The atypical 5‐HT 2 receptor mediating tachycardia in pithed rats: pharmacological correlation with the 5‐HT 2A receptor subtype

In pithed rats, 5‐HT mediates tachycardia both directly (by 5‐HT 2 receptors) and indirectly (by a tyramine‐like effect). The receptor mediating tachycardia directly has been classified as an ‘atypical’ 5‐HT 2 receptor since it was ‘weakly’ blocked by ketanserin. Moreover, 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI), a 5‐HT 2 agonist, failed to mimic 5‐HT‐induced tachycardia. Since 5‐HT 2 receptors consist of 5‐HT 2A , 5‐HT 2B and 5‐HT 2C subtypes, this study investigated if these subtypes mediate the above response. In pithed rats, intraperitoneally (i.p.) pre‐treated with reserpine (5 mg kg −1 ), intravenous (i.v.) administration of 5‐HT, 5‐methoxytryptamine (5‐MeO‐T), 1‐(3‐chlorophenyl) piperazine ( m CPP) and 5‐carboxamidotryptamine (5‐CT) (10, 30, 100 and 300 μg kg −1 each), produced dose‐dependent tachycardic responses. Interestingly, DOI (10 – 1000 μg kg −1 , i.v.) induced only slight, dose‐unrelated, tachycardic responses, whilst the 5‐HT 2C agonist, Ro 60‐0175 (10 – 1000 μg kg −1 , i.v.), produced a slight tachycardia only at 300 and 1000 μg kg −1 . In contrast, sumatriptan and 1‐(m‐trifluoromethylphenyl)‐ piperazine (TFMPP) were inactive. The rank order of potency was: 5‐HT5‐MeO‐T> m CPP5‐CTDOI>Ro 60‐0175. The tachycardic responses to 5‐HT, which remained unaffected after i.v. saline (0.3 and 1 ml kg −1 ) or propranolol (3 mg kg −1 ), were selectively blocked by the 5‐HT 2A antagonists ketanserin (30 and 100 μg kg −1 ) or spiperone (10 and 30 μg kg −1 ) as well as by the non‐selective 5‐HT 2 antagonists, ritanserin (10 and 30 μg kg −1 ) or mesulergine (100 μg kg −1 ). Remarkably, these responses were unaffected by the antagonists rauwolscine (5‐HT 2B ), SB204741 (5‐HT 2B/2C ) or Ro 04‐6790 (5‐ht 6 ) (300 and 1000 μg kg −1 each). These results suggest that the ‘atypical’ 5‐HT 2 receptors mediating tachycardia in reserpinized pithed rats are pharmacologically similar to the 5‐HT 2A receptor subtype.British Journal of Pharmacology (2002) 135 , 1531–1539; doi: 10.1038/sj.bjp.0704593