Abstract
Rationale
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.
Objectives
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-HT1B/1D receptors, [3H]ketanserin to 5-HT2A receptors, and [3H]prazosin to α1-adrenoceptors were determined.
Results
Repeated treatment of guinea pigs with AR-A000002 did not change the 5-HT1B/1D, 5-HT1A, 5-HT2A or α1-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.
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Acknowledgement
We thank Maria Sällemark for the receptor binding studies.
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Stenfors, C., Ahlgren, C., Yu, H. et al. Effects of long-term administration of the 5-hydroxytryptamine1B receptor antagonist AR-A000002 to guinea pigs. Psychopharmacology 172, 333–340 (2004). https://doi.org/10.1007/s00213-003-1667-8
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DOI: https://doi.org/10.1007/s00213-003-1667-8