Proconvulsive effect of vasopressin; mediation by a putative V 2 receptor subtype in the central nervous system

Abstract

Subcutaneously (s.c.) administered [Arg 8]vasopressin (AVP) potentiated seizures induced by intracerebroventricular (i.c.v.) injection of 1.95 mg pilocarpine (a muscarinic cholinergic agonist). A bell-shaped relation between dose and effect was found. I.c.v. pretreatment with a V 1, V 2 or oxytocin receptor antagonist was performed to determine whether and what type of receptor is involved in this proconvulsive effect of vasopressin. For these experiments a higher dose of pilocarpine (2.4 mg i.c.v.) was injected. This caused seizures in a slightly but not significantly higher percentage of the rats. A dose-dependent protective action of the V 2 receptor antagonist d(CH 2) 5[ d-Ile 2,Ile 4]AVP (effective doses were 25 and 125 ng) on seizures was found. A reduction was observed in the number of animals that developed tonic-clonic convulsions. Neither the V 1 receptor antagonist d(CH 2) 5[Tyr(Me) 2]AVP nor the oxytocin receptor antagonist desGly(NH 2) 9d(CH 2) 5[Tyr(Me) 2Thr 4]OVT possessed anti-convulsive activity. Subsequently the type of receptor was studied in detail with fragments of AVP with either V 1 or V 2 activity. AVP (with V 1 and V 2 affinity) (1 and 3 μg s.c.) potentiated pilocarpine (1.95 mg) induced seizures. Vasotocin and oxytocin were without effect. Interestingly neither s.c. nor i.c.v. administration of the selective kidney type vasopressin receptor (V 2) agonist dDAVP potentiated pilocarpine induced seizures. Several selective antidiuretic agonists (V 2), such as d[Val 4]AVP, d[Phe 2,Val 4, d-Arg 8]vasopressin (3 μg), [Val 4, d-Arg 8]vasopressin (3 μg) and d[Val 4, d-Arg 8]vasopressin (3 μg) were active. Other selective antidiuretic compounds, such as [Val 4]AVP, dAVP, d[Tyr(Me) 2]AVP and HO[ d-Arg 8]vasopressin (3 μg) did not influence seizures. These results demonstrate that a combination of substitution of aminoacid 4 (Gln) by Val and to a lesser extent deamination and the d-arginine form yield an active molecule, which can potentiate pilocarpine induced seizures and suggest the existence of a V 2 receptor subtype in the brain.