptors (Fink et al., 1992). There is a functional interaction between striatal DA D2 and adenosine A2A receptors (Ferré, 1997; Fink et al., 1992), which frequently has been studied in regard to neostriatal motor functions that are related to parkinsonism (Correa et al., 2004; Ferré et al., 2001; Hauber, Neuscheler, Nagel, & Muller, 2001; Morelli & Pinna, 2002; Salamone et al., 2008). Researchers also have characterized aspects of adenosine A2A receptor function related to anxiety (Correa & Font, 2008), cognitive processes (Takahashi, Pamplona, & Prediger, 2008) and motivation (Mingote et al., 2008; Salamone et al., 2007). Indeed, several recent studies have focused upon the motivational significance of adenosine A2A receptors, and the interactions between adenosine and DA receptors, in relation to aspects of behavioral activation and effort-related processes (Farrar et al., 2007; Font et al., 2008; Mingote et al., 2008; Mott et al., 2009; Worden et al., 2009).

Intra-accumbens injections of the adenosine A2A agonist CGS 21680 produce effects that resemble those of accumbens DA depletions or antagonism. CGS 21680 reduced locomotor activity when injected directly into nucleus accumbens (Barraco, Martens, Parizon, & Normile, 1993). A more recent paper has demonstrated that local injection of CGS 21680 into the accumbens reduced responding on a variable interval 60 s schedule with a FR10 requirement attached, but did not impair performance on a conventional variable interval 60 s schedule (Mingote et al., 2008), an effect that had previously been demonstrated to occur with accumbens DA depletions (Mingote et al., 2005). In rats responding on the operant FR5/chow feeding concurrent choice procedure, injections of CGS 21680 into the accumbens decreased lever pressing and increased chow intake (Font et al., 2008), a pattern of effects similar to that produced by accumbens DA depletions and antagonism. Consistent with the observation that an adenosine A2A agonist could produce actions similar to those resulting from DA depletion, it also has been reported that adenosine A2A receptor antagonists can reverse the effects of DA D2 antagonists on both the operant concurrent choice task (Farrar et al., 2007; Worden et al., 2009) and the T-maze choice procedure (Mott et al., 2009).

Several lines of evidence indicate that there is a very specific interaction between DA D2 and adenosine A2A receptor subtypes. Although the adenosine A2A receptor antagonists MSX-3 and KW 6002 can attenuate the effects of D2 antagonists such as haloperidol and eticlopride in rats responding on the operant concurrent choice procedure (Farrar et al., 2007; Salamone et al., 2009; Worden et al., 2009), MSX-3 was shown to be relatively ineffective at reducing the effects of the D1 antagonist ecopipam (SCH 39166; Worden et al., 2009). Furthermore, although the non-selective adenosine antagonist caffeine was able to partially reverse the effects of haloperidol on the concurrent choice task, the adenosine A1 receptor selective antagonist DPCPX was ineffective (Salamone et al., 2009). Similar results were obtained with rats responding on the T-maze choice procedure with the barrier being used to provide the effort-related challenge. Although MSX-3 could reverse the attenuation of barrier climbing induced by haloperidol, the A1 antagonist DPCPX was shown to be ineffective (Mott et al., 2009).

This pattern of results indicates that there is a relatively selective interaction between DA D2 and adenosine A2A receptors, and it is possible that this is related to the pattern of cellular localization of adenosine A1 and A2A receptors in striatal areas, including the nucleus accumbens (Ferré, 1997). Adenosine A2A receptors generally are co-localized on striatal and accumbens medium spiny neurons with DA D2 receptors (i.e., enkephalin positive medium spiny neurons), and these receptors converge onto the same signal transduction pathways and show the capacity for forming heteromeric complexes (Ferré, 1997; Fink et al., 1992). Thus, it is reasonable to suggest that adenosine A2A receptor antagonists are so effective in reversing the effort-related actions of D2 antagonists because of direct interactions between DA D2 and adenosine A2A receptors located on the same neurons. In contrast, DA D1 receptors are more likely to be co-localized with adenosine A1 receptors (Ferré, 1997). This pattern of receptor localization could help to explain why it is more difficult for adenosine A1 receptor antagonists to reverse the effects of D2 receptor blockade.

Summary and conclusions

In summary, there is considerable evidence that low doses of DA antagonists, as well as accumbens DA depletions or antagonism, while leaving fundamental aspects of appetite or primary food motivation intact, nevertheless reduce the tendency of animals to work for food reinforcement. Furthermore, adenosine A2A antagonists can attenuate the effort-related behavioral effects of DA D2 antagonists. The findings described above support the hypothesis that DA and adenosine systems in the nucleus accumbens interact in the regulation of instrumental response output and effort-related choice behavior (Farrar et al., 2007; Font et al., 2008; Mingote et al., 2008; Mott et al., 2009; Salamone et al., 2007, 2009; Worden et al., 2009), and they also illustrate the specific nature of the interaction between adenosine A2A and DA D2 receptors. Characterization of the neurochemical mechanisms involved in regulating behavioral activation and effort-based choice behavior can shed light on these important facets of natural motivation for food, and also have implications for understanding pathologies related to behavioral activation and effort (Salamone et al., 2007), such as anergia, psychomotor slowing, and fatigue in depression and other disorders (Demyttenaere, De Fruyt, & Stahl, 2005; Salamone et al., 2007). In addition, it is possible that A2A receptor antagonists could be beneficial for ameliorating the motivational effects of D2 antagonists that are used clinically, and also for treating other energy-related disorders (Salamone et al., 2007).

Acknowledgments

This review summarizes the presentation of J.S. to the Appetitive Behavior Seminar at Columbia University on April 2, 2009. The work was supported by a grant to J.S. from the NIMH (MH078023).

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