Effects of d-amphetamine and DOI (2,5-dimethoxy-4-iodoamphetamine) on timing behavior: interaction between D1 and 5-HT2A receptors.
BACKGROUND
The dopamine-releasing agent d-amphetamine and the 5-HT(2) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) have similar effects on free-operant timing behavior. The selective D(1) dopamine receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566), but not the D(2) dopamine receptor antagonist haloperidol, can antagonize the effect of d-amphetamine, and the selective 5-HT(2A) receptor antagonist (+/-)2,3-dimethoxyphenyl-1-(2-(4-piperidine)-methanol (MDL-100907) can antagonize the effect of DOI. However, it is not known whether the effect of d-amphetamine can be reversed by MDL-100907 and the effect of DOI by dopamine receptor antagonists.


OBJECTIVE
The objective of this work is to examine the interactions of d-amphetamine and DOI with MDL-100907, SKF-83566, and haloperidol on timing performance.


METHODS
Rats (n = 12-15 per experiment) were trained under the free-operant psychophysical procedure to press two 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 from each rat for the derivation of timing indices [T (50) (time corresponding to %B = 50); Weber fraction]. Rats were treated systemically with d-amphetamine or DOI, alone and in combination with haloperidol, SKF-83566, or MDL-100907.


RESULTS
d-Amphetamine (0.4 mg kg(-1)) reduced T (50) compared to vehicle; this effect was antagonized by SKF-83566 (0.03 mg kg(-1)) and MDL-100907 (0.5 mg kg(-1)), but not by haloperidol (0.05, 0.1 mg kg(-1)). DOI (0.25 mg kg(-1)) also reduced T (50); this effect was reversed by MDL-100907 (0.5 mg kg(-1)), but not by SKF-83566 (0.03 mg kg(-1)) or haloperidol (0.05 mg kg(-1)).


CONCLUSIONS
The results suggest that both 5-HT(2A) and D(1) receptors, but not D(2) receptors, are involved in d-amphetamine's effect on timing behavior in the free-operant psychophysical procedure. DOI's effect on timing is mediated by 5-HT(2A) receptors, but neither D(1) nor D(2) receptors are involved in this effect.
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Psychopharmacology Section, Division of Psychiatry, University of Nottingham, Room B109, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK. stephanie.body@nottingham.ac.uk
Cheung
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Bezzina
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Asgari
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Fone
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Glennon
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Bradshaw
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Szabadi
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D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology*; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D003216:Conditioning, Operant; D004347:Drug Interactions; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013998:Time Perception / Q000187:drug effects* / Q000502:physiology
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000661:Amphetamine; D000662:Amphetamines; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C044846:SKF83566; C079049:volinanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine