Attenuation of the effects of d-amphetamine on interval timing behavior by central 5-hydroxytryptamine depletion

RATIONALE: Interval timing in the free-operant psychophysical procedure is sensitive to the monoamine-releasing agent d-amphetamine, the D(2)-like dopamine receptor agonist quinpirole, and the D(1)-like agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzepine (SKF-81297). The effect of d-amphetamine can be antagonized by selective D(1)-like and 5-HT(2A) receptor antagonists. It is not known whether d-amphetamine’s effect requires an intact 5-hydroxytryptamine (5-HT) pathway. OBJECTIVE: The objective of this study was to examine the effects of d-amphetamine, quinpirole, and SKF-81297 on timing in intact rats and rats whose 5-hydroxytryptaminergic (5-HTergic) pathways had been ablated. MATERIALS AND METHODS: Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s 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 5-s epochs of the trials; logistic functions were fitted to the data for derivation of timing indices (T(50), time corresponding to %B = 50%; Weber fraction). The effects of d-amphetamine (0.4 mg kg(−1) i.p.), quinpirole (0.08 mg kg(−1) i.p.), and SKF-81297 (0.4 mg kg(−1) s.c.) were compared between intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. RESULTS: Quinpirole and SKF-81297 reduced T(50) in both groups; d-amphetamine reduced T(50) only in the sham-lesioned group. The lesion reduced 5-HT levels by 80%; catecholamine levels were not affected. CONCLUSIONS: d-Amphetamine’s effect on performance in the free-operant psychophysical procedure requires an intact 5-HTergic system. 5-HT, possibly acting at 5-HT(2A) receptors, may play a ‘permissive’ role in dopamine release.