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Expression and Functional Analysis of Dopamine Receptor Subtype 2 and Somatostatin Receptor Subtypes in Canine Cushing’s Disease

Department of Internal Medicine (C.d.B., A.M.W., P.U., S.W.J.L., L.J.H.), Division of Endocrinology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; and Department of Clinical Sciences of Companion Animals (J.M.H., B.P.M., H.S.K.), Faculty of Veterinary Medicine, Utrecht University, 3508 TD Utrecht, The Netherlands

Address all correspondence and requests for reprints to: C. de Bruin, M.D., Department of Internal Medicine, Room Ee569, Erasmus Medical Center, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. E-mail: c.debruin{at}erasmusmc.nl.

Cushing’s disease (CD) is a severe disorder characterized by chronic hypercortisolism due to an ACTH-secreting pituitary adenoma. Transsphenoidal adenomectomy is the treatment of choice in humans with CD, but recurrences occur frequently. Finding an effective and safe medical treatment for CD may improve long-term clinical outcome. The recent demonstration of expression of somatostatin receptor subtypes (mainly sst₅) and dopamine receptor subtype 2 (D₂) in human corticotroph adenomas offers the possibility for medical treatment of CD with novel somatostatin analogs and dopamine agonists. Investigation of the effects of these drugs is hampered by the low incidence of CD in humans. Interestingly, CD is a frequent disorder in dogs with striking clinical similarities with CD in humans. Therefore, we investigated the expression and functional role of D₂ and somatostatin receptors in corticotroph adenoma cells from 13 dogs with active CD that underwent therapeutic hypophysectomy and normal anterior pituitary cells from five dogs. Quantitative RT-PCR and immunohistochemistry revealed that both in CD and normal anterior pituitary, sst₂ was the predominant receptor subtype expressed, whereas D₂ was modestly expressed and sst₅ was expressed only at very low levels. In primary cultures of canine adenomas (n = 7), the sst₂-preferring agonist octreotide also showed the strongest ACTH-suppressive effects. In conclusion, canine corticotroph adenomas provide an interesting model to study CD, but differences in somatostatin and dopamine receptor expression between humans and dogs should be taken into account when using dogs with CD as a model to evaluate efficacy of novel somatostatin analogs and dopamine agonists for human CD.