Abstract
The present review summarizes the behavioral pharmacology conducted to profile the anxiolytic and antidepressant potential of the selective 5-hydroxytryptamine (HT)1B antagonist (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide (AR-A000002). AR-A000002 functions as a 5-HT1B antagonist in vivo, which was shown by the antagonism of the discriminative stimulus effects in the guinea pig of the 5-HT1B agonist 3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-lH-indole (CP135,807). Anxiolytic activity of AR-A000002 was demonstrated in the separation-induced vocalization paradigm in guinea pig pups, and in a suppressed responding procedure in pigeons and guinea pigs, but only a weak trend was noted in a suppressed responding procedure in squirrel monkeys. Antidepressant efficacy was shown in a number of paradigms. In pigeons and guinea pigs responding under a differential reinforcement of low rates schedule of reinforcement (DRL), AR-A000002 increased the number of reinforcers earned without altering the number of responses made. In guinea pigs trained under a response duration differentiation paradigm, AR-A000002 increased mean lever-press duration. Finally, AR-A000002 was shown to block escape failures in guinea pigs submitted to a learned helplessness paradigm. Taken together, these data suggest utility for 5-HT1B antagonists in the treatment of both anxiety and affective disorders.
Footnotes
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DOI: 10.1124/jpet.102.045468
- Abbreviations:
- AR-A000002
- (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide
- CP135,807
- 3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-lH-indole
- 5-HT
- 5-hydroxytryptamine
- SSRI
- selective serotonin reuptake inhibitor
- DRL
- differential reinforcement of low rates
- RDD
- response duration differentiation
- FR
- fixed ratio
- FI
- fixed interval
- VI
- variable interval
- ANOVA
- analysis of variance
- IRT
- inter-response time
- 8-OH-DPAT
- 8-hydroxy-2-dipropylaminotetralin
- GR127935
- 2′-methyl-4′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-(5-methoxy-3(4-methyl-piperazin-1-yl)-phenyl]amide
- CP135807
- 3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-lH-indole
- NAS-181
- ((R)-(+)-2-(3-morpholinomethyl-2H-chromen-8-yl)oxy-methyl morpholine
- Received October 10, 2002.
- Accepted November 18, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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