Nerve terminal effects of indoleamine psychotomimetics on 5-hydroxytryptamine.

Indoleamine psychotomimetics like LSD increase serotonin (5-HT) levels in rat brain nerve endings, particularly in synaptic vesicles, an effect not seen with mescaline. Pretreatment with reserpine shifts the serotonin increase to a juxtavesicular compartment. The serotonin increment originates from newly synthesized amine, as shown by experiments with synthesis blockers. Destruction of raphé cell bodies does not abolish LSD's effect early after lesioning, but destruction of cortical serotonin neurons with 5,7-dihydroxytryptamine does, indicating an intact nerve terminal is required. An LSD 'autoreceptor,' possibly a presynaptic serotonin receptor that inhibits release, is postulated.

Study at a glance

Abstract

The mode of action of indoleamine psychotomimetics has been closely linked to 5-HT. Early work showed increases in rat brain levels of 5-HT which were later localized to the nerve-ending fraction. With improved methodology, the 5-HT increment was further detected in the synaptic vesicle fraction. These effects were obtained with several indoleamine hallucinogens but not with mescaline. LSD has been most thoroughly studied and has served as the prototypical compound in ascertaining the mode of action of these drugs. Pretreatment with reserpine abolished the 5-HT effects of LSD in the vesicular fraction. However, a new compartment, termed "juxtavesicular," displayed 5-HT increases following reserpine and LSD. A soluble binding site for 5-HT within the synaptoplasm has been postulated in confirmation of independent results by other groups of investigators. The origin of the 5-HT increment appears to be associated with newly synthesized amine. This was deduced from experiments involving various 5-HT synthesis blockers. To ascertain whether inhibition of raphé neuronal firing is responsible for the accumulation of 5-HT at the nerve terminal, two sets of experiments were performed. Destruction of the raphé cell bodies by radiofrequency lesions failed to abolish the LSD-induced 5-HT increase early after the lesion. Destruction of cortical 5-HT neurons with the neurotoxin 5,7-dihydroxytryptamine completely abolished the 5-HT effect of LSD. It was concluded that an intact nerve terminal is necessary for the expression of the LSD-mediated increases in 5-HT. A LSD "autoreceptor" is postulated, possibly identical to a 5-HT presynaptic receptor inhibiting the release of 5-HT.