Presynaptic uptake blockade hypothesis for LSD action at the lateral inhibitory synapse in Limulus

Area of Science:

• Neuroscience
• Pharmacology
• Vision research

Background:

• The lateral eye of Limulus polyphemus provides a model for studying synaptic transmission.
• Understanding the mechanisms of action for psychoactive compounds like LSD is crucial.

Purpose of the Study:

• To investigate the effects of LSD on the indoleaminergic lateral inhibitory synapse in the Limulus lateral eye.
• To elucidate the mechanism by which LSD modulates synaptic inhibition.

Main Methods:

• Extracellular and intracellular voltage recordings from eccentric cells in Limulus.
• Modulation of synaptic transmission using varying concentrations of LSD, serotonin (5-HT), and chlorimipramine.
• Utilizing high Mg++ and low Ca++ bathing media to block synaptic transmission.

Main Results:

• Low concentrations (1-5 microM) of LSD enhanced lateral inhibition, while higher concentrations (5-20 microM) suppressed it.
• LSD's effects were diminished in high Mg++/low Ca++ conditions, indicating a requirement for intact synaptic mechanisms.
• Chlorimipramine mimicked LSD's effects, suggesting a role in serotonin reuptake inhibition.
• Serotonin (5-HT) depressed lateral inhibition at all tested concentrations.

Conclusions:

• LSD likely acts by blocking presynaptic serotonin reuptake, prolonging synaptic effects at low doses.
• High LSD concentrations may lead to postsynaptic desensitization due to transmitter accumulation.
• Serotonin appears to have a direct postsynaptic effect, contrasting with LSD's presynaptic action.