Research reportDifferential actions of adenosine A1 and A2A antagonists on the effort-related effects of dopamine D2 antagonism
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).
References (84)
- et al.
Nucleus accumbens dopamine depletions make rats more sensitive to high ratio requirements but do not impair primary food reinforcement
Neuroscience
(1999) - et al.
Evidence for adenosine- and serotonin-mediated antihyperalgesic effects of cizolirtine in rats suffering from diabetic neuropathy
Neuropharmacology
(2007) - et al.
Nucleus accumbens dopamine and work requirements on interval schedules
Behav Brain Res
(2002) - et al.
The adenosine A2A antagonist KF17837 reverses the locomotor suppression and tremulous jaw movements induced by haloperidol in rats: possible relevance to parkinsonism
Behav Brain Res
(2004) - et al.
Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task
Behav Brain Res
(1996) - et al.
Nucleus accumbens dopamine depletions in rats affect relative response allocation in a novel cost/benefit procedure
Pharmacol Biochem Behav
(1994) - et al.
Forebrain circuitry involved in effort-related choice: injections of the GABAA agonist muscimol into ventral pallidum alters response allocation in food-seeking behavior
Neuroscience
(2008) - et al.
Adenosine A2A–dopamine D2 receptor–receptor heteromers. Targets for neuro-psychiatric disorders
Parkinsonism Relat Disord
(2004) - et al.
Adenosine–dopamine receptor–receptor interactions as an integrative mechanism in the basal ganglia
Trends Neurosci
(1997) - et al.
Antagonistic interaction between adenosine A2A receptors and dopamine D2 receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia
Neuroscience
(1994)
Adenosine/dopamine interaction: implications for the treatment of Parkinson's disease
Parkinsonism Relat Disord
Adenosine receptor–dopamine receptor interactions in the basal ganglia and their relevance for brain function
Physiol Behav
Motor depressant effects mediated by dopamine D2 and adenosine A2A receptors in the nucleus accumbens and the caudate-putamen
Eur J Pharmacol
Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors
J Biol Chem
Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats
Behav Brain Res
Direct autoradiographic localization of adenosine A2A receptors in the rat brain using the A2A-selective agonist, [3H]CGS 21680
Eur J Pharmacol
Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward
Physiol Behav
Involvement of the adenosine A1 and A2A receptors in the antidepressant-like effect of zinc in the forced swimming test
Prog Neuropsychopharmacol Biol Psychiatry
The antinociceptive effect of 2-chloro-2′-C-methyl-N6-cyclopentyladenosine (2′-Me-CCPA), a highly selective adenosine A1 receptor agonist, in the rat
Pain
IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C
Brain Behav Immun
D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption
Pharmacol Biochem Behav
Involvement of adenosine A2A receptors in the induction of c-fos expression by clozapine and haloperidol
Neuropsychopharmacol
New therapies for the treatment of Parkinson's disease: adenosine A2A receptor antagonists
Life Sci
Blockade of adenosine A2A receptors reverses short-term social memory impairments in spontaneously hypertensive rats
Behav Brain Res
Modulation of short-term social memory in rats by adenosine A1 and A(2A) receptors
Neurosci Lett
Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine
Behav Brain Res
Beyond the reward hypothesis: alternative functions of nucleus accumbens dopamine
Curr Opin Pharmacol
Anhedonia or anergia? Effects of haloperidol and nucleus accumbens dopamine depletion on instrumental response selection in a T-maze cost/benefit procedure
Behav Brain Res
Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis
Neurosci Biobehav Rev
Dopamine/adenosine interactions related to locomotion and tremor in animal models: possible relevance to parkinsonism
Parkinsonism Relat Disord
The role of nucleus accumbens dopamine in lever pressing and response allocation: effects of 6-OHDA injected into core and dorsomedial shell
Pharmacol Biochem Behav
Distribution, biochemistry and function of striatal adenosine A2A receptors
Prog Neurobiol
Rats assess costs and benefits according to an internal standard
Behav Brain Res
Weighing up the benefits of work: behavioral and neural analyses of effort-related decision making
Neural Netw
Mood disorders
Neuroimaging Clin N Am
Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding
Psychopharmacology
Opioids for hedonic experience and dopamine to get ready for it
Psychopharmacology
Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy
Neuropsychopharmacology
Different effects of nucleus accumbens and ventrolateral striatal dopamine depletions on instrumental response selection in the rat
Pharmacol Biochem Behav
Pharmacological characterization of performance on a concurrent lever pressing/feeding choice procedure: effects of dopamine antagonist, cholinomimetic, sedative and stimulant drugs
Psychopharmacology
Localization of adenosine A2A-receptors in rat brain with [3H]ZM-241385
Naunyn Schmiedebergs Arch Pharmacol
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.