Hallucinogens, mechanism of action, Difference between 2A agonists and 2A agonists that are hallucinogens Options

[Orbz]

Gonzalez-Maeso et al (2007)
Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior
Neuron 53;3, 439-452

The study looked at 5-HT2A agonists which are hallucinogens and 5-HT2A agonists which are not. The difference is in the down stream signalling.

While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric Gi/o proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.

Might this also be the difference betwen atypical and typical antipsychotics causing neurloeptic malignant syndrome? Typical antipsychotics induce second messengers through D2 receptors which atypicals don't?

[trojan_libido]

I'm totally ignorant of almost all the terminology used in your post, sorry

[Maykel]

Gonzalez-Maeso et al (2007)
Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior
Neuron 53;3, 439-452

The study looked at 5-HT2A agonists which are hallucinogens and 5-HT2A agonists which are not. The difference is in the down stream signalling.

While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric Gi/o proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.

Might this also be the difference betwen atypical and typical antipsychotics causing neurloeptic malignant syndrome? Typical antipsychotics induce second messengers through D2 receptors which atypicals don't?

For NMS, the antipsychotic medicine is targeted through the mesolimbic pathway? excess dopamine not bringing the true function of dopamine if not in excess?
is believed if patients take chloropromizine (typical antipsychotic) can get NMS in rare cases, atypical antipsychotics are better for their affinity to 5-HT2 ser.

[Orbz]

For NMS, the antipsychotic medicine is targeted through the mesolimbic pathway?

I think its more the nigrostriatal area. The nigrostriatal has more to do with movement, whereas the mesolimbic has more to do with motivation and probably some of the positive symptoms.

excess dopamine not bringing the true function of dopamine if not in excess?

I think I agree, can you rephrase please?

is believed if patients take chloropromizine (typical antipsychotic) can get NMS in rare cases, atypical antipsychotics are better for their affinity to 5-HT2 ser.

What about amisulpride, (I think they class as atypical) which has a very low affinity for 5-HT2?

It seems that they've just labelled atypicals as those producing less side effects. But it could just be that they're given at such a dose so as not to occupy more than 80% DA receptors, leaving the person susceptible to side effects. Some recent research has suggested that typicals given at a lower dose, targeting the 70% range, will have the same side effect profile as the atypicals but with the same therapeutic benefit.

[Maykel]

For NMS, the antipsychotic medicine is targeted through the mesolimbic pathway?

I think its more the nigrostriatal area. The nigrostriatal has more to do with movement, whereas the mesolimbic has more to do with motivation and probably some of the positive symptoms.

excess dopamine not bringing the true function of dopamine if not in excess?

I think I agree, can you rephrase please?

is believed if patients take chloropromizine (typical antipsychotic) can get NMS in rare cases, atypical antipsychotics are better for their affinity to 5-HT2 ser.

What about amisulpride, (I think they class as atypical) which has a very low affinity for 5-HT2?

It seems that they've just labelled atypicals as those producing less side effects. But it could just be that they're given at such a dose so as not to occupy more than 80% DA receptors, leaving the person susceptible to side effects. Some recent research has suggested that typicals given at a lower dose, targeting the 70% range, will have the same side effect profile as the atypicals but with the same therapeutic benefit.

that seems reasonable. do you know the risks of tardive dyskinesia when taking atypicals? using dopamine antagonist and would you say that is targeted in the nigrostriatal area also? thnx

[Orbz]

that seems reasonable. do you know the risks of tardive dyskinesia when taking atypicals? using dopamine antagonist and would you say that is targeted in the nigrostriatal area also? thnx

Yes, would likely target the nigrostriatal area.
I think the risk is less with clozapine, but I'm not sure.

[Orbz]

to treat tardive dyskinesia , should discontinue or use low dose of benzodiazepines? whats the limit for the hypnotic atypical drugs. recent research suggests it can has an adverse effect in terms of potential addiction increase.

I think a psychiatrist/physician could better answer your treatment questions.

All benzodiazepines (that I know of) have a problem with dependence, they work in a similar way to how alcohol does in the brain to sedate it. So they also affect mesolimbic areas, as well as pretty much the rest of your brain. Other than that they're fairly safe (as long as you're not concurrently taking other sedatives or opiates or drinking) and psychiatrists don't have too many problems considering them for, well, anything. Although, some people do have bad reactions on, but mostly coming off, benzos.

[Maykel Abdelmessih]

Gonzalez-Maeso et al (2007)
Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior
Neuron 53;3, 439-452

The study looked at 5-HT2A agonists which are hallucinogens and 5-HT2A agonists which are not. The difference is in the down stream signalling.



While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric Gi/o proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.


[/quote

I agree, this is why typical antipsychotics are not as good as LSD. just LSD affecting large number of Gprotien receptors and adrenoreceptors and binding to most seratonin receptors increasing glutamate release and excitation, Also it's action in DARPP-32 gene will definitely block action potentials activity in the brain stem.



Might this also be the difference betwen atypical and typical antipsychotics causing neurloeptic malignant syndrome? Typical antipsychotics induce second messengers through D2 receptors which atypicals don't?

I think that atypicals are more selective to 5HT-2A, and 5HT1A, where that typicals are not selective , just bocking D2 receptors in different pathways other than mesolimbic and nigrostriatal pathway in long term has the potential in giving NMS
In addition if primary cause if NMS also has genetic factors that causes this neuromalignant syndrome, reduced levels of dopamine receptors and this will raise levels of creatine phosphokinase in plasma and get increase in muscle activity and shift in congitive pattern. I don't think that people would go nuts or anything though.

what about the Tardive dyskinesia syndrome, in terms of the dopaminc receptor bockage mechanism, is it similar to the way atypicals drugs also affect the seratonin receptors?

[Orbz]

I think that atypicals are more selective to 5HT-2A, and 5HT1A, where that typicals are not selective , just bocking D2 receptors in different pathways other than mesolimbic and nigrostriatal pathway in long term has the potential in giving NMS.

There are typicals which have 5HT-2A activity and atypicals which don't have much 5HT-1A activity. It could be a combination of receptor targets; e.g., dopamine, serotonin, adrenergic blockade brings about a combination of dopamine antagonistic effects in mesolimbic areas, but other system blockades lead to increase of dopamine activity in the frontal areas alleviating more negative symtpoms.

Have a look at:
CNS Drugs;20(5):389-409
Horacek et al., (2006)
Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia.