P.6.008 - Role of noradrenergic, dopaminergic, serotonergic and opioidergic systems on the effect of neonatal handling in learned helplessness

Abstract

The dysregulation of arginine vasopressin (AVP) release and activation of vasopressin V1A and V2 receptors may play a role in disease. The in vitro and in vivo pharmacology of RWJ-676070, a potent, balanced antagonist of both the V1A and V2 receptors is described. RWJ-676070 binding and intracellular functional antagonist activity was characterized using cells expressing V1A, V1B or V2 receptors. Its inhibition of V1A receptor-mediated contraction of vascular rings and platelet aggregation was determined. V2 receptor-medated aquaresis was determined in rats, dogs and monkeys. V1A receptor-mediated inhibitory activity was assessed in vivo in a vasopressin-induced hypertension model and in normotensive rats and in two hypertensive rat models. RWJ-676070 inhibited AVP binding to human V1A and V2 receptors (Ki = 1 and 14 nM, respectively). RWJ-676070 inhibited V1A receptor-induced intracellular calcium mobilization and V2 receptor-induced cAMP accumulation with Ki values of 14 nM and 13 nM, respectively. The compound was slightly less potent against rat V1A receptors. RWJ-676070 inhibited V1A receptor-mediated vasoconstriction in rat and dog vascular rings and AVP-induced human platelet aggregation. Dose dependent aquaresis was demonstrated in rats, dogs and monkeys following oral administration. RWJ-676070 inhibited AVP-induced hypertension in rats but had no effect on arterial pressure in normotensive and spontaneously hypertensive rats but did decrease arterial pressure in Dahl, salt-sensitive hypertensive rats. RWJ-676070 is a new, potent antagonist of V1A and V2 receptors that may be useful for treatment of diseases benefiting from balanced inhibition of both V1A and V2 receptors.