Anxiogenic-like effects and reduced stereological counting of immunolabelled 5-hydroxytryptamine(6) receptors in rat nucleus accumbens by antisense oligonucleotides

The physiological role of 5-hydroxytryptamine(6) receptors in the central n ervous system has not yet been elucidated. The high affinity of Various psy chotropic drugs for 5-hydroxytryptamine(6) receptors has led to the suggest ion that this receptor type may be a novel target in neuropsychiatry. We ha ve found that continuous intracerebroventricular administration of a 5-hydr oxytryptamine(6) receptor antisense oligonucleotide, but not of a missense oligonucleotide, produced an anxiogenic-like response in rats using two dif ferent models of anxiety, the social interaction test and the elevated plus -maze. Neither oligonucleotide treatment modified locomotor activity, recta l temperature or food intake, suggesting a low or null neurotoxicity. The e ffectiveness of the treatment with the designed antisense oligonucleotide t o block the synthesis of the protein encoded by the target mRNA was assesse d by immunolabelling 5-hydroxytryptamine6 receptors in the nucleus accumben s, where this receptor is highly expressed, using previously characterized specific antibodies. The density of the immunostaining was quantified by me ans of an unbiased three-dimensional stereologic procedure, which revealed a significant reduction (-25%) in the number of immunolabelled neuronal ele ments. These results suggest that, in addition to other 5-hydroxytryptamine recept or subtypes, 5-hydroxytryptamine6 receptors in the nucleus accumbens may pa rticipate in anxiety-related neurobiological mechanisms. (C) 1999 IBRO. Pub lished by Elsevier Science Ltd.