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


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.
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Psychopharmacology Section, Division of Psychiatry, Medical School, Queen's Medical Centre, University of Nottingham, Room B109, Nottingham NG7 2UH, UK. stephanie.body@nottingham.ac.uk
Cheung
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Hampson
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den Boon
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Bezzina
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Bradshaw
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Szabadi
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects*; D003913:Dextroamphetamine / Q000633:toxicity*; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*
D001552:Benzazepines; D018491:Dopamine Agonists; D012701:Serotonin; C067113:SK&F 81297; D003913:Dextroamphetamine