PHARMACOLOGICAL CHARACTERIZATION OF A SIMPLE BEHAVIORAL-RESPONSE MEDIATED SELECTIVELY BY CENTRAL ADENOSINE A(1) RECEPTORS, USING IN-VIVO AND IN-VITRO TECHNIQUES

The behavioral profile of a range of adenosine receptor ligands was ex amined in rats using a locomotor activity model. Adenosine receptor ag onists, including the selective A(1) receptor agonist, N-6-cyclopentyl adenosine (CPA) and the A(2A) agonist, hyl-phenylethylamino]-5'-ethylc arboxamidoadenosine (APEC), reduced spontaneous motor activity in a do se-dependent manner. CPA-induced locomotor depression was attenuated b y adenosine A(1) receptor selective antagonists, such as 8-cyclopentyl -1,3-dipropylxanthine (DPCPX), yrazolo[1,5-a]pyridin-3-yl)-acryloyl]-2 -piperidine ethanol (FK453), and azolo[1,5-a]pyridin-3-yl)-acryloyl]-p iperidin-2-yl acetic acid (FK352), but not by the A(2A) receptor antag onist, -dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KF17837). B y contrast, APEC-induced hypolocomotion was attenuated by KF17837 but not by DPCPX, confirming that adenosine A(1) and A(2A) receptor activa tion mediates locomotor output independently. it was found that two pe ripheral adenosine receptor antagonists, 8-(p-sulphophenyl)-1,3-diprop ylxanthine (DPSPX) and 8-(p-sulphophenyl)-1,3-dimethylxanthine (8-PST) , did not alter CPA-induced hypolocomotion. This confirmed that pharma cological reversal of the adenosine A(1) receptor-mediated response in volved a central site of drug action. The relationship between occupan cy of central adenosine A(1) receptors and behavioral effect was there fore assessed. Regression analysis on log transformed data confirmed a ssociations between antagonist affinity for brain [H-3]DPCPX binding s ites and, in order of increasing significance, the equivalent behavior al dose (EBD) for reversal of CPA-induced hypolocomotion (r(2) = 0.32) , the serum concentration of drug (r(2) = 0.65), and most significantl y with the brain concentration of drug detected 20 min after administr ation of the (EBD) (r(2) = 0.95). These data suggest that competition between agonists and antagonists, for occupancy of central adenosine A , receptors, is intrinsic to the pharmacological reversal of CPA-induc ed hypolocomotion. The validity of the model as a simple predictive sc reen for the blood/brain barrier permeability of adenosine A(1) recept or antagonists was thereby confirmed.