Effects of long-term administration of the 5-hydroxytryptamine1B receptor antagonist AR-A000002 to guinea pigs.
BACKGROUND
Recently a new 5-hydroxytryptamine1B (5-HT1B)-receptor antagonist, AR-A000002, was described. It was shown that this compound dose dependently increased 5-HT metabolism and release in guinea pig brain following a single injection.


OBJECTIVE
The present study investigated effects of 3 weeks twice-daily treatment of guinea pigs with the 5-HT1B-receptor antagonist AR-A000002 on the serotonergic neurons and receptor densities.


METHODS
Guinea pigs were injected subcutaneously with AR-A000002, citalopram or saline twice daily for 3 weeks. Groups of animals were treated with challenge doses of AR-A000002 or saline 24 h after the last chronic treatment (citalopram group 48 h) and sacrificed 2 h thereafter. The effect on 5-HT metabolism and 5-HT release was assessed. Plasma and brain concentrations of AR-A000002 were analysed. The effects on binding of [3H]8-OH-DPAT to 5-HT1A receptors, [3H]GR125743 to 5-HT(1B/1D) receptors, [3H]ketanserin to 5-HT2A receptors, and [3H]prazosin to alpha1-adrenoceptors were determined.


RESULTS
Repeated treatment of guinea pigs with AR-A000002 did not change the 5-HT(1B/1D), 5-HT1A, 5-HT2A or alpha1-adrenergic receptor densities. Following repeated treatment of guinea pigs for 3 weeks with AR-A000002, the 5-HT1B receptors were still receptive to a challenge with the same compound. Thus, an increase in the 5-HIAA/5-HT ratio and 5-HT release was seen following challenge doses of AR-A000002. No difference in the plasma and brain concentrations of AR-A000002 was found between the sub-chronic treated AR-A000002 and saline-treated guinea pigs.


CONCLUSIONS
It is concluded that AR-A000002 is a 5-HT1B receptor antagonist, which enhances persistently the serotonergic neurotransmission in guinea pig brain.
Stenfors
Carina
C
Local Discovery, AstraZeneca R&D Södertälje, 151 85 Södertälje, Sweden. carina.stenfors@astrazeneca.com
Ahlgren
Charlotte
C
Yu
Hong
H
Wedén
Maria
M
Larsson
Lars-Gunnar
LG
Ross
Svante B
SB
D000818:Animals; D001549:Benzamides / Q000097:blood / Q000494:pharmacology*; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D017551:Microdialysis; D009025:Morpholines / Q000097:blood / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D001549:Benzamides; D015283:Citalopram; D009025:Morpholines; D012701:Serotonin; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C473209:N-(5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl)-4-morpholinobenzamide