Done Cocaine, Meth, Morphine 1 TIME!? Why you might want more even if you hated it.

By Richard_smoker · Mar 14, 2006 · ·
  1. Richard_smoker
    A single cocaine exposure increases BDNF and D3 receptor expression: implications for drug-conditioning.

    So this seriously might answer the question of why you taste whiskey or go out to a bar and suddenly you need some coke. Or why any drug motivation associations always seem more powerful than other types of associations.

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  1. Aaron
    Interesting, hopefully this could lead to some type of solution for those who can't kick the habit due to addiction.
  2. Richard_smoker
    Good idea. I wonder if anyone's thought of researching that very question, Aaron! You should have kept that idea to yourself and sold it to a hard-up psychiatry researcher! j/k

    But you might be onto something if you could find a compound that could either decrease production of dopamine D3 receptor (Drd3) protein or perhaps irreversibly bind to the receptors without activating them... in effect, decreasing the net number of available D3 receptors.

    I wonder what the effects of downregulating D3 receptors would be?
  3. IHrtHalucingens
    What is the biological purpose of the receptors in question? This would lead you to the answer to you question i suspect.
  4. Richard_smoker
    Nucleus accumbens--situated in the prefrontal cortex--is the part of the brain associated with pleasure and reward. it's actually known as one of the addiction centers (if not the primary center for addiction/pleasure/reward). It has been shown to grow and shrink from application of cocaine and other addictive drugs.

    So, to answer your question IHrtHs, the biological purpose is more than likely tied in to the very essence of what makes the activities & compounds addictive in the first place. i.e. what makes them 'feel good.'

    So, this might not have been such an enlightening thread after all...

    sorry if I have added to the background noise on this forum... :(
  5. Richard_smoker
    OK. Here's some educational material on the nucleus accumbens for those who wish to know more about the so-called "reward center." Here lies the key to motivation, reward, addiction, and feeding.

    Differential Modulation of Nucleus Accumbens Synapses.
    by James M. Brundege and John T. Williams. The Vollum Institute, Oregon Health and Science University, Portland, Oregon 97201. The Journal of Neurophysiology Vol. 88 No. 1 July 2002
  6. Richard_smoker
    Now that we understand the difference between the shell and core of the nucleus accumbens, here's some research about rats who are addicted to shooting cocaine directly into the shell rather than the core...

    Cocaine is self-administered into the shell but not the core of the nucleus accumbens of wistar rats.

    Rodd-Henricks ZA, McKinzie DL, Li TK, Murphy JM, McBride WJ. Institute of Psychiatric Research and Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana. J Pharmacol Exp Ther 2002 Dec;303(3):1216-26
  7. Forthesevenlakes
    This might explain why SWIM once heard a theory that the nucleus accumbens was the ONLY component to addiction. Personally SWIM believes its a little more complex than that, but the person was quite adamant about it. Downregulating the D3 receptors could have some kind of calming if not anhedonic quality, depending on where in the brain they're distributed. Wonder if one would run the risk of developing parkinson's if theyre downregulated too far.
  8. Richard_smoker
    AWESOME, sevenlakes!

    Only thing is--and I'm sure you know this--Parkinsons is caused by loss of dopaminergic neurons in the substantia nigra--a totally different area of the brain. I don't know for sure, but I don't think there are d3 receptors there. (right? not sure about this one. someone should know the answer to this.)

    The SN is located further back-stream from the nucleus accumbens which is located in the prefrontal area. The substantia nigra is involved in the motor area--with movement, balance, & coordination.

  9. Forthesevenlakes
    you're probably very right, swim wasnt really thinking about receptor subtypes when he made that post. funny thing is he just read that information you posted yesterday too, but you did a very good job explaining it, props to you! now swim is wondering where D3 receptors ARE located. if we knew where they were, we could probably guess the effects of downregulating them.
  10. Richard_smoker
    Hey, I had insomnia and searched around the net for a while and found out the answer to the question about where the D3 receptors are found: Nucleus accumbens, olfactory tubercle, islands of Calleja, cerebral cortex (low). So the answer to the question (good q) about parkinson's dz is that it shouldn't have any effect whatsoever.

    But I was partially wrong as well, because the D2 receptors that actually would cause parkinson's disease if missing are located in the caudate and putamen--the target for the substantia nigra.

    This is what you were thinking of by receptor down-regulation. This is a very interesting concept because as far as I know, all reported cases of parkinson's are caused by gradual blow-out of the substantia nigra tracts that carry the dopamine to the caudate/putamen. But parkinson's could ALSO be caused (theoretically) by knocking out the D2 receptors on the caudate/putamen. Good call. This concept MIGHT shed some light on some of these new cases of much younger-than-normal people who have been getting parkinson's earlier in life. (Michael J. Fox)
  11. Forthesevenlakes
    i'm wondering if the "induced parkinsons" cases caused by injection of synthetic demerol(?) relative MPTP would have been due to damage to the caudate/putamen as well. I did some searching online briefly, seems that the nucleus accumbens (which i'm guessing would be packed with opioid receptors) is relatively close to the caudate nucleus...and if MPTP not only bound opioid receptors but was an irreversible D2 antagonist, it would account for the parkinson's-like symptoms. this I think would lend some support to your hypothesis on the early-onset parkinsons patients. SWIM isnt eager to attempt to prove these theories firsthand, but is incidentally going to go look up where the mu opioid receptors are located, one of his experimental monkeys feels some fentanyl citrate needs to be administered and SWIM would like to know where exactly the test subject will be affected.

    SWIM has also read some literature stating that there are minor opioid receptors aside from the mu/kappa/delta ones. 4 other subtypes, apparently, swim will probably raise this question in another forum, but is wondering if any drugs have been discovered that affect these subtypes, and if so, have they been scheduled?
  12. Richard_smoker
    Actually, you're correct 100% on the MPTP-induced parkinson's patients. This is exactly why synthetic demerol analogues are dangerous at best. Very good insight there, sevenlakes! You'd make a fine neurologist, indeed!
  13. Forthesevenlakes
    why thank you! You as well, This kind of discussion stimulates me more than any dopamine binding compound, ha ha.
  14. Richard_smoker
    um... hmmm, I don't know about what that says about YOU, but MY answer to the same question is, unfortunately this: Yes, while this conversation is excellent and stimulating and indeed challenging, if I were forced at gunpoint (because I DONT do drugs) to decide whether I wanted to keep re-reading this conversation or to hit a fat rail...

    I would have to tell that mother-fucker to SHOOT ME!!

    ah... stupid joke. funnier than a deadbaby joke, but still very poor. Of course, the correct answer would be that I would feel obliged to indulge my D1 receptors in a D1 receptor orgy--complete with fucking and tit-fucking and all the other fun stuff that goes on inside my nucleus accumbens... hell, i'd even kill some DAT proteins in the process--that's how you remember that you had fun, right? wait--does DAT go up or down when you have fun?

    I forget. If that isn't a sign of something going on WHILE we are describing it, I don't know what is... is there a name for this experience? It's kinda like deja vue except it's more like you experienced something BEFORE you actually experience it--only when you actually experience it later, you've already forgotten that you experienced it the first time while discussing a hypothetical scenario on drugs-forum.

    Hence, another round of stimulating conversation and great ideas suddenly lose its luster to a drunken, drugged series of lifestyle choices on an online meeting place called drugs-forum-dot-com.
  15. Forthesevenlakes
    hm, my only guess for the experience would be 'jamais vu'. If you find out what happens to the DAT proteins though, please let me know because I have no idea how those work!
  16. Richard_smoker
    That sounds like a project for SOBER DICK!!!!

    He will be on it tomorrow. In fact, this will be his easiest task of the entire day. All he has to do is search for one of his last few posts on the DAT protein and some other argument-type stuff about what makes coke addictive.

    Then I'll get back with you. It's not much of nothing, actually. DAT is just an intracellular protein that transports either MORE of the D1 receptor protein from the nucleus to the cell membrane, or it chews up dopamine that has already been uptaken by one of the d1-d3's in the nucleus accumbens.

    Stands for Dopamine Active Transporter. Its concentration (or genetic expression... you say tomato, I say tomahto) is severely altered by only one single dose of the cocaine or the horsey. that's why you want to keep doing more and more and more coke even after you already realize that it just makes you feel like shit. your MEMORY tells you that it was fun last time you did it,but your memory is probably serving you WRONG--that is, unless you waited until you were under-the-table drunk and THEN hit the coke. otherwise, it's your DAT's playing tricks on you.
  17. Forthesevenlakes
    Interesting, wonder if the opposite kind of thing happens when people do dissociatives for the first time, and then cant remember that they had fun. Maybe not with the DAT protein per se, but some similar mechanism in reverse, a lower transcription of some protein that inhibits the memory of good times while under the influence.
  18. Richard_smoker
    Oh, well that problem's easy enough to solve! You just need to run up to wally-world and buy a thought-recorder. Just turn it to the 'on' position right before you dose. Assuming your tape is long enough, you should catch everything you need to know.

    Then of course, you just go back and compare what you actually remember with the thought-strip pattern.

    -Sober Dick aka "Dick-Head"
  19. Forthesevenlakes
    SWIM's friend did that a while back, and the next day played for several people a recording of himself loudly declaring "I can survive on sound alone" after drinking a bottle of robotussin. I nearly died laughing.
  20. glitterfly
    i've read through most of these posts but didn't have time to read all right now so sorry if redundant. but here's some stuff from a take home exam from my drugs and behavior class i took last semester. the professor is one of the leading researchers in psychostimulant use and addiction (this man is a true genius). i'll find some of his articles and post them later. i kinda wanna remain incognito here so don't wanna reveal his name sorry

    about LTP and sensitization.
    When someone is given a psychostimulant, does the drug act at the accumbens and VTA?
    psychostimulants act anywhere there is a dopamine transporter... but its action in the messo-accumbens pathway is responsible for the high experienced by the user... neurons in the VTA send axons to the accumbens that have dopamine receptors... since cocaine and amphetamine bind to DATs there is more dopamine in the synaptic cleft between the axon from the VTA and the soma of the medium spiney neuon (NAS) so the over activation of the DARs on the postsynaptic cell (medium spiney) cause the euphoric behavioral effects.
    Does sensitization depend on a LTP mechanism in the VTA or NAS? yes, VTA
    And how exactly does that work? glutamate activate AMPA receptors depolarizing the cell enough for magnesium to vacate the NMDA receptor and since glutamate is also binding to the NMDA receptor at the same time as the AMPA receptor, then the NMDA receptor opens the calcium channel allowing calcium to flow into the cell and modulate the upregulation of AMPA receptors and simultaneously causing more dopamine to be released therefore having a greater motor effect with the same amount of drug.
    How does a stimulus become associated with a drug reward, through what mechanism? the rat sees a flash of light and the afferents from the pre-frontal cortex release glutamate depolarizing the medium spiney neurons in the striatum and accumbens (this is a weak connection) at the same time the infused drug increased dopamine transmission in the messo-accumbens pathway causing a rewarding effect (Strong connection) if these two neuons fire simultaneously or close enough together (light first) for x number of days... then the light alone will cause a greater depolarization of the medium spiney (through mechanism stated above with glu and AMPA/NMDA) and will trigger the response of the rewarding effects of the drug since the light has now come to predict the administration of the drug. (neurons that fire together wire together... fire out of sync, loose the link)
    And what causes a relapse in the future, a molecular change in the NAS or the VTA? NAS
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