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Abstract Rationale: Orexins A and B have recently been discovered and shown to be derived from preproorexin, primarily expressed in the rat hypothalamus. Orexin-A has been ascribed a number of in vivo functions in the rat after intracerebroventricular (ICV) administration, including hyperphagia, neuroendocrine modulation and, most recently, evidence for a behavioural response characterised by an increase in grooming. Objectives: Here, we have investigated the orexin-receptor subtypes involved in the grooming response to orexin-A (3 micro g, ICV) in the rat. Methods: Male rats, habituated to clear Perspex behavioural observation boxes, were pretreated with antagonists with mixed selectivity for OX[sub 1], OX[sub 2], 5-HT[sub 2B] and 5-HT[sub 2C] receptor subtypes prior to the administration of orexin-A and the intense grooming response elicited by this peptide assessed. Results: Pretreatment of rats with a mixed OX[sub 1]/5-HT[sub 2B/2C] receptor antagonist 1-(4-methylsulfanylphenyl)-3-quinolin-4-ylurea (SB-284422), revealed a significant, but incomplete, blockade of orexin-A-induced grooming. Despite the low potency of orexin-A at 5-HT[sub 2B] and 5HT[sub 2C] receptors in vitro (pKi<5), studies were undertaken to determine whether downstream 5-HT[sub 2B] or 5-HT[sub 2C] receptors mediate in the grooming-elicited by orexin-A. Whilst the selective 5-HT[sub 2B] receptor antagonist, SB-215505 (3 mg/kg, PO, 5-HT[sub 2B], pKi=8.58; OX[sub 1], pK[sub B]<5.15) failed to effect orexin-A-induced grooming, the selective 5-HT[sub 2C] receptor antagonist, SB-242084 (1 mg/kg, IP, 5-HT[sub 2C], pKi=8.95; OX[sub 1], pK[sub B]<5.1) potently antagonised the grooming response to this peptide. This suggested that the partial blockade of... [ABSTRACT FROM AUTHOR]