Cardiovascular and behavioral responses to novelty stress after single or dual orexin receptor blockade in the rat

Abstract

Orexins play a critical role in the regulation of arousal by acting on two receptors, OX1 and OX2. We have previously reported that blockade of OX1 and OX2 with the dual receptor antagonist Almorexant reduces the cardiovascular and behavioral responses to novelty stress. The aim of the study was to compare Almorexant to two new selective OX1 and OX2 antagonists. Rats implanted with telemetric probes were given i.p. injections of either Almorexant, ACT‐335827 (OX1 antagonist, Actelion Pharmaceuticals), or EMPA (OX2 antagonist, Roche) and after 2.5 hours were subjected to novelty stress for 30 min. In vehicle‐injected rats, Novelty increased locomotor activity, blood pressure and heart rate. At 30 mg/kg, Almorexant (n=12) significantly reduced the locomotor and cardiac responses, but neither ACT‐335827 (n=12) nor EMPA (n=8) nor a cocktail of ACT‐335827 and EMPA (n=8) had any significant effect. At 100 mg/kg, Almorexant (n=10) significantly reduced all three responses, ACT‐335827 (n=9), the pressor and cardiac but not locomotor response, EMPA (n=10) the cardiac response only and the cocktail of ACT‐335827 and EMPA (n=11) all three responses at the same magnitude as Almorexant. Thus, systemic blockade of one orexin receptor alone is not sufficient to produce the same effect as blockade of both receptors, at least for novelty stress. The two receptors may act synergistically.Supported by NHMRC‐Australia