Research report
Differential actions of adenosine A1 and A2A antagonists on the effort-related effects of dopamine D2 antagonism

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Abstract

Adenosine and dopamine receptors in striatal areas interact to regulate a number of different functions, including aspects of motor control and motivation. Recent studies indicate that adenosine A2A receptor antagonists can reverse the effects of dopamine (DA) D2 antagonists on instrumental tasks that provide measures of effort-related choice behavior. The present experiments compared the ability of the adenosine A2A antagonist KW6002, the nonselective adenosine antagonist caffeine, and the adenosine A1 receptor selective antagonist DPCPX, to reverse the behavioral effects of the DA D2 antagonist haloperidol. For these studies, a concurrent choice procedure was used in which rats could select between lever pressing on a fixed ratio 5 schedule for a preferred food or approaching and consuming a less preferred lab chow that was concurrently available in the chamber. Under baseline or control conditions, rats show a strong preference for lever pressing, and eat little of the chow; IP injections of 0.1 mg/kg haloperidol significantly reduced lever pressing and substantially increased chow intake. The adenosine A2A antagonist KW6002 (0.125–0.5 mg/kg IP) and the nonselective adenosine antagonist caffeine (5.0–20.0 mg/kg) significantly reversed the effects of haloperidol. However, the adenosine A1 antagonist DPCPX (0.1875–0.75 mg/kg IP) failed to reverse the effects of the D2 antagonist. The rank order of effect sizes in the reversal experiments was KW6002 > caffeine > DPCPX. None of these drugs had any effect on behavior when they were injected in the absence of haloperidol. These results indicate that the ability of an adenosine antagonist to reverse the effort-related effects of a D2 antagonist depends upon the subtype of adenosine receptor being blocked. Together with other recent results, these experiments indicate that there is a specific interaction between DA D2 and adenosine A2A receptors, which could be related to the co-localization of these receptors on the same population of striatal neurons.

Introduction

Several lines of evidence indicate that dopamine (DA) and adenosine systems interact in the brain. Striatal areas such as neostriatum and nucleus accumbens are very rich in adenosine A2A receptors [13], [18], [19], [33], [70], and several papers have reported that there is a functional interaction between striatal DA D2 and adenosine A2A receptors [17], [18], [19], [20], [21], [22], [23], [27], [28], [31]. This interaction frequently has been studied in regard to neostriatal motor functions that are related to parkinsonian symptoms [8], [20], [22], [29], [32], [34], [35], [46], [52], [53], [59], [67], [82]. Researchers also have characterized aspects of adenosine A2A receptor function related to cognitive processes [76] and motivation [26], [44], [50]. In particular, several recent studies have focused upon the functional significance of adenosine A2A receptors, and the interactions between adenosine and DA receptors, in relation to aspects of behavioral activation and effort-related processes [16], [26], [44], [47], [83].

Previous studies have shown that nucleus accumbens DA is a critical component of the brain circuitry involved in behavioral activation and effort-related behavioral processes. Nucleus accumbens DA depletions make rats highly sensitive to ratio requirements in operant schedules [1], [7], [45], [73], and affect response allocation in tasks that measure effort-related choice behavior [58], [61], [62], [63], [66], [68]. Some studies in this area have employed maze tasks to assess effort-related choice [9], [24], [47], [65], while others have used a concurrent fixed ratio 5 (FR5)/chow-feeding procedure [38], [58], [68], [73]. In the latter task, rats have a choice between responding on a FR5 lever-pressing schedule for a highly preferred food (i.e., high carbohydrate operant pellets) or approaching and consuming freely available food (i.e., less preferred rodent laboratory chow). Under baseline or control conditions, rats that are trained to respond on this procedure spend most of their time pressing the lever for the preferred food, and eat very little of the concurrently available chow. Low doses of DA antagonists alter choice behavior such that lever pressing for food is suppressed, but chow intake is substantially increased [12], [38], [58], [68], [72]. Nucleus accumbens is the DA terminal region most closely associated with these effects [10], [11], [38], [49], [68], [73]. The actions of DA antagonists or accumbens DA depletions differ substantially from those produced by motivational manipulations such as pre-feeding [38], and appetite suppressant drugs [12], [58], [72]. These appetite-related manipulations all failed to increase chow intake under conditions that suppressed lever pressing.

Recent papers have reported that intra-accumbens injections of the adenosine A2A agonist CGS 21680 produced effects that resembled those of accumbens DA depletions or antagonism, i.e., they impaired performance of operant schedules that had high ratio requirements [44], and they decreased lever pressing and increased chow intake in rats responding on the concurrent choice procedure [26]. In addition, the adenosine A2A receptor antagonist MSX-3 has been reported to reverse the effects of DA D2 antagonists such as haloperidol and eticlopride on tasks that provide measures of effort-related choice behavior, such as the operant concurrent choice task [16], [83] and the T-maze choice procedure [47]. The present studies were conducted to investigate the role of DA/adenosine A2A receptor interactions in effort-related choice behavior, using the concurrent lever-pressing/chow-feeding procedure. Specifically, these experiments were undertaken to determine if the ability of an adenosine receptor antagonist to reverse the effect of a DA D2 antagonist is dependent upon the particular subtype of adenosine receptor that was being blocked. In the first group of experiments, three drugs were assessed for their ability to reverse the effects of 0.1 mg/kg of the DA D2 antagonist haloperidol: the well-known adenosine A2A antagonist KW6002 (istradefylline; 0.125–0.5 mg/kg IP), the nonselective adenosine antagonist and minor stimulant caffeine (5.0–20.0 mg/kg), and the adenosine A1 antagonist DPCPX (0.1875–0.75 mg/kg IP). The fourth experiment studied the effects of the higher doses of KW6002, caffeine, and DPCPX in the absence of haloperidol. In view of the anatomical data demonstrating colocalization of DA D2 receptors and adenosine A2A receptors in striatum and nucleus accumbens, and the well-documented interactions between these receptors, it was hypothesized that the adenosine A2A antagonist would be more effective at reversing the effects of haloperidol than the A1 selective antagonist.

Section snippets

Animals

A total of 33 adult male Sprague–Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) were used in these experiments. They weighed 295–352 g at the beginning of the experiments, and were deprived to 85% of their free-feeding body weight for initial lever press training, but then were allowed modest growth (i.e., an additional 5–10%) throughout the course of the studies. All rats were housed in a climate-controlled animal colony maintained at 23 °C, with 12 h light–dark cycle (lights on 07:00 h),

Experiments 1–3: KW6002, caffeine and DPCPX combined with haloperidol

KW6002 significantly attenuated the effects of haloperidol on the concurrent lever-pressing/chow-feeding task. The overall treatment effect for lever pressing was statistically significant (Fig. 1A; [F(4,28) = 16.6, p < 0.01]). Planned comparisons revealed that haloperidol decreased lever pressing compared to injection of Veh/Veh (p < 0.01). KW6002 significantly increased responding in haloperidol-treated rats, with all three doses being significantly different from haloperidol plus vehicle (p < 0.05).

Discussion

In the experiments presented above, a concurrent choice lever-pressing/chow-feeding task was used to investigate the interaction between adenosine receptor antagonists with different profiles of selectivity and the DA D2 family antagonist haloperidol. Injection of haloperidol without co-administration of an adenosine antagonist produced a well-documented shift in response allocation; 0.1 mg/kg haloperidol significantly decreased lever pressing and increased chow intake in all experiments. These

Acknowledgement

This work was supported by a grant to J.S. from the National Institute of Mental Health (MH078023).

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  • Cited by (0)

    1

    Present address: Area de Psicobiol., Dept. Psic., Universitat de Jaume I, Castelló 12071, Spain.

    2

    Present address: University of Connecticut Health Center, Farmington, CT, USA.

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