Behavioral Pharmacology of AR-A000002, a Novel, Selective 5-Hydroxytryptamine1B Antagonist (original) (raw)

2002, J Pharmacol Exp Ther

The present review summarizes the behavioral pharmacology conducted to profile the anxiolytic and antidepressant potential of the selective 5-HT 1B antagonist, AR-A000002 ((R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4tetrahydro-2-naphthyl]-4-morpholinobenzamide). AR-A000002 functions as a 5-HT 1B antagonist in vivo, which was shown by the antagonism of the discriminative stimulus effects in the guinea pig of the 5-HT 1B agonist CP135,807 ([3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-lH-indole]). 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 (DRL) schedule of reinforcement, AR-A000002 increased the number of reinforcers earned without altering the number of responses made. In guinea pigs trained under a response duration differentiation (RDD) 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-HT 1B antagonists in the treatment of both anxiety and affective disorders.

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