Behavioral effects of A1- and A2-selective adenosine agonists and antagonists: evidence for synergism and antagonism

Abstract

The locomotor effects in mice of selective A1 and A2 adenosine agonists, antagonists and combinations of agonists were investigated using a computerized activity monitor. The A2-selective agonist 2-[(2-aminoethylamino)carbonylethylphenylethylamino[-5'-N- ethylcarboxamidoadenosine (APEC), an amine derivative of 2-(carboxyethylphenylethylamino)adenosine-5'-carboxamide, was a more potent locomotor depressant than its amide conjugates. The rank order of potency after i.p. injection for adenosine agonists was 5'-N-ethylcarboxamidoadenosine (NECA) (ED50, 5.8 nmol/kg) greater than APEC (ED50, 25 nmol/kg) greater than N6-cyclohexyladenosine (CHA) (ED50, 270 nmol/kg). An A1-selective, centrally acting, adenosine antagonist, 8-cyclopentyltheophylline (10 mg/kg), completely reversed the locomotor depressant effects of CHA (A1-selective) and NECA (nonselective) at doses of agonists as high as twice the ED50, and shifted the dose-response curves to the right, suggesting a primary involvement of A1 receptors. 8-cyclopentyltheophylline did not affect the depressant effects of APEC at the ED50, consistent with the A2-selectivity of APEC. The locomotor effects of APEC and CHA were completely reversed by theophylline, but not by the peripherally active 8-p-sulfophenyltheophylline, indicating central action of the adenosine agonists. The depressant effects of APEC, but not of NECA or CHA, were reversed significantly by an A2-selective adenosine receptor antagonist, 4-amino-8-chloro-1-phenyl-[1,2,4]triazol[4,3-a]quinoxaline. Low or subthreshold doses of CHA potentiated the depressant effects of APEC. A subthreshold dose of CHA did not alter the depressant effect of NECA, whereas a subthreshold dose of APEC increased the depressant effects of low doses of NECA. Thus, it appears that A1- and A2-selective adenosine agonists have separate central depressant effects, which can be potentiative.(ABSTRACT TRUNCATED AT 250 WORDS)

Fig. 1

Locomotor activity over 60 min in control animals (∎) and for animals injected i.p. with APEC (30 nmol/kg), an A₂selective adenosine agonist (●). Activity counts for total distance traveled are shown in relation to time elapsed since the beginning of monitoring in a Digiscan activity monitor, initiated 10 min after injection i.p. (n = 6). This dose of APEC in other experiments (see fig. 7) corresponded to the ED₅₀ dose.

Fig. 2

Dose-response curves for locomotor stimulation and depression in mice by the adenosine antagonist theophylline. Activity counts for total distance traveled (mean ± S.E.) over a 30-min period are shown as a function of dose of theophylline injected i.p (n = 6–8).

Fig. 3

Reversal by theophylline (10 mg/kg) of locomotor depression elicited by the A₂-selective adenosine agonist APEC. The antagonist or vehicle was injected 10 min before the agonist. The activity reflects the total distance traveled (mean ± S.E.) over a 30-min period, begun 10 min after the agonist injection in the absence (◯) or presence (●) of theophylline (n = 6–12).

Fig. 4

Reversal by theophylline (10 mg/kg) of locomotor depression elicited by the A₁-selective adenosine agonist CHA. The antagonist or vehicle was injected 10 min before the agonist. The activity reflects the total distance traveled (mean ± S.E.) over a 30-min period, begun 10 min after the agonist injection in the absence (◯) or presence (●) of theophylline (n = 6–12).

Fig. 5

Dose-response curves for locomotor depression in mice by the adenosine agonist CHA in the absence (◯) or presence (●) of the A₁-selective antagonist CPT (10 mg/kg). The antagonist or vehicle was injected 10 min before the agonist. The activity reflects the total distance traveled (mean ± S.E.) over a 30-min period (n = 6–12).

Fig. 6

Dose-response curves for locomotor depression in mice by the adenosine agonist NECA in the absence (◯) or presence (●) of the A₁-selective antagonist CPT (10 mg/kg). The antagonist or vehicle was injected 10 min before the agonist. The activity reflects the total distance traveled (mean ± S.E.) over a 30-min period (n = 6–12).

Fig. 7

Dose-response curves for locomotor depression in mice by the adenosine agonist APEC in the absence (◯) or presence (●) of the A₁-selective antagonist CPT (10 mg/kg). The antagonist or vehicle was injected 10 min before the agonist. The activity reflects the total distance traveled (mean ± S.E.) over a 30-min period (n = 6–12).

Fig. 8

Dose-response curves for locomotor depression in mice by the adenosine agonist APEC in the absence (◯) or presence (●) of an A₂-setective adenosine antagonist, CP-66,713 (1.5 mg/kg). The antagonist was injected 10 min before the agonist. The activity reflects the total distance traveled (mean ± S.E.) over a 30-min period (n = 8). In this set of experiments and those of table 2, APEC was more potent than in others (see fig. 7, tables 1 and 3).

Fig. 9

An isobotogram depicting the effects of combinations of adenosine agonists at various doses, which indicates that the interaction of A₁ and A₂ agonists is synergistic. The construction of the dose-effect curves and determination of ED₅₀ values was based on the probit procedure (Kissin et al., 1990; Finney, 1971). A CHA-APEC subseries, in which the ratio of doses was between 4:1 and 6:1 (combinations of approximately equieffective doses), was administered. The ED₅₀ values for the combination were 6.1 nmol/kg for APEC and 54 nmol/kg for CHA. The inset shows the data from which the ED₅₀ values were determined. Percent locomotor depression is plotted as a function of the dose of each agonist in the combination subseries.