A new study helps explain why psychedelic or hallucinogenic drugs like LSD (lysergic acid diethylamide) produce unique and different effects in mood and behavior than their chemical cousins, such as lisuride, a treatment for Parkinson’s disease. The answer? It’s not where these drugs trigger neurological activity, but how, a finding that could have implications in developing more targeted medications without the unwanted side effects that often occur in the treatment of drug abuse and neurological and psychiatric disorders, explains study co-author Stuart C. Sealfon, MD, Professor of Neurology, Neuroscience, and Pharmacology and Biological Chemistry at Mount Sinai School of Medicine. The findings are published in the February 1 issue of the journal Neuron.To understand the neurochemical circuitry, the study focused on how these two different, but similar drugs switched on the serotonin 2A receptor, a member of the largest family of receptors. Receptors are proteins located on nerve cell membranes and bind to neurotransmitters, or brain chemicals, such as serotonin, to initiate cellular responses. Altered serotonin levels are involved in many common psychiatric illnesses, including depression. Dr. Sealfon and his colleagues compared the mechanism by which hallucinogenics and non-hallucinogenic drugs like lisuride turned on the serotonin 2A receptor.
“The big mystery has been why drugs like lisuride, which are similar in chemical structure to hallucinogens and switch on the exact same serotonin 2A receptor, do not have a similar impact on mood and behavior” says Dr. Sealfon. “Our tests in mice revealed that once the hallucinogenic drugs turn on the serotonin 2A receptor, they also go on to activate another neurological pathway, whereas lisuride does not take any further action.”
They found that laboratory tests showed the serotonin 2A receptor has two “on” positions; drugs like LSD make the receptor go into one “on” position, whereas non-psychedelic drugs like lisuride activate serotonin 2A receptor in a different way.
In a related finding, the research team also unraveled another neurochemical mystery. Previously, scientists had suspected that hallucinogenic drugs acted on the serotonin 2A receptors by traveling to the cerebral cortex, a key structure in the brain associated with multiple complex brain functions, including memory, attention, language, and consciousness. Using genetically-altered mice developed by their collaborators at the Laboratory of Mouse Genetics and Behavior led by Jay A. Gingrich, MD, PhD, an assistant professor at Columbia University, the two groups found that the serotonin 2A receptor was acted on in the cerebral cortex, but not by cells traveling to the cerebral cortex. “This clarified the pathway so that we could really narrow down where this serotonin 2A receptor activity was taking place,” Dr. Sealfon says.
The next step is to investigate and understand the patterns of serotonin 2A receptor activation. “This could open many doors,” Dr. Sealfon says. “When developing drugs to treat drug abuse or neurodegenerative disorders or psychiatric illnesses, scientists can look beyond just the target or the receptor they want to activate, and start tinkering with how they want to activate the receptor, which would then create very specific responses and results. Instead of prescribing a treatment and hoping for the best, this approach could put scientists and physicians in the driver’s seat, and give them better control, which ultimately will lead to better patient outcomes.”