AbstractThe recent observation that the central oxytocin (OT) receptor has high affinity for both OT and arginine vasopressin (AVP) raises the possibility that it may be involved in some of the central actions of AVP. Repeated intracerebroventricular (icv) injections of AVP in rats evoke an unusual sensitization phenomenon in that a first exposure to the peptide enhances the sensitivity (sensitization) of the brain to a second exposure. This report investigates the possibility that the OT receptor may be involved in the mediation of the phenomenon of sensitization, using OT, a specific OT receptor agonist, [Thr4, Gly7]OT, and a specific OT receptor antagonist, d(CH2)5, [Tyr(Me)2, Thr4, Tyr‐NH29]OVT (compound 6; cpd 6), as well as a V1 AVP receptor antagonist, d(CH2)5Tyr(Me)AVP. Peptides were injected icv in conscious, adult male Sprague‐Dawley rats. The data showed that: 1) a first icv AVP injection (10 pmol/5μl) enhanced the sensitivity of the rat brain to the motor response of a second AVP injection (10 pmol/5 μl) given 24 h later; 2) injection of d(CH2)5Tyr(Me)AVP (100 pmol/5 μl icv) but not cpd 6, (100 pmol/5 μl icv) 2 min prior to the first AVP injection, blocked AVP‐induced sensitization; 3) a first injection of OT or [Thr4, Gly7]OT (10 pmol/5 μl) enhanced the sensitivity of the brain to the motor actions of a subsequent AVP injection given 24 h later; 4) the magnitude of this cross‐sensitization induced by OT pretreatment varied with dose and appeared to be ten times more potent than the sensitization induced by a first AVP injection; 5) injection of cpd 6 (100 pmol/5 μl) but not d(CH2)5Tyr(Me)AVP (100 pmol/5 μl icv) 2 min prior to the first OT injection (1 pmol/5 μl) blocked the cross‐sensitization induced by OT; 6) an injection of OT (100 to 1,000 pmol/5 μl) or [Thr4, Gly7]OT (10 pmol/5 μl) in rats that had been cross‐sensitized with OT or [Thr4, Gly7]OT pretreatment did not evoke enhanced motor responses; 7) OT injected 2 min prior to the second AVP injection in AVP‐sensitized rats did not block the enhanced AVP‐induced motor responses; 8) AVP‐induced [3H]inositol monophosphate accumulation in septal slices was also enhanced in rats cross‐sensitized by OT pretreatment.These results suggest that while pre‐exposure of the rat brain to both AVP and OT alters the responsiveness of the rat brain to subsequent AVP exposures, AVP sensitization appears to be mediated via the V1 AVP receptor, whereas cross‐sensitization by OT may be mediated via the OT receptor. The ability of OT to alter the responsiveness of the rat brain to subsequent AVP injection suggests a role for this peptide