Synaptic Transmitters Involved in LSD Administration

Synaptic Transmitters Involved in LSD Administration

The nearly concurrent discovery of serotonin (5-HT) and LSD-25

in the 1950 's encouraged a lot of research to be done on the

relationship between LSD and serotonin, which helped to develop

a greater understanding of the role serotonin plays as a

neurotransmitter in the brain (Nichols, 2004). Today it is

believed that LSD (and other hallucinogens) stimulate 5-HT2A

receptors (Kalat, 2004). Activation of these receptors causes

cortical glutamate levels to increase. This is presumed to be a

result of a "presynaptic receptor-mediated release" from neurons

in the thalumus (Nichols, 2004).

Early studies proposed that LSD antagonized the effects of

serotonin on peripheral tissues. It was later proposed that the

psychoactive properties of LSD may be a result of the blocking

of serotonin receptors in the central nervous system (Nichols,

2004). This theory was short-lived however when it was

discovered that a brominated derivative of LSD (BOL),a potent

serotonin antagonist in peripheral tissues, was found to have

essentially no LSD like effects. In 1961, Freedman found that

systematic use of LSD elevated serotonin content in the brain

(cited in Nichols, 2004). In a later study in 1967, Rosencrans,

et al. reported that LSD also reduced brain levels of acetic

acid (5-HIAA) (cited in Nichols, 2004). The combined findings of

these two studies demonstrated that LSD decreased serotonin

turnover in the brain.

It is now widely accepted that hallucinogen action is primarily

located on receptor 5-HT2A. In a study done in 1955, scientists

found that daily administration of LSD resulted in an almost

complete loss of sensitivity to the drug after 4 days. It is now

believed that this is a result of 5-HT2A receptor down-regulation

(cited in Nichols, 2004). In a later study published in 1985, it

was found that daily LSD administration selectively decreased 5-

HT2 receptor density in rat brains (Nichols, 2004).

Studies have shown that activation of 5-HT2A receptors increase

inhibitory post-synaptic potentials. However, when compared to

serotonin, the maximum effect produced by LSD is 30-50% of that

of serotonin. LSD is therefore a partial agonist, rather than an

antagonist (Nichols, 2004). Antagonists block the action of a

neurotransmitter, whereas agonists mimic or increase the effects

of a neurotransmitter (Kalat, 2004). Conversely, LSD is a weak

agonist when compared to less intoxicating compounds with

stronger behavioral influences. Therefore it is thought that LSD

must either activate another monoamine receptor that works with