Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice

Abstract

Adenosine receptors modulate dopaminergic function by regulating dopamine release in presynaptic neurons and intracellular signaling in postsynaptic striatal neurons. To investigate how adenosine impinges on the action of dopamine in feeding and locomotion, genetically altered, dopamine-deficient mice were treated with adenosine receptor antagonists. Acute administration of the nonselective adenosine receptor antagonist, caffeine (5-25 mgkg i.p.), reversed the hypophagia of mutant mice and induced hyperactivity in both control and mutant animals. However, caffeine treatment elicited much less hyperactivity in dopamine-deficient mice than did l-3,4-dihydroxyphenylalanine (l-dopa) administration, which partially restores dopamine content. Caffeine treatment enhanced feeding of l-dopa-treated mutants but, unexpectedly, it reduced their hyperlocomotion. Caffeine administration induced c-Fos expression in the cortex of dopamine-deficient mice but had no effect in the striatum by itself. Caffeine attenuated dopamine agonist-induced striatal c-Fos expression. An antagonist selective for adenosine A(2A) receptors induced feeding and locomotion in mutants much more effectively than an A(1) receptor antagonist. l-dopa-elicited feeding and hyperlocomotion were reduced in mutants treated with an A(1) receptor agonist, whereas an A(2A) receptor agonist decreased l-dopa-induced feeding without affecting locomotion. The observations suggest that the hypophagia and hypoactivity of mutants result not only because of the absence of dopamine but also because of the presence of A(2A) receptor signaling. This study of a genetic model of dopamine depletion provides evidence that A(2A) receptor antagonists could ameliorate the hypokinetic symptoms of advanced Parkinson's disease patients without inducing excessive motor activity.

Figure 1

Caffeine- and l-dopa-induced feeding behavior and locomotor activity over 4 h. (A) Food consumption, g/kg body weight (mean ± SEM). (B) Locomotion is reported as distance traveled in meters. Control mice, white bars (n = 8); Th^−/−; Dbh^Th/+ mice, black bars (n = 8). Numbers indicate dose of drug (mg/kg body weight).

Figure 2

Effects of coadministration of l-dopa and caffeine on feeding behavior and locomotor activity over 4 h. (A) Food consumption, g/kg body weight (mean ± SEM). (B) Locomotion is reported as distance traveled in meters. Control mice, white bars (n = 8); Th^−/−; Dbh^Th/+ mice, black bars (n = 8). Numbers indicate dose of drug (mg/kg body weight).

Figure 3

Selective adenosine A₁, A_2A, and dual antagonist effects on feeding behavior and locomotor activity over 4 h. (A) Food consumption, g/kg body weight (mean ± SEM). (B) Locomotion is reported as distance traveled in meters. Control mice, white bars (n = 4–8); Th^−/−; Dbh^Th/+ mice, black bars (n = 4–8). Numbers indicate dose of drug (mg/kg body weight).

Figure 4

Selective adenosine A₁ and A_2A agonist effects on feeding behavior and locomotor activity over 2 h. (A) Food consumption, g/kg body weight (mean ± SEM). (B) Locomotion is reported as distance traveled in meters. Control mice, white bars (n = 8); Th^−/−; Dbh^Th/+ mice, black bars (n = 8). Numbers indicate dose of drug (mg/kg body weight).

Figure 5

Induction of c-Fos immunoreactivity in the striatum after 2 h. (A, C, E, and G) Representative control coronal sections showing the dorsal caudate putamen (top, dorsal; right, lateral). (B, D, F, and H) Representative Th^−/−; Dbh^Th/+ sections. (A and B) Sections after l-dopa (50 mg/kg) treatment. (C and D) Sections after SKF 81297 (1.25 mg/kg) treatment. (E and F) Sections after l-dopa (50 mg/kg) treatment + caffeine (25 mg/kg) treatment. (G and H) Sections after SKF 81297 (1.25 mg/kg) treatment + caffeine (25 mg/kg) treatment. (I) c-Fos-positive nuclei in dorsal CPu (mean ± range). Control mice, white bars (n = 2 mice, three images per mouse); Th^−/−; Dbh^Th/+ mice, black bars (n = 2 mice, three images per mouse). Dashed line indicates region where nuclei were counted. Numbers indicate dose of drug (mg/kg body weight).

Figure 6

c-Fos expression in the cortex, amygdala, and hypothalamus of Th^−/−; Dbh^Th/+ mice after 2 h. (A, D, and G) Representative coronal sections showing the cortex (top, dorsal; right, lateral). (B, E, and H) Representative coronal sections showing the amygdala (top, dorsal; right, medial; La, lateral amygdala; BLA, basolateral amygdala; BMA, basomedial amygdala, ACo, cortical amygdaloid nucleus; CeA, central amygdala; MeA, medial amygdala; MGP, medial globus pallidus). (C, F, and I) Representative coronal sections showing the hypothalamus (top, dorsal; right, lateral; PH, paraventricular hypothalamic nucleus; Arc, arcuate; LH, lateral hypothalamus, f, fornix). (A–C) Sections after 0.9% saline treatment. (D–F) Sections after caffeine (25 mg/kg) treatment. (G–I) Sections after l-dopa (50 mg/kg) treatment. (J–L) Number of c-Fos-positive nuclei in cortex, amygdala, and hypothalamus, respectively (mean ± range; n = 2 mice, three images per mouse). Numbers indicate dose of drug (mg/kg body weight).