Thread: Erowid/BlueLight Neuropharmacology Text

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    Erowid/BlueLight Neuropharmacology Text 
    I contacted erowid recently, with the proposal to write a text that would hopefully bring the laymen up to a reasonable standard, as far as neuropharmacology/neurophysiology goes, in regards to psychoactive drugs.

    The erowid team replied, saying that they would love it.

    What I'm now proposing to you guys, is that we write it. I suggest that a single person is asked to write a section/chaper (hopefully one you're familiar with). Erowid suggested using a Wiki, and I think that after we've written it up in posts in here, we can port it over to one, and link it all up.

    The chapter layout I proposed to erowid basically looked like this

    -What is a cell (BilZ0r)
    ---What is a Neuron? (ksi and BilZ0r)
    -What is a Protein?
    ---How proteins are produced (crOOk and BilZ0r)
    -----What is a receptor? (BilZ0r)
    -----What is an Enzyme? BilZ0r)
    -Electrical properties of the Neuron (BilZ0r)
    ---Ion Channels
    -----Voltage Gated Ion channels (BilZ0r)
    -----Ligand Gated Ion channels (BilZ0r)
    -Chemical properties of the Neuron
    ---The synapse (BilZ0r)
    ---G-Protein Coupled Receptors, and signalling cascades (BilZ0r)
    ---Homeostasis in Neuronal Signalling (BilZ0r)

    Special Topics
    -Pharmacokinetics (BilZ0r)
    -Learning, memory and addiction on a cellular level (BilZ0r)
    -Monoamine transporters and the amphetamines (BilZ0r)
    -GPCRs under the microscope (mitogen)

    Drug Glossary

    And then maybe some special topics, like neurotoxicity, or anything a particular contributor has a zest for (so long as its appropriate).

    Right, so do I have any volunteers? Any suggestion on changing the chapter structure

    Printable PDF available here
    Last edited by sekio; 20-02-2013 at 22:14.
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    Re: Erowid/BlueLight Neuropharmacology Text 
    Join Date
    Oct 2004
    Originally posted by BilZ0r
    I contacted erowid recently, with the proposal to write a text that would hopefully bring the laymen up to a reasonable standard, as far as neuropharmacology/neurophysiology goes, in regards to psychoactive drugs.
    Sounds like a neat idea. I have a good background in neurophisiology, so I'd be up for doing a writeup about the electrical properties of a neuron. It shouldn't be too hard explaining action potentials, sodium/potassium current, membrane depolarization, etc in a simple, easy to understand way.

    My only worry is that some of those proposed chapter topics would be hard to conceptualize without some background in biochemistry (ie what is a protein/enzyme/lipid) and cell biology, (ie plasma membrane structure/function). Maybe there should be an introductory chapter on some of these basics, focusing on the aspects relevant to some of the subsequent chapters.
    Last edited by raybeez; 07-11-2004 at 05:07.
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    Well those exact things are what hopefully is going to be covered in the first two chapters... With "what is a neuron", explaining what a cell is, what the important parts of a cell are... and what is a receptor, what is a protein, about protein production, about enzymes...

    There, I edited the chapter structure, so that receptors and enzymes are both subchaters under a protein section.

    What I'm really looking for is someone to write something about Voltage Gated Ion channels... Although I understand them (the concept is preety simple), I feel that it would still be better if someone who felt they really had a good grasp of it wrote it (sure we would be going into Hodgkin-Huxley kinetics or anything, but still...)
    Last edited by BilZ0r; 07-11-2004 at 04:00.
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    Well you sound perfect to tackle a section on how proteins are produced... That shouldn't be a very big section.. transcription, translation... an explaination that the cell can traffic the protein either intracellular or to the membrane...

    You think that sounds like it would be enough?
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    Join Date
    Oct 2004
    Originally posted by BilZ0r
    Well you sound perfect to tackle a section on how proteins are produced... That shouldn't be a very big section.. transcription, translation... an explaination that the cell can traffic the protein either intracellular or to the membrane...

    You think that sounds like it would be enough?
    Sure, easily doable. I'll PM you with a question or two that I have.
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    exactly how complex do you intend to make this? 
    writing a textbook is, as i am sure you am already aware bilZ0r, an incredibly large undertaking...
    is it designed to be a general summary providing links and resources or a fully self-contained tome?

    either way, i'd be happy to contribute.
    protein structure (and its intergration with neuropharmacology) and general molecular cell bio is really my field. i know quite a lot about trafficking and mitogenesis etc.

    this said, i'd have to be more than slightly conceited to think that i can write definitive articles on, say, the structure of connexin or something

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    Writing a textbook is an incredibly large undertaking...
    is it designed to be a general summary providing links and resources or a fully self-contained tome?

    Ah my man! I wondered when you'd show up...

    ...Well it's going to be neither I hope... not a list of links, or a tome... hopefully it will be the kind of thing you could read in a 2 to 3 sittings... I hope each chapter will be around 500-2000 words... Depending on the chapter, I don't you'd even references, just a bibliography...

    So would you be down for writing a chapter? Maybe down regulation, and desensetization of receptors?
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    i think it would be interesting to have two parts to each chapter: the first being a general intro, and the second being a collection of some of the latest research in the field.
    just a link to an abstract, a couple sentences describing the paper, then a sentence saying why this particular piece of research is exciting.

    receptor trafficking is good for me. signalling, transmodulation etc. and protein structure...

    we need a geneticist

    damn my mum just found my pot of opium tea and chucked it :/ "what are you doing brewing up plants? youll poison yourself! you know your father just sprayed everything in the garden with Confidor?"
    she thinks the opium poppies are poisonous...
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    ... well I hope to keep it pretty simple if someone wants to get advanced then they can go read neuropsychopharmacology the 5th generation or something...

    I don't think we really need a geneticist, there isn't much genetics that is relevant to the pharmacology of recreational drugs... not in my opinion at least.

    I wasn't really going to have much of a mention on receptor trafficking, as a) it's relavence to recreational drugs is limited b) it's pretty advanced and c) it's still pretty uncharted... Don't you think? But any of those chapters above apart from the one raybeez has taken, are still open.
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    Join Date
    Mar 2002
    Ive read neuropsychopharmacology one of the editions. I dont know much about it anymore. But Im sure I can assist a bit in writing up a bit.
    Besides that we had a good dutch print of some of the most important chapters for our farmacotherapy course.
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    Whats your educational background? Is there any chapter you're especailly skilled to tackle?
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    "-Chemical properties of the Neuron
    ---The synapse
    ---G-Protein Coupled Receptors, and signalling cascades
    ---Receptor downregulation"

    sounds like me

    "what is tolerance and how do the mechanisms vary between drugs?"
    molecular tolerance:
    pharmacokinetic tolerance etc.

    perhaps a chapter on some psych experiments, like discriminative stimulus etc. would be good.
    i know sweet FA about that sort of stuff. would be interesting to learn a bit more.

    also, maybe a comment on how a little knowledge of the underlying pharmacology of recreational substances can enhance the safety or comfort of using that substance.
    for instance (not the greatest example but i cant think of anything better right now,) MDMA induced hyperthermia, or the fact that tolerance develops to the majority of the effects of opioids, but that this does not include inhibition of gastric motility (constipation!)
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    Well we'll put you down for downregulation and desensitization for the moment?
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    Maybe I am missing something here, but I do not see any drug-related material in the proposed chapter layout.
    Is this to serve simply as an introduction to the neural system, or are specific 'neurotoxins' going to be discussed?
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    An introduction to the neural system, with the objective of helping people understand other research on recreational drugs.

    Thats why we don't need to cover molecular biology, because that interaction isn't probably particularly important in regards to recreational drugs.

    Hopefully, where appropriate, people will use recreational drugs as examples though.
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    Bluelight Crew Pander Bear's Avatar
    Join Date
    Jun 2001
    East Atlanta Cockin' Hammers
    my high school/college bio/anat/phys should give me adequate background for what is a cell, and the important parts of a cell, and if anybody jumps ship on "how a neuron works", I could pick that up too. . Can we use copyrighted images. Lord knows most of these concepts are better expressed through diagrams.
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    atlas, it shouldn't be a problem using copyrighted images as long as they are identified as such and cited in a bibliography.
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    Bluelighter Sledge's Avatar
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    May 2003
    I just finished the chapter in my school book about enzymes (I study biochemistry) so I can write about them. I could use common enzymes working in drug metabolism, inhibition by MAO's, and some other things. I really don't know what enzymes has to do with the neuropharmacology but if it needs to be explained I'll gladly do so. Since english isn't my primary language there might be some grammatical errors, hopefully some of you could fix them.
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    i think creating an extensive glossary (preferably with a feeback page and refular updates) would be really helpful; i'd bookmark it.
    i've only taken cog-neuro at an undergraduate level, and find that a major problem for me is not knowing the shorthand for specific neurotransmitters that i only know the group name for.

    Similarly a section on how abbreviations, acronyms, & other diction are conjoined would be helpful.

    I'd be happy to collaborate with atlas on how a neuron functions. if i can find my notes/tests i have also have alot of drawings (some rather meticulously done). i can contribute those, and possibly do more drawings for other topics if needed.

    I'd also be willing to do some work for the vocab section. This page might help for vocab if nothing more:
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    I think it would be best to create our own diagrams...

    If you "don't know what enzymes has to do with the neuropharmacology", then it's probably best if you don't write the section specifically dealing with that question.
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    This text is the best idea I have seen on Bluelight as of yet...
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    Hmm, might I suggest that people only write things that they believe they have an extensive interest in.
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    ^^^ I hoped that was kind of implied... either interest or knowledge...

    Anyways, heres my first attempt at a chapter, have fun hacking it to bits (Figures will come much later).

    Electrical properties of the Neuron

    As already mentioned, one of the most distinctive and functionally important property of a neuron is that it is electrically excitable. This excitability is an emergent property of the neurons ability to alter its membrane potential (the word potential can be used interchangeably with voltage). All cells have a membrane potential, and it is generated by the uneven distribution of charged atoms (ions) across the cells membrane, which is impermeable to these ions. The most important ions for generating and altering the membrane potential are the positively charged sodium (Na+) and potassium ions (K+), and the negatively charged chloride ions (Cl-). In general, Na+ and Cl- is found at a higher concentration outside the cell, while K+ is found at high concentration inside the cell. The distribution is found because a protein, usually called the Na+-K+ pump (or ATPase), swaps three intracellular Na+ ions for two extracellular K+ ions. Not only does this action produce a chemical gradient of high extracellular Na+ and intracellular K+, but it also produces a electrical gradient because it swaps three intracellular positive charges, for two extracellular positive charges i.e. a net movement of one positive charge out of the cell. The eventually leads to a difference of charges, i.e. a voltage, of somewhere around –50 to –80mV. This is called the resting potential

    Because particles have a natural urge to equally distribute themselves (2nd law of thermodynamics), it can be said that there is a chemical driving force on these unevenly spread ions. Na+ wants to flow into the cell, and K+ wants to flow out of the cell (i.e. into the areas where the particular ion is at low concentration). Because charged particles are attracted to areas of opposite charge, there is also an electrical driving force on the ions. Na+ wants to flow into the negatively charged cell, which would make the cell more positive, and if this was allowed to happen, it would make the cell increasing positive until the cell became so positive it began to repel the positively charged Na+. Eventually, the electrical force pushing Na+ out would become equal to the chemical force drawing it in. The voltage at which a cell would usually reach this Na+ equilibrium is around +55mV (called the Na+ equilibrium potential or reversal potential).

    K+ wishes to leave the cell because of its high intracellular concentration and if it did so, it would make the cell increasing negative, until the electrical force drawing K+ back into the cell caused K+ flow to reach equilibrium. This K+ equilibrium potential is around –75mV. Because Cl- is a negative ion, it is repelled from entering the negative cell, even though there is a chemical force drawing it in (because of the high extracellular concentration). So Cl- has its equilibrium potential around –60mV, or very close to the membrane potential. This means that if the cell at resting potential became permeable to Cl-, not much Cl- would flow. Ca2+ is another important ion, which is distributed nearly exclusively extracellularly, and has an equilibrium potential of around +60mV. Importantly, you can see that the distribution of a particular ion, and the charge of the cell, dictates that ions equilibrium potential, which is the voltage that ion is trying to pull the cell towards.

    This brings us back to the important property of the neuron: it is excitable. A neuron’s cell membrane can rapidly change its permeability to particular ions, by opening ion channels. Ion channels are pores formed by proteins that allow the flow of ions (usually a particular kind). Usually, these ion channels are can be opened (i.e. gated), by chemicals or by the cells voltage, which leads these kinds of ion channels to be called ligand, or voltage gated ion channels respectively. These channels are explained in more detail in the next chapters.

    If the membrane of a cell were to suddenly become permeable to K+ ions due to potassium channels opening, potassium would flow out of the cell. This would make the cell more negative than its usual resting potential, down to a maximum of the K+ equilibrium potential of –75mV. When a cell becomes more negative than usual, it can be described as being hyperpolarised. If, on the other hand, the cell became permeable to Na+ ions, because of sodium channels opening, Na+ would flow into the cell, making the cell less negative, and up to a maximum of +55mV. When a cell becomes less negative than usual it can be described as being depolarised.

    You can see that the neuron has a mechanism for changing its membrane potential. While it may not be obvious to you now why this is so important, it will be explained in the following chapters how this allows the neuron integrate as well as transmit information over long distances.
    Last edited by BilZ0r; 14-11-2004 at 09:11.
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    Voltage gated ion channels

    As already mentioned ion channels are pores in the membrane of a cell which allow ions to pass through the otherwise impermeable membrane. These channels can be gated (i.e. opened) by various things. In this chapter we will look at ion channels which can be gated by the voltage across the cells membrane itself, or voltage-gated ion channels.

    There are many individual kinds of voltage-gated ion channels, but all we will be concerned about are three large families, voltage-gated sodium, potassium and calcium ion channels; channels, which when open pass sodium, potassium and calcium respectively.

    The most important function of two of these voltage gated ion channels is to generate the action potential. The action potential is a often thought of as an electrical signal which passes down the axons of neurons, like current down a wire. In reality it is caused by a chain reaction of voltage gated ion channels opening. The third channel is responsible for converting the electrical nature of the action potential into chemical signals a neuron can deal with.

    If a part of a neuron expressing voltage gated sodium and potassium channels (usually the axon and cell body) became depolarized (less positive) to around –50mV, voltage gated ion channels start to become active i.e. they reach threshold. At the cell body, the fastest activating voltage gated ion channel is the sodium channel. The sodium channels start to open, allowing Na+ to enter the cell, further depolarizing the cell, encouraging more sodium channels to open. The Na+ passively diffuses down the axon of the neuron, causing neighboring areas of neurons to become depolarized, where further voltage gated sodium channels open. This causes a chain reaction of Na+ entering the cell, depolarizing close-by areas of cell, opening further sodium channels, causing more Na+ to pour into the cell etc… If this were to happen unabated, the neuron would fire one action potential, Na+ would reach its equilibrium potential and the cell would become electrically dead. But two things happen to stop this, 1) sodium channels inactivate and 2) slower activating potassium channels being to open.

    Inactivation of sodium channels happens normally around 1 millisecond after they begin to open. Inactivation is a transient block of a channel, which in the case of voltage gated sodium channels is caused by a length of the protein which forms the channel, physically blocking the channel like a cork. This inactivation limits both the time and voltage of the action potential. As stated, inactivation is transient, and if the neuron wasn’t returned to its resting potential, or at least below threshold, as soon as inactivation passed, the sodium channels would open again. This is when voltage gated potassium channels began to play their part. As potassium channels take about 1-2ms to open after they reach threshold, they are beginning to become fully activated when sodium channel inactivation is in full swing. K+ ions being to flood out of the cell, rapidly making the neuron more negative (repolarizing). Potassium channels do not show inactivation, but as they act to repolarize the cell the pull it below the threshold for sodium and potassium channel activation, which closes the potassium channels.

    Importantly the action potential is all-or-none, that is to say, the body can’t code information in the amplitude of the action potential, the action potential either happens or it doesn’t. The body codes information in the frequency of action potentials. For instance, in neurons which transmit pain, more painful stimuli causes the neurons to fire more frequently, but with the same amplitude. Cocaine, apart from its well-known action of increasing dopamine, also blocks voltage gated sodium channels, which stops the formation and propagation of the action potential. This is why it causes numbness, by blocking the transmission in sensory neurons.

    Finally, when the action potential has travelled the whole length of the axon, it depolarizes the ends of the neuron, (usually -synaptic terminals-), here voltage gated calcium channels can open, causing Ca2+ to enter the cell. This Ca2+ influx causes neurotransmitter release (as described in the synapse). Although this Ca2+ influx shares many properties with the sodium/potassium action potential, it is not all-or-none. Alcohol is believed to inhibit Ca2+ channel function directly (Hendricson et al., 2003), and many common drugs effects Ca2+ channel indirectly. For instance, D9-THC from cannabis and yohimbine from Yohimbe. By effecting Ca2+ influx, these drugs effect neurotransmitter release (discussed further in the synapse and G-Protein Coupled Receptors, and signalling cascades).

    Hendricson AW, Thomas MP, Lippmann MJ, Morrisett RA. Suppression of L-type voltage-gated calcium channel-dependent synaptic plasticity by ethanol: analysis of miniature synaptic currents and dendritic calcium transients. J Pharmacol Exp Ther. 2003;307(2):550-8
    Last edited by BilZ0r; 12-11-2004 at 11:52.
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    Ligand gated ion channels

    Ligand gated ion channels are, as their name suggests, channels in a cells membrane that are gated by ligands, i.e. drugs/chemicals. The physiological role of nearly all ligand gated ion channels is to receive chemical signals in the way of neurotransmitters (discussed further in the synapse), and to transduce them to electrical signals. In order for these ion channels to be gated by a neurotransmitter, they have a receptor for the specific neurotransmitter as part of the proteins that make up the receptors. Therefore the ion channel complex is often refereed to by the name of the neurotransmitter/chemical/drug which is has a receptor for, and for the rest of this chapter we will largely use this style.

    The two most common types ligand gated ion channels (also called ionotropic receptors) are the ion channels that are opened by the neurotransmitters glutamate and GABA, or ionotropic glutamate and GABA receptors. The ionotropic glutamate receptors may be further divided up into AMPA, kainic acid and NMDA receptors (named after drugs that specifically activate these types). While it is possible to further subdivide these receptors based on the individual proteins that make them up, it is outside the scope of this text. AMPA and kainic acid receptors are generally similar; both are opened by glutamate and both are largely selective for the flow of Na+ ions, which in all physiological situations is into the neuron. This flow of Na+ depolarizes the cell, making it more positive and bringing it closer to the threshold for firing an action potential. Because of this, it can be said that AMPA and kainic acid receptors are “excitatory”. The NMDA receptor is an anomaly amongst ligand gated ion channels, in that it is also partially voltage gated. The channel of the NMDA receptor has a site in which Mg2+ ions can sit. This Mg2+ is much larger than the normal ions that flow through the NMDA receptor (Na+ and Ca2+) and hence blocks it. When the cell partially depolarized, positive Mg2+ ions begin to be pushed out of the NMDA receptor channel (presumably because of the positive charge inside the neuron repelling it). Also, because the NMDA receptor is very permeable to Ca2+ channels, not only does it depolarize (excite) the cell, it also can cause many of the chemical changes within the cell caused by Ca2+ (see G-Protein Coupled Receptors, and signalling cascades). Largely, it is the release of glutamate, and its action of ionotropic glutamate receptors that allow one cell to excite another cell into firing (although usually it requires 100s of cells to release glutamate onto a cell to cause this).

    The most famous drugs which directly effect ionotropic glutamate receptors are the so called “anaesthetic dissociates”, e.g. ketamine, PCP and DXM. These drugs all block the NMDA receptors ion channel, i.e. they are NMDA channel antagonists. Alcohol's actions is thought to be at least in part due to its ability to block NMDA receptor channels (Woodward, 2000).

    The ligand gated ion channel that is gated by GABA is called the GABA-A receptor (to distinguish it from the non-ion channel GABA-B receptor). This channel is largely selective for the transit of Cl- ions. As stated before, Cl- ions have a reversal potential of around -60mV, so if a cell has a resting membrane potential of around –60mV GABA-A receptors do not cause much of an effect on membrane potential i.e. they neither hyperpolarise nor depolarise the cell. But if the cell is being depolarised by the action of ionotropic glutamate receptors, then GABA-A receptors strongly oppose this, and hence its action is often referred to as inhibitory).

    A wealth of drugs directly effect GABA-A receptors, specifically benzodiazepines and barbiturates which bind to sites apart from the GABA binding site or the channel, to increase channel opening only when GABA normally opens the receptor. This is an example of allosteric modulation, and is a common feature of ligand gated ionc channels. Muscimol is a direct agonist, acting like GABA. Alcohol is also though to stimulate GABA-A receptors, though whether this is a direct action is still debated (Aguaya et al., 2002)

    There are other kinds of ligand gated ion channels, though the only ones which have much relevance to recreational drugs are the ionotropic acetylcholine and serotonin receptors, also called the nicotinic and 5-HT3 receptors. Both of these receptors are ligand gated sodium channels. Nicotine activates the nicotinic receptor, and serotonin, which could be released by the action of MDMA, can activate 5-HT3 receptors (which may cause MDMA-induced vomiting). There are also the glycine, P2X and VR1 ligand gated ion channels expressed in the central nervous system.

    As you can see, ligand gated ion channels are an important (probably the most important) mechanism of neuron-to-neuron communication, and drugs acting on this form of chemical to electrical transmission have a powerful way to alter neuronal activity (discussed more in Signalling properties of neurons).

    Woodward JJ. Ethanol and NMDA receptor signaling. Crit Rev Neurobiol. 2000;14(1):69-89.

    Aguayo LG, Peoples RW, Yeh HH, Yevenes GE. GABA(A) receptors as molecular sites of ethanol action. Direct or indirect actions? Curr Top Med Chem. 2002; 2(:869-85.
    Last edited by BilZ0r; 14-11-2004 at 09:09.
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