ejp ELSEVIER European Journal of Pharmacology 255 (1994) 239-243 Short communication Activation of adenosine A 1 receptors underlies anticonvulsant effect of CGS21680 Ge Zhang 1, Paul H. Franklin, Thomas F. Murray * College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA (Received 26 January 1994; accepted 4 February 1994) Abstract Focal injection of the adenosine A2A receptor agonist CGS21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethyl- carboxamidoadenosine) in the rat prepiriform cortex produced a reduction in the severity of bicuculline methiodide-induced motor seizures. The anticonvulsant effect of CGS21680 exhibited dose-dependency and modest potency (EDs0 = 605 + 47 pmol/rat). Pharmacological characterization of the anticonvulsant response in the prepiriform cortex revealed a significant correlation between the potency of adenosine analogs as anticonvulsants and their respective affinities for adenosine A 1 receptors in vitro. These results indicate that the low affinity of CGS21680 for adenosine A 1 receptors is sufficient to account for the anticonvulsant activity of this compound in the rat prepiriform cortex. Key words: CGS21680; Adenosine A 1 receptor; Adenosine A2A receptor; Seizure; Prepiriform cortex; [3H]DPCPX (8-Cyclopen- tyl-l,3-[aH]dipropylxanthine) 1. Introduction The piriform cortex is the largest subdivision of olfactory cortex which is a phylogenetically old type of cerebral cortex. Although the piriform cortex repre- sents a primary receiving area for olfactory sensory input, its function clearly extends beyond the process- ing of olfactory information. As an example of a non- olfactory function of the piriform cortex, several lines of evidence now indicate that the piriform cortex may be involved in certain epileptogenic processes (Piredda and Gale, 1985; H6nack et al., 1991). Our previous studies demonstrated that intracere- bral administration of adenosine analogs into rat prepiriform cortex potently blocks the convulsant ef- fects of focally injected bicuculline methiodide or kainic acid; this anticonvulsant response of adenosine analogs was selectively antagonized by an adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline, indicative of an adenosine receptor-mediated event (Franklin et al., * Corresponding author. Tel. (503) 737-3424, fax (503) 737-3999. 1 Present address: Dept. of Physiology, Oregon Health Sciences University, Portland, OR 97201, USA. Elsevier Science B.V. SSDI 0014-2999(94)00086-M 1988, 1989; Zhang et al., 1990). The physiological and pharmacological relevance of activation of adenosine receptors in the central nervous system was further underscored in a recent report documenting the role of endogenous adenosine in the regulation of seizure susceptibility in the prepiriform cortex (Zhang et al., 1993). Manipulation of the levels of this endogenous purine in the prepiriform cortex was accomplished by focal injection of inhibitors of adenosine metabolism. The results of these studies indicate that accumulation of endogenous adenosine in this forebrain area pro- tects animals from convulsions induced by bicuculline methiodide, whereas a reduction of extracellular adenosine formation resulted in generalized seizures (Zhang et al., 1993). These data strongly support the hypothesis that endogenous adenosine exerts a toni- cally active anticonvulsant modulatory tone, and that an adenosine A~ receptor population in this paleocor- tical area represents a fundamental element in the regulation of seizure susceptibility. The anticonvulsant response to adenosine and adenosine analogs is thought to be mediated via an interaction with adenosine receptors of the A 1 subtype (Franklin et al., 1989); however, involvement of adeno- sine A 2 receptors in the modulation of neuronal ex-