Aripiprazole (OPC-14597) fully substitutes for the 5-HT1A receptor agonist LY293284 in the drug discrimination assay in rats.
BACKGROUND
Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug with a low incidence of side effects. The therapeutic action of aripiprazole has been attributed to its unique agonist/antagonist effects at D(2) dopamine receptors; however, aripiprazole also has significant in vitro affinity at 5-HT(1A) receptors.


OBJECTIVE
The 5-HT(1A) agonist property of aripiprazole has so far not been evaluated in any in vivo assay.


METHODS
Thirteen male Sprague Dawley rats trained to discriminate the 5-HT(1A) agonist LY 293284 (75 nmol/kg) from saline, using a fixed ratio (FR) 50 schedule of food-reinforcement in a two-lever operant-conditioning task, were used to evaluate the behavioral effect of aripiprazole at 5-HT(1A) receptors.


RESULTS
Aripiprazole fully mimicked LY 293284 in a drug-discrimination assay with an ED(50) of 1.39 micromol/kg (0.62 mg/kg). In combination tests, aripiprazole did not block the LY 293284 cue but at 8.92 micromol/kg (4 mg/kg) significantly reduced the response rate by lowering the threshold for induction of the 5-HT syndrome produced by the training dose of LY 293284. Moreover, the selective 5HT(1A) receptor antagonist WAY 100635 was able to block the substitution of aripiprazole in LY-293284 trained rats.


CONCLUSIONS
Although the efficacy of aripiprazole against the positive symptoms of schizophrenia may be related to its dopamine receptor interactions, it seems possible that its atypical profile may derive, at least in part, from its 5-HT(1A) agonist effect, rather than from unusual D(2) receptor properties.
Marona-Lewicka
Danuta
D
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy-RHPH, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907-2091, USA.
Nichols
David E
DE
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D004347:Drug Interactions; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D014363:Tryptamines / Q000494:pharmacology*
D014150:Antipsychotic Agents; D010879:Piperazines; D011725:Pyridines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D014363:Tryptamines; C089776:LY 293284; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000068180:Aripiprazole