INTRACEREBROVENTRICULAR ADMINISTRATION OF ANGIOTENSIN TYPE-1 (AT(1)) RECEPTOR ANTISENSE OLIGONUCLEOTIDES ATTENUATE THIRST IN THE RAT

The central actions of the peptide hormone angiotensin II (AngII) are importantly involved in body fluid homeostasis. Included amongst these actions is a potent dipsogenic response that has been implicated in t he thirst that develops during many forms of extracellular dehydration . The use of highly selective receptor antagonists has revealed that t he Type 1 (AT(1)), and not the Type 2 (AT(2)), AngII receptor subtype mediates this drinking response. More recently, antisense oligonucleot ides specific for the AT(1) receptor have been developed and after int racerebroventricular (i.c.v.) administration, they significantly reduc e the dipsogenic response elicited by a similar injection of AngII. In the present study AT(1) antisense oligonucleotides were used to furth er investigate their effect on experimentally induced thirst in the ra t. In addition, immunohistochemical analysis of biotin-labeled oligonu cleotides was performed in order to correlate the behavioral effects o f the oligonucleotides with their distribution in the brain. The resul ts demonstrated that the antidipsogenic effects of the oligonucleotide s were dose and time-dependent and were limited to those thirst challe nges that involve activation of the renin-angiotensin system. Collecti vely, these results demonstrate the efficacy and behavioral specificit y of these oligonucleotides, as well as their utility in investigating the physiological role of cerebral AngII receptor subpopulations in v arious models of thirst.