Evidence that the effect of 5-HT2 receptor stimulation on temporal differentiation is not mediated by receptors in the dorsal striatum.

5-HT2 receptor stimulation alters temporal differentiation in free-operant timing schedules. The anatomical location of the receptor population responsible for this effect is unknown. We examined the effect of a 5-HT2 receptor agonist and antagonists, injected systemically and into the dorsal striatum, a region that is believed to play a major role in interval timing. Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5s epochs of the trials; logistic functions were fitted to the data from each rat to derive timing indices (T50: time corresponding to %B = 50; Weber fraction: [T75-T25]/2T50, where T75 and T25 are the times corresponding to %B = 75 and %B = 25). Systemic treatment with the 5-HT(2A/2C) receptor agonist 2,5,-dimethoxy-4-iodo-amphetamine (DOI) (0.25 mg/kg, s.c.) reduced T50; the 5-HT2A receptor antagonist MDL-100907 (0.5 mg/kg, i.p.) did not affect performance, but completely blocked the effect of DOI. DOI (1 and 3 microg) injected bilaterally into the dorsal striatum did not alter T50. The effect of systemic treatment with DOI (0.25 mg/kg, s.c.) was not altered by intra-striatal injection of MDL-100907 (0.3 microg) or the 5-HT2C receptor antagonist RS-102221 (0.15 microg). The ability of systemically administered MDL-100907 to reverse DOI's effect on T50 confirms the sensitivity of temporal differentiation to 5-HT2A receptor stimulation. The failure of intra-striatal MDL-100907 to antagonize the effects of DOI suggests that 5-HT2A receptors in the dorsal striatum are unlikely to be primarily responsible for DOI's effects on timing. Furthermore, the results provide no evidence for a role of striatal 5-HT2C receptors in DOI's effect on timing.