5-Hydroxytryptamine1C/2 agonists in the thoracic spinal cord: cardiovascular effects and binding sites in the...

The presence of 5-hydroxytryptamine (5-HT)1C/2 binding sites in autonomic regions of the thoracic spinal cord and their role in the regulation of sympathetic outflow to the cardiovascular system were examined. Light microscopic receptor autoradiography was used to visualize the binding of the 5-HT1C/2 ligand, [125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [( 125I]DOI). In thoracic spinal cord, a discrete and preferential localization of specific [125I]DOI binding sites was found in the intermediolateral cell column. To determine the mean arterial pressure (MAP) and heart rate (HR) effects resulting from activation of 5-HT1C/2 receptors in spinal cord, DOI and alpha-methyl-5-HT were administered intrathecally (i.t.) to anesthetized, artificially ventilated rats. DOI (1-100 micrograms) caused initial decreases followed by increases in MAP and HR, whereas alpha-methyl-5-HT (1-30 micrograms) only decreased MAP and HR. The distribution of [125I]DOI after i.t. administration and the effects of a peripherally administered 5-HT1C/2 antagonist 6-methyl-1-(1-methylethyl)-ergoline-8 beta-carboxylic acid, 2-hydroxyl-1-methyl propyl ester and maleate salt (LY53857) showed that the pressor effects of i.t. DOI were due to peripheral leakage and suggested that the depressor effects were due to a spinal site of action. The depressor effects of DOI were prevented by peripheral administration of phentolamine. Pretreatment with i.t. administration of 5-HT1C/2 antagonists (LY53857, ketanserin and mianserin) did not block the depressor or bradycardic effects of i.t. administration of DOI. Only LY53857 was effective in blocking the depressor effects of i.t. administration of alpha-methyl-5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)