Central 5-HT2 Receptors Research Articles

Central Hypotensive Activity of Ketanserin in Cats

Ketanserin, when infused into the left thoracic vertebral artery of chloralose-anaesthetized cats, induced a significantly stronger hypotensive effect than when administered via the systemic circulation. The effect of ketanserin, which is initiated most likely in the pontomedullary region of the brain, proved to be dose dependent. The central hypotensive effect of ketanserin was accompanied by modest bradycardia, which was probably also of central nervous origin. The selective 5-HT2-receptor antagonist ritanserin, when infused into the left vertebral artery, did not lower blood pressure or heart rate, thus suggesting that central 5-HT2 receptors do not play a significant role in the initiation of ketanserin's central hypotensive action. Similarly, neither α1- nor α2-adrenoceptors in the central nervous system (CNS) appear to be involved in the hypotensive action of ketanserin, as concluded from pretreat-ment experiments with corynanthine and rauwolscine, respectively. The central hypotensive action could be blocked by atropine. This effect is located within the CNS but does not implicate a direct influence of ketanserin on CNS muscarinic receptors.

2-[125Iodo]LSD, a new ligand for the characterisation and localisation of 5-HT2 receptors.

LSD was iodinated with Na125I and chloramine T, to get the radioligand [125I]LSD ( 125IOL ) and with N-I-succinimide to obtain the nonradioactive compound 2-I-LSD (IOL) for comparative pharmacological studies. The introduction of iodine in position 2 of LSD leads to an increase in selectivity for 5HT2 receptors. In rat cortex membranes, 125IOL possesses a KD = 0.9 +/- 0.1 nmol/l, Bmax = 240 +/- 20 fmoles/mg, and a nonspecific binding of 30-40% in presence of 100 nmol/l ketanserin. In competition experiments, 5HT antagonists showed monophasic displacement curves. Their KI-values correlate well with pD'2-values for inhibition of 5HT-induced contraction of canine basilar artery. It can be concluded that the sites labelled by 125IOL have pharmacological properties in common with central 5HT2 receptors, which are identical with vascular postjunctional 5HT receptors. The high specific radioactivity of 125IOL permits detection of even small 5HT2 receptor densities which exist in the guinea pig ileum. These 125IOL binding sites are pharmacologically different to those found in the brain or on the vessels and might be a special subpopulation of 5HT2 sites. For example, ketanserin has a high affinity to the sites labelled by 125IOL in the brain and a 100 times lower affinity to the sites labelled in the ileum. In a routine binding screen with various ligands, the inhibition constants of IOL for alpha 1, alpha 2, beta, histamine and muscarinic receptors are greater than 100 nmol/l with the exception for dopamine receptors, 40 nmol/l. 125IOL was employed for the autoradiographic localisation of its binding sites after in vitro labelling of microtome rat brain sections. 125IOL labelled 5HT2 sites in the cortex and dopamine receptors in the nucleus caudatus. The exposure times required were very short, compared to those of other 5HT2 ligands available.