WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D(4) receptor activation

In-vitro studies have shown that WAY 100635 is not only a potent 5-HT1A antagonist, but also has high affinity and efficacy at the dopamine D(4) receptor. Nevertheless, the behavioral effects of this compound have not been investigated. This study sought to characterize the discriminative stimulus effects produced by WAY 100635. Male Sprague-Dawley rats were trained in a two-lever, fixed ratio 50, food-reinforced task with WAY 100635 (10 micromol/kg) as a discriminative stimulus. Substitution tests with different doses of WAY 100635 and (-)-pindolol, and combination tests with two 5-HT1A agonists, 8-OH-DPAT and LY 293284; and two dopamine D(4) antagonists, sonepiprazole and A-381393, were performed. Rats trained with a low dose (0.74 micromol/kg) of WAY 100635 could not learn the discrimination task after more than 3 months of sessions. Rats trained to discriminate 10 micromol/kg of WAY 100635 from saline achieved the criterion of accuracy after approximately 35 training sessions. WAY 100635 (2.5-10 micromol/kg) produced a dose-dependent increase in WAY 100635-appropriate responding, with a mean effective dose of 3.44 micromol/kg, whereas saline or pindolol (5-25 micromol/kg) administration resulted in 0% drug lever responding. Pretreatment with the 5-HT(1A) agonists 8-OH-DPAT or LY 293284 did not modify the WAY 100635 curve, but pretreatment with the selective dopamine D(4) antagonists sonepiprazole or A-381393 completely blocked the cue. These results indicate that the discriminative stimulus effect produced by WAY 100635 is mediated by activation of dopamine D(4) receptors.