Receptor mechanisms in increased sensitivity to serotonin agonists after dihydroxytryptamine shown by electronic monitoring of muscle twitches in the rat

Rats whose serotonin-producing neurons were destroyed by the chemical 5,7-DHT developed muscle twitching (myoclonus) after receiving L-5-HTP or a serotonin-like drug. The twitching was dose-dependent and blocked by serotonin antagonists. Even large serotonin increases in intact rats did not cause twitching unless an enzyme was first inhibited. Repeated drug doses reduced the response, and this reduction was blocked by a serotonin antagonist, while repeated antagonist pretreatment increased the response. The findings suggest that after serotonin nerve damage, changes in postsynaptic receptors underlie behavioral supersensitivity, and restoring serotonin or stimulating its receptors may suppress the development of supersensitivity at the receiving membranes.

Study at a glance

Abstract

Muscle twitches and autonomic changes were induced by systemic injections of L -5-hydroxytryptophan (5-HTP) or the serotonin agonist 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT) in rats previously lesioned with intracranial 5,7-dihydroxytryptamine (5,7-DHT) after desmethylimipramine. Movements were recorded sensitively and continuously by an electronic activity monitor. Spontaneous locomotor activity was strongly reduced after 5-HTP in both intact and lesioned rats, so that electronically recorded activity correlated very closely with disordered jerking movements scored by a behavioral rating scale. This myoclonus was dependent on the doses of 5-HTP and of 5,7-DHT and was strongly inhibited by serotonin antagonists. In lesioned rats, myoclonus occurred with unaltered activity of monoamine oxidase (MAO) and after only small increases in serotonin levels after 5-HTP, but even large increases in availability of serotonin in intact rats, or strong inhibition of serotonin uptake failed to induce myoclonus unless MAO was first inhibited. The response to 5-HTP in lesioned rats was attenuated by repeated injections of 5-HTP or 5-MeO-DMT. This decreased response was in turn blocked by repeated doses of a serotonin antagonist, but appeared not to be due to altered metabolism of 5-HTP or of serotonin; repeated pretreatment with cyproheptadine potentiated the myoclonic response to 5-HTP after DHT. Changes in postsynaptic receptors may be important in the behavioral supersentivity following 5,7-DHT, and restitution of serotonin or stimulation of its receptors after presynaptic denervation may suppress an evolving supersensitivity at receptive postsynaptic membranes.