Posted by Shawn. T. on August 3, 2003, at 17:59:27
In reply to Re: The effects of illegal drugs (long) » Rickson Gracie, posted by Ame Sans Vie on August 3, 2003, at 16:33:26
I don't believe that LSD's hallucinogenic effects have anything do to with the dorsal raphe; I know of no current research that supports this view. Its hallucinogenic effects are due to postsynaptic receptors outside of the dorsal raphe. 5-HT2A receptor activation increases excitatory postsynaptic currents (EPSCs) in layer V pyramidal cells of the neocortex (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9836015&dopt=Abstract ). This is the mechanism most likely to be involved in the hallucinogenic activity of LSD. One theory argues that the increase in layer V EPSCs is due to 5-HT2A heteroceptors on thalamocortical glutamatergic neurons (see http://www.jneurosci.org/cgi/content/full/20/23/8846 ). However, recent evidence has suggested that 5-HT2A mediated modulation of pyramidal neurons in regions such as the medial prefrontal cortex (in rats) is due to postsynaptic 5-HT2A receptors "unrelated to thalamocortical afferents." (See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12853374&dopt=Abstract ). Note that layer V pyramidal neurons have been shown to express 5-HT2A receptor mRNA (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=7706547&dopt=Abstract ).
Switching topics, I believe that the role of dopamine in MDMA induced neurotoxicity involves the initiation of hyperthermia. D1 and D2 receptors are likely involved. Drugs that cause hypothermia generally block the neurotoxic effects of MDMA; however, the hyperthermic effects alone cannot induce neurotoxicity. I personally believe that MDMA's toxicity and mechanism of action involves two key effects: direct PKC alpha activation by the drug (in 5-HT/DA terminals) and vesicle depletion (due to VMAT-2 inhibition which releases monoamines into the cytoplasm). Other effects like dopamine release/hypothermia occur after PKC activation/VMAT-2 inhibition is initiated. See http://www.neurotransmitter.net/mdmatoxicity.html for a compilation of research on MDMA neurotoxicity.
Shawn
poster:Shawn. T.
thread:247730
URL: http://www.dr-bob.org/babble/20030802/msgs/247844.html