Nicotine receptor action switching from agonist to antagonist?

Discussion in 'Pharmacology' started by psyche, Jul 2, 2006.

  1. psyche

    psyche Palladium Member

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    I know nicotine acts as an agonist at nicotinic acetylcholine receptors but after being used for a period of time it starts to act as an antagonist. Does anyone know how exactly does this change in action happen? Why doesn't it happen with other receptors? Is the receptor in question ionotropic or metabotropic receptor at first place?
     
  2. psyche

    psyche Palladium Member

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    No one got a clue?! Or is my question requiring too much of a research that should be done by myself?
     
  3. Benzeneringz

    Benzeneringz Titanium Member

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    Hm, your post is really interesting. I didn't know nicotine acted as an antagonist after a while. What I DID know was nicotinic acetylcholine receptors re-regulate after nicotine exposure and cause a type of 'numbness' in the area of the brain associated with the reinforcing effects of nicotine. I believe one of the areas affected is the nucleus accumbens, since nicotine affects dopamine reuptake in this part of the brain.
     
  4. psyche

    psyche Palladium Member

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    It certainly is. This numbness a while after nicotinebath could also be result of nicotine being metabolised to cotinine, which is more of a depressant. Instead I just wondered how come chronic smokers get great sedation when they finally get a cigarette in those sweating and shaking hands after a long night. Nicotine is supposed to be a stimulant but somehow it works as an antagonist in chronic smokers' head and causes depression. I didn't mean sedation after some hours after tobacco, but after some weeks of regular use. Somehow I always manage to be misunderstood..
     
  5. thadj

    thadj Newbie

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    Nicotine acts as an agonist at nicotinic receptors. I think you are right about it starting to act as an antagonist after a short time. This phenomenon is called 'depolarization block', look it up on google/pubmed.

    Nicotin's pharmacology and addictive properties is still a mystery for the major part.
     
  6. Bajeda

    Bajeda Super Moderator Platinum Member & Advisor

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    Proc Natl Sci Counc Repub China B. 1987 Apr;11(2):148-54. Related Articles, Links
    [SIZE=+1]Pre- and postsynaptic effects of nicotine on the mouse phrenic nerve-diaphragm preparation.

    Chang CC, Jou MJ, Hong SJ, Chiou LC.

    Nicotine at less than or equal to 33 microM enhanced the single twitch response to indirect stimulation but potentiated the blocking effect of tubocurarine. Failure of tetanic contraction (tetanic fade) occurred on stimulation at 100 Hz. At 76 microM, nicotine induced a first phase rapid (10 min) inhibition of twitch response followed later (60-90 min) by a second phase complete block. Neostigmine partially restored the response at either phase of block whereas diaminopyridine completely antagonized the blockade. The end-plate was depolarized maximally by only 10-15 mV within 30 min with 43 microM nicotine. The depolarization was maintained but was antagonized by tubocurarine. The twitch response induced by direct stimulation was unchanged indicating no depolarization block ensued. The amplitudes of both EPP (0.7 Hz) and MEPP were markedly depressed in parallel indicating a curare-like postsynaptic inhibition without an effect on the release of transmitter. It is concluded that nicotine blocks the neuromuscular transmission by a dual mechanism by its partial agonist action. At higher frequencies of transmission, nicotine (greater than or equal to 22 microM) also produced a remarkable run-down of EPP just like other receptor antagonists suggesting that the nerve terminal acetylcholine receptors are not particularly sensitive to nicotine as those on the autonomic ganglia.
    Abstract—Depolarization-induced suppression of inhibition is a transient decrease in GABAergic input to a hippocampal pyramidal cell following a brief depolarization of that cell. When recorded under wholecell voltage clamp, monosynaptic, bicuculline-sensitive, GABAA-mediated currents are suppressed for a period lasting up to 1 min in response to a retrograde signal released by the pyramidal cell. The depolarization-induced suppression of inhibition process affects spontaneous, action-potential-dependent inhibitory postsynaptic currents, but suppression of these currents is seldom observed in the absence of carbachol, a cholinergic agonist. Because of the central roles played by cholinergic and GABAergic transmission in the regulation of hippocampal rhythmic activity, it will be important to understand the mechanism by which carbachol facilitates the appearance of depolarization-induced suppression of inhibition. As preliminary steps in the investigation of cholinergic actions on depolarization-induced suppression of inhibition, it is necessary to determine which cholinergic receptors are involved and the degree to which activation of these receptors is required for depolarization-induced suppression of inhibition. Nicotine did not mimic the effects of carbachol, and mecamylamine, a nicotinic receptor antagonist, did not block them. In contrast, the actions of carbachol were abolished by atropine and other muscarinic receptor antagonists. The actions of antagonists with relative selectivities for various subtypes of muscarinic receptors {4-diphenylacetoxy-N-methylpiperidine methiodide, pirenzepine, 11-([2-1-piperidinyl]acetyl)-,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one} suggested that cholinergic facilitation of the occurrence of depolarization-induced suppression of inhibition is likely to be mediated through muscarinic receptors of the M1 or M3 rather than M2 subtype. Despite its potent facilitation of the occurrence of depolarization-induced suppression of inhibition, muscarinic stimulation was not required for expression of depolarization-induced suppression of inhibition. Occasionally, depolarization-induced suppression of inhibition of spontaneous inhibitory postsynaptic currents occurred in the absence of carbachol and could not be blocked by atropine, and hence was not likely to be mediated by endogenous acetylcholine. Also, depolarization-induced suppression of inhibition of monosynaptically evoked inhibitory postsynaptic currents occurred without carbachol perfusion, and this was also insensitive to atropine. Therefore, the mechanism of depolarization-induced suppression of inhibition is not dependent on muscarinic receptor activation. Nevertheless, in vivo, septal cholinergic input to the hippocampus may
    provide the necessary activation of interneurons to allow depolarization-induced suppression of inhibition to occur. q1999 IBRO. Published by Elsevier Science Ltd.

    Nctine.pdf




    Title: Tolerance and sensitization to stimulant and depressant effects of nicotine in intracranial self-stimulation in the rat. Author: Herberg, L.J. Add.Author / Editor: Rose, I.C. Montgomery, A.M.J. Citation: Behav Pharmacol. Volume: 4, Issue: 4, Date: 2001 Feb 26, Pages: 419-427 Year: 1993 Abstract: Nicotine is thought to be an important factor in addiction to tobacco but its psychopharmacological properties are still uncertain. In the present study, rats were trained to operate a pedal to obtain threshold-current, variable-interval hypothalmic stimulation. Response rates were printed out at 10min intervals to provide a continuous record of facilitatory or depressant effects by injected nicotine. Responding was enhanced in all rats but this depended on dose, time after injection, and previous exposure to the drug. In the first 10min after injection, responding by drug-naive rats was either unaffected (40-130mg/kg s.c., as base) or strongly depressed (400µg/kg). This phase was followed by prolonged (>50min) dose-dependent facilitation. Higher doses (1.3mg/kg) caused prostration. Chronic exposure to nicotine (400µg/kg x 10 at 2-5 day intervals) reduced the initial depressant effect; it also augmented subsequent responding, but only in the early minutes after injection; the latter finding indicates that apparent sensitization to chronic nicotine may depend primarily on tolerance to its depressant effects, rather than on receptor upregulation. Stimulant and depressant effects of nicotine were prevented by pretreatment with the centrally acting antagonist, mecamylamine (2.0mg/kg s.c.), but not by the peripheral antagonist, hexamethonium (1.0mg/kg s.c.) or by the muscarinic receptor antagonist, hyoscine (scopolamine; 100-300µg/kg s.c.). Self-stimulation was unaffected by mecamylamine alone. Thus the inhibitory action of nicotine is unlikely to be due to depolarization block, peripheral activity or muscarinic activity. Its facilitatory and depressant effects appear to be narrowly time- and dose-specific, thus accounting for divergent findings in many studies. ISSN: 0955-8810






    I am usually ok on understanding basic pharmacological research but this is a bit over my head. These articles seemed to have something to do with the antagonistic function of nicotine as you are describing it but I had trouble finding studies on this.

    If anyone can give a better idea of what to look for (keywords, specific names) I can probably pull up a few more articles on this topic.

    Let me know if any of these helped.
     

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  7. mush2130

    mush2130 Mercury Member

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    If i look in my life, i can say than a cigarette(tabaco) after weed increase the trip between 15% to 30%.

    somebody agree!?
     
  8. Bajeda

    Bajeda Super Moderator Platinum Member & Advisor

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    Swim used to get that before he started smoking cigarettes but after smoking for a few years he found that it didn't improve the high anymore, it just felt nice to do. Probably because I didn't get nicotine rush at all anymore, though it also could be that swim smokes spliffs much of the time so the nicotine adds to the high while he is smoking.

    He does notice that right after smoking or simultaneously to smoking marijuana smoking a cigarette makes the high come on faster, though smoking a cig later into the high doesn't seem to do as much.
     
  9. psyche

    psyche Palladium Member

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    I have noticed that, particularly when smoking after weed, not during the best high. It's nice to stretch the weed with it, however sometimes SWIM tends to smoke too much and gets nauseous.