ADENOSINE AGONISTS REDUCE CONDITIONED AVOIDANCE RESPONDING IN THE RAT

Because adenosine agonists may possess therapeutic potential as antipsychotic agents, we examined the activity of several prototypic agents in vivo in blocking conditioned avoidance responding (CAR) in the rat, a behavioral test predictive of antipsychotic efficacy in humans. Potency in blocking CAR is directly proportional to potency in alleviating schizophrenia. Hence, the adenosine A,-selective agonists [cyclopentyl adenosine (CPA) and (R)-phenylisopropyl adenosine (R-PIA)], A2-selective agonists [CV-1808 and (2-(p-(carboxyethyl)-phenethylamino)-5'-N-ethyl-carboxamido adenosine (CGS 21680)], and a nonselective agonist [5'-N-carboxamido adenosine (NECA)] were examined in this test. Block of CAR was first determined for standard antipsychotic agents [ED50 mg/kg, IP, and 95% confidence level (CL) in parentheses], such as haloperidol [0.23 (0.18, 0.39)], trifluoperazine [(0.9 (0.7, 1.0)], thioridazine [12.5 (10.5, 15.3)], metoclopramide [7.8 (6.4, 9.2)], and chlorpromazine [4.9 (4.2, 5.9)]. The paradigm consisted of a light- and tone-signaled footshock that could be avoided via a discrete lever press. Affinity for A1 and A2 binding sites in brain tissue from Fischer 344 rats was ascertained to be similar to that seen in other rodent strains. Each adenosine agonist blocked CAR. NECA [ED50 value (95% CL) = 0.07 (0.004,0.12) mg/kg, IP] was the most potent agent, followed by: R-PIA 10.34 (0.23, 0.44)]; CGS 21680 [1.1 (0.8, 2.0)]; CV-1808 [1.3 (1.0, 1.8)]; and CPA [1.5 (1.3, 1.7)]. Pretreatment with caffeine (25 mg/kg, IP, - 10 min) blocked the inhibition of CAR produced by the adenosine agonists, suggesting the event is mediated via purinergic receptors. As a test for extrapyramidal side effect potential, each agonist was administered at dose levels corresponding to the ED25, ED50, and ED75 values for block of CAR and catalepsy was measured. Catalepsy was prominently produced by NECA and CPA, whereas CGS 21680 and R-PIA produced little. Neither potency in blocking CAR nor inducing catalepsy could be highly correlated with either relative affinity or selectivity for either A1 or A2 binding sites. The data suggest purinergic agonists might be effective antipsychotic agents but may possess side effects that might preclude their use.