Antagonism by WAY-100635 of the effects of 8-OH-DPAT on performance on a free-operant timing schedule in intact and 5-HT-depleted rats

In this experiment we examined the effect of a serotonin receptor (5-HT1A) agonist and antagonist WAY-100635 (N-12-(4-12-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide) on temporal differentiation, in intact rats and rats whose serotonergic (5-HTergic) pathways had been destroyed by 5,7-dihydroxytryptamine (5,7-DHT). Thirteen rats received 5,7-DHT-induced lesions of the median and dorsal raphe nuclei; 14 rats received sham lesions. They were trained to press two levers (A and B) in 50-s trials, in which reinforcement was contingent upon responding on A in the first half, and B in the second half, of the trial. Logistic psychophysical curves were fitted to the relative response rate data (percent responding on B, %B), for derivation of timing indices [T-50 (time corresponding to %B = 50%), slope, Weber fraction] following WAY-100635, 8-OH-DPAT 18-hydroxy-2-(di-n-propylamino)tetralin], combinations of WAY-100635+8-OH-DPAT, and vehicle alone. WAY-100635 (30, 100 and 300 mug/kg, s.c.) did not affect the timing indices. 8-OH-DPAT (100, 200 mug/kg, s.c.) reduced T-50 without affecting the Weber fraction. WAY-100635 (300 mug/kg) abolished the effect of 8-OH-DPAT on T-50 in both the lesioned and sham-lesioned groups. 5-HT levels in the neocortex, hippocampus, amygdala, nucleus accumbens and hypothalamus of the lesioned group were <20% of those in the sham-lesioned group; catecholamine levels were unaffected. The results confirm that 8-OH-DPAT disrupts temporal differentiation in a free-operant psychophysical schedule, reducing T-50, and indicate that this effect of 8-OH-DPAT is mediated by postsynaptic 5-HT1A receptors. (C) 2002 Lippincott Williams & Wilkins.