aced126
Bluelighter
- Joined
- May 18, 2015
- Messages
- 1,047
I recently came across this paper: http://www.ncbi.nlm.nih.gov/pubmed/9408919
"Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors."
In the paper, it noted that lisuride was a 5HT2a agonist and 5HT2c antagonist, and quoted a 1991 study. A more recent 1998 study addresses the fact that lisuride was reported to have antagonist activity at 2c but then went on to show that in fact both LSD and lisuride are partial agonists at 2a and 2c. https://www.ncbi.nlm.nih.gov/pubmed/9600588
Back to the topic of discussion. The authors of the NAN paper (one of which is Olney) used the incorrect 1991 finding to hypothesise that 5HT2a was responsible for NAN attenuation, but not 5HT2c, since lisuride was tested and found to block NAN more potently than any other drugs tested. LSD, along with other psychedelics, blocked NAN in a dose dependent manner. Curiously, DOB was better at blocking NAN than LSD, even though DOB has a lower 2a affinity than LSD. Lisuride does not produce psychedelic effects, and this has been attributed to biased signalling of 2a. Finally, the researchers also tested a selective 2c agonist and found that it did not block NAN at any dose, showing that 2a but not 2c was relevant. So if LSD and lisuride activate different signalling pathways, how can they both attenuate NAN?
I also noticed that one of the stereogenic centres in lisuride was different to its counterpart in LSD (lisuride had stereochemistry akin to iso-LSD). Iso-LSD is inactive, but could this also suggest that iso-LSD could have 2a and 2c activity but simply be biased and therefore not elicit psychedelic activity?
Finally, they mention serotonergic innervation of inhibitory GABA interneurons which project onto the cells which undergo excitotoxicity when NMDA receptors on the interneurons are blocked, and that activation of the 55HT neurons can stimulate the GABA interneurons to fire again and prevent excitotoxicity of the neurons they project on to. I feel this is a fairly simplistic theory and that there might be more going on here. Any speculations?
"Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors."
In the paper, it noted that lisuride was a 5HT2a agonist and 5HT2c antagonist, and quoted a 1991 study. A more recent 1998 study addresses the fact that lisuride was reported to have antagonist activity at 2c but then went on to show that in fact both LSD and lisuride are partial agonists at 2a and 2c. https://www.ncbi.nlm.nih.gov/pubmed/9600588
Back to the topic of discussion. The authors of the NAN paper (one of which is Olney) used the incorrect 1991 finding to hypothesise that 5HT2a was responsible for NAN attenuation, but not 5HT2c, since lisuride was tested and found to block NAN more potently than any other drugs tested. LSD, along with other psychedelics, blocked NAN in a dose dependent manner. Curiously, DOB was better at blocking NAN than LSD, even though DOB has a lower 2a affinity than LSD. Lisuride does not produce psychedelic effects, and this has been attributed to biased signalling of 2a. Finally, the researchers also tested a selective 2c agonist and found that it did not block NAN at any dose, showing that 2a but not 2c was relevant. So if LSD and lisuride activate different signalling pathways, how can they both attenuate NAN?
I also noticed that one of the stereogenic centres in lisuride was different to its counterpart in LSD (lisuride had stereochemistry akin to iso-LSD). Iso-LSD is inactive, but could this also suggest that iso-LSD could have 2a and 2c activity but simply be biased and therefore not elicit psychedelic activity?
Finally, they mention serotonergic innervation of inhibitory GABA interneurons which project onto the cells which undergo excitotoxicity when NMDA receptors on the interneurons are blocked, and that activation of the 55HT neurons can stimulate the GABA interneurons to fire again and prevent excitotoxicity of the neurons they project on to. I feel this is a fairly simplistic theory and that there might be more going on here. Any speculations?
