Adenosine receptors and behavioral actions of methylxanthines.

Abstract

Central stimulant actions of 10 methylxanthines in mice correlate with affinities for adenosine receptors labeled with N6-[3H]cyclohexyladenosine. Affinities of methylxanthines for adenosine receptors are consonant with central levels attained at behaviorally effective doses. The much higher concentrations ofmethylxanthines required to influence benzodiazepine receptor binding do not correlate with behavioral potency. N6-(L-Phenylisopropyl)adenosine (L-PIA), a metabolically stable analog ofadenosine with high affinity for adenosine receptors, is an extremely potent behavioral depressant, reducing locomotor activity of mice at doses as little as 0.05 ,.mol/kg. The D isomer, which has much less affinity for adenosine receptors, is much less active as a central depressant. Theophylline stimulates locomotor activity and reverses depressant effects of L-PIA. Caffeine or 1,7-dimethylxanthine, when administered alone, elicits biphasic effects, with locomotor depression at lower doses and stimulation at higher doses. When administered with L-PIA, even low doses of caffeine produce marked stimulation. 3-Isobutyl-1-methylxanthine given alone elicits only behavioral depression. However, like theophylline and caffeine, isobutylmethylxanthine reverses the L-PIA-evoked depression, converting it into pronounced locomotor stimulation. The data strongly suggest that the behavioral stimulant effects of methylxanthines involve a blockade of central adenosine receptors. Although methylxanthines such as caffeine and theophylline are among the most widely used behavioral stimulant substances, molecular mechanisms for their stimulant effects are unclear. Methylxanthines can inhibit phosphodiesterase, and thus prevent inactivation of cyclic AMP (1), but the concentrations of caffeine and theophylline required to inhibit phosphodiesterases are substantially greater than those which occur in brain at behaviorally effective doses (2, 3). Moreover, several potent phosphodiesterase inhibitors lack behavioral stimulant actions and indeed are central depressants (4). Adenosine receptor activity is blocked by methylxanthines in concentrations similar to those that occur after stimulant doses (5, 6). Because the general neurophysiologic actions of adenosine are inhibitory (7), it is conceivable that methylxanthines exert stimulant actions by blocking adenosine effects.In several attempts to measure binding of adenosine-related ligands to membranes, binding sites largely lacked the specificity of physiologic adenosine receptors (8-12). Recently, we (13, 14) and others (15,16) have demonstrated binding of 3H-labeled ligands to adenosine receptors in brain and testes (15,17).In the present study we show a correlation between potencies of a series of methylxanthines in stimulating locomotor activity of mice and in competing at adenosine receptors labeled with [3H]CHA (14 Ci/mmol; 1 Ci = 3.7 x 101 becquerels) and[3H]flunitrazepam (79 Ci/mmol) were obtained from New England Nuclear. The sources ofxanthines were as described (13).Behavioral. ...

Dopaminergic Mechanism for Caffeine-Produced Cocaine Seeking in Rats

“…Caffeine and theophylline produced a dose-dependent reinstatement of extinguished cocaine-taking behavior with relative potencies similar to those at adenosinergic receptors (Snyder et al 1981). A selective A2 adenosine antagonist, however, failed to produce drug seeking, even at a dose that produced hyperactivity.…”

“…The primary effect of low doses of caffeine is blockade of adenosine receptors with secondary effects on a number of neurochemical systems (see Daly 1993 for review), and many of the behavioral effects of caffeine and other methylxanthines are correlated with their potency as adenosine antagonists (Snyder et al 1981;Katims et al 1983;Mumford and Holtzman 1991b). Secondary to this effect at adenosine receptors, caffeine also has effects on dopaminergic substrates (Fuxe et al 1998) via interactions between adenosine A2 and dopamine D2 receptors (Ferre et al 1991(Ferre et al , 1993Dasgupta et al 1996;Fuxe et al 1998).…”

Locomotor activity in mice during chronic treatment with caffeine and withdrawal

“…Differing degrees of penetration into the brain, with IBMX presumably penetrating less well than the trisubstituted homolog of caffeine 1,3-dipropyl-7-methylxanthine [cf. (42)], probably are the basis for such a difference in relative potencies in vitro compared to in vivo. IBMX is well known as a behavioral depressant in rodents (9,27,39,42,45).…”

“…(42)], probably are the basis for such a difference in relative potencies in vitro compared to in vivo. IBMX is well known as a behavioral depressant in rodents (9,27,39,42,45). Remarkably, IBMX becomes a behavioral stimulant when administered with a depressant dose of an adenosine analog (27,42).…”

“…At present, it is in general accepted that caffeine, at least in part, owes its behavioral stimulant activity to blockade of adenosine receptors (2). Caffeine and other stimulant xanthines block adenosine receptors and reverse the depressant effects of adenosine analogs (4,19,27,29,39,42). Adenosine analogs appear capable of eliciting behavioral depression through activation of either A 1 or A 2 adenosine receptors (37,38).…”