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

[Richard_smoker]

A single cocaine exposure increases BDNF and D3 receptor expression: implications for drug-conditioning.

Neuroreport. 16(2):175-178, February 8, 2005. Le Foll, Bernard CA 2; Diaz, Jorge 1; Sokoloff, Pierre

Abstract:
Environmental stimuli associated with a single cocaine exposure acquire long-lasting motivational properties that are able to induce relapse. We measured Brain-derived neurotrophic factor (BDNF) and dopamine D3 receptor (Drd3) expressions in rat brain regions that have been involved in drug-conditioning. Acute cocaine produced a transient increase in BDNF mRNA in the prefrontal cortex, associated with a long-lasting increase in drd3 mRNA, and a delayed and long-lasting increase in Drd3 protein in the nucleus accumbens. Methamphetamine and morphine, two drugs known to easily induce drug-conditioning, also markedly elevated BDNF mRNA. Nicotine had more limited effects. Abused drugs increase acutely BDNF expression, which leads to subsequent long-lasting elevation of Drd3 in the nucleus accumbens that may facilitate responding to drug-associated stimuli.

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.

[Aaron]

Interesting, hopefully this could lead to some type of solution for those who can't kick the habit due to addiction.

[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?

[IHrtHalucingens]

What is the biological purpose of the receptors in question? This would lead you to the answer to you question i suspect.

[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...

[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

ABSTRACT

The nucleus accumbens (NAcc) is a brain region involved in functions ranging from motivation and reward to feeding and drug addiction. The NAcc is typically divided into two major subdivisions, the shell and the core. The primary output neurons of both of these areas are medium spiny neurons (MSNs), which are quiescent at rest and depend on the relative input of excitatory and inhibitory synapses to determine when they fire action potentials. These synaptic inputs are, in turn, regulated by a number of neurochemical signaling agents that can ultimately influence information processing in the NAcc. The present study characterized the ability of three major signaling pathways to modulate synaptic transmission in NAcc MSNs and compared this modulation across different synapses within the NAcc. The opioid [Met]5enkephalin (ME) inhibited excitatory postsynaptic currents (EPSCs) in shell MSNs, an effect mediated primarily by µ-opioid receptors. Forskolin, an activator of adenylyl cyclase, potentiated shell EPSCs. An analysis of miniature EPSCs indicated a primarily presynaptic site of action, although a smaller postsynaptic effect may have also contributed to the potentiation. Adenosine and an adenosine A1-receptor agonist inhibited shell EPSCs, although no significant tonic inhibition by endogenous adenosine was detected. The effects of these signaling agents were then compared across four different synapses in the NAcc: glutamatergic EPSCs and GABAergic inhibitory postsynaptic currents (IPSCs) in both the core and shell subregions. ME inhibited all four of these synapses but produced a significantly greater inhibition of shell IPSCs than the other synapses. Forskolin produced an increase in transmission at each of the synapses tested. However, analysis of miniature IPSCs in the shell showed no sign of a postsynaptic contribution to this potentiation, in contrast to the shell miniature EPSCs. Tonic inhibition of synaptic currents by endogenous adenosine, which was not observed in shell EPSCs, was clearly present at the other three synapses tested. These results indicate that neuromodulation can vary between the different subregions of the NAcc and between the different synapses within each subregion. This may reflect differences in neuronal interconnections and functional roles between subregions and may contribute to the effects of drugs acting on these systems.

[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

ABSTRACT

The rewarding properties of cocaine have been postulated to be regulated, in part, by the mesolimbic dopamine system. However, the possibility that the rewarding properties of cocaine are mediated by direct activation of this system has yielded contradictory findings. The intracranial self-administration technique is used to identify specific brain regions involved in the initiation of response-contingent behaviors for the delivery of a reinforcer. The present study assessed whether adult Wistar rats would self-administer cocaine directly into the nucleus accumbens shell (AcbSh) and core (AcbC). For each subregion, subjects were placed in standard two-lever operant chambers and randomly assigned to one of five groups for each site that were given either artificial cerebrospinal fluid (aCSF), or 400, 800, 1200, or 1600 pmol of cocaine/100 nl to self-administer. The data indicate that rats with placements within the AcbSh readily self-administered 800 to 1600 pmol of cocaine/100 nl and responded significantly more on the active than inactive lever. These subjects also decreased responding on the active lever when aCSF was substituted for cocaine and reinstated responding on the active lever when cocaine was reintroduced. Coinfusion of the D(2)-like receptor antagonist sulpiride inhibited cocaine self-infusion in the AcbSh. In contrast to the AcbSh data, rats failed to self-administer any tested dose of cocaine into the AcbC or areas ventral to the AcbSh. These findings suggest that the AcbSh is a neuroanatomical substrate for the reinforcing effects of cocaine and that activation of D2-like receptors is involved.

[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.

Reputation Comments on this post:

AWESOME!! Thanks for the input. Keeps my brain juices flowing for cross-talk to occur! thanks

[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.


[IMG]file:///C:/DOCUME%7E1/KRAMER%7E1/LOCALS%7E1/Temp/moz-screenshot-2.jpg[/IMG]

Nerve cells in the substantia nigra send out fibers to tissue located in both sides of the brain. There the cells release essential neurotransmitters that help control movement and coordination.

[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.

[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)

[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?

[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!

[Forthesevenlakes]

why thank you! You as well, This kind of discussion stimulates me more than any dopamine binding compound, ha ha.

[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.

[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!

[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.

[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.

[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"

[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

Reputation Comments on this post:

	great explanations for these phenomena!
	nice! I miss ya... where'd you go!? i thought you were adding a lot of good-ole information to the conversation!

[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.

[Richard_smoker]

OK glitterfly...

Is he really a GENIUS!? ...or is he just a professor with a PhD in Cell Biology?A genius can solve a Rubik's Cube, but anyone can learn neurobiology. They just have to go to lots of classes, memorize things, and be interested, that's all.

Hey, your teacher/class wouldn't happen to be in Pennsylvania, would it? What's it called? Lebanon Valley? There's some guy named Laguna up there... that test reminds me of him.

I think the guys you're talking about who did this are professors at Brown. Dr. Kauer & Li. also, Drs. Giorgetti, Hotsenpiller, Ward, Teppen & Wolf(?) in Chicago do some pretty decent work on that same type stuff.

OK, back to the point--for the sake of everyone reading your pink words, could you please translate some of your abbreviations?? I don't doubt that your teacher is a genius, but he needs to spell out words better for those of us who aren't geniuses.

I'm guessing on some of these. please correct me.

LTP="Long Term Potentiation?"
VTA="Ventral Tegmental Area?"
NAS="???" Nucleus Accumbens?
DAR=? Dopamine Receptors?

thanks!

[glitterfly]

lol i'm not saying that he's a genius just b/c he's studying psychostimulants and addiction, HELL SWIM herself is studying the same thing. haha you would have to know him to understand, anyway, i will explain all of these abbreviations n such better tomorrow i promise but i've spent way too much time on here already tonight and have work to do. and no, not brown univ
btw, didn't know pink was aversive to the eyes my bad is purple offensive also

[Forthesevenlakes]

glitterfly, thats a good post. however what i dont get is the hebbian mechanism explaining how a stimuli could get tried to drug reward. seems if both dopamine and glutamate neurons were firing together to begin with, and then you have only the light-dependent glutamate neurons firing in response to a light in the absence of a drug, it would create a small rewarding effect in the animal, instead of craving, which is what my intuitive sense would predict. oh well. i may just be reading it wrong.

[Richard_smoker]

Glitterfly, sorry for the sarcasm in my last post. I was shooting in the dark, trying to guess your school &/or teacher based on the subject material of your test. I think I was having PMS... no wait. sorry, that was my wife! Yeah, that PMS really pisses me off and makes me mean. I know it doesn't even phase most women, but ME--wow, it really takes its toll on me!

Anyways, I appreciated your post. If you notice, none of these discussions have included your suggestions in the pathways to addiction and habituation. This realization sent me into a web-searching frenzy and I found some good data to support your claims. It seems that the 'extended amygdala' circuits and other neighboring cells in the meso-limbic system are quite involved, not only in stimulant addiction, but also in other addictive drugs as well.

Correct me if I'm wrong here, but is "meso-limbic" the same as the "limbic system"??? This is the cingulate gyrus and ?something else? and it's involved in emotional reactions... right?

well, anyways, here's some pretty good stuff I unearthed about your contribution about the VTA (Ventral Tegmental Area) & meso-limbic's involvement in addictive behaviors, repetitive activities, pleasure, etc.

The following is some info I summarized & edited from Drugs of abuse and the brain. Leshner AI, Koob GF. Proc Assoc Am Physicians 1999 Mar-Apr; 111(2):99-108.

New research shows that drugs' effects on brain functioning are an important cause of abuse & addiction.

Drugs of abuse have been hypothesized to produce their rewarding effects by neuropharmacological actions on a common brain reward circuit called the extended amygdala.

Extended amygdala: area including mesolimbic dopamine system, part of dorsal forebrain (shell of nucleus accumbens, bed nucleus of stria terminalis, & central nucleus of the amygdala.

Stimulants (cocaine & amphetamine) & Nicotine and THC activate mesolimbic dopamine system & opiates activate opioid peptide receptors within & independent of mesolimbic dopamine system.

Sedatives (benzos) alter multiple neurotransmitter systems in this circuit, including: GABA, Dopamine, 5-HT, glutamate & opioid peptides.

ADDICTION:
Repeated and prolonged drug abuse leads to compulsive use, and the mechanism for this transition involves, at the behavioral level, a progressive dysregulation of brain reward circuitry and a recruitment of brain stress systems such as CRF (corticotropin-releasing factor).

**VERY IMPORTANT STATEMENT CONCERNING THE ISSUE OF RELAPSE:

The molecular mechanisms of signal transduction in these systems are a likely target for residual changes in that they convey allostatic changes in reward set point, which lead to vulnerability to relapse.

My interpretation of this last statement is that the authors are hypothesizing something that forthesevenlakes and I have actually discussed previously via PMs. We think that it may be possible to neutralize drug withdrawals and minimize the urge to take opiates in an addict by discovering and administering uncontrolled, nonaddictive compounds which cause the same intra-cellular signal transduction cascades as opiates binding to the opiate receptors.

For example: it might not be necessary for an opioid binding to a Mu receptor to increase cAMP in neuronal cells. I'm sorry. this is purely hypothetical; i'm not even asserting that opiates use the cAMP pathway--so, it's probably a terrible and confusing example, but there are only a handful of intracellular changes (i.e. signal transduction cascades) that non-steroid and non-thyroid NT's can actually cause in their target cells.

Some examples of intracellular signal transduction cascades are G-protein Receptors, Tyrosine Kinases, cAMP, ion channels and some other shit that I have mostly forgotten details concerning. Please, if anyone knows these specifics, I would appreciate if you could post them here, as I've been too busy working out the extracellular effects of Ibogaine to even research and re-learn signal transduction cascades.

I have been working on a paper (to post here when I'm done) comparing some unregulated drugs that will mimick many of the neurochemical activities of ibogaine, and possibly even mimick MOST of the effects. I still have a few missing piecees and I'm working out some obvious flaws, so I'm not sure how much longer this post will take to complete... but so far, I haven't even touched the idea of targeting the internal cellular environment specifically--instead, I've had my hands full with the EXTRA-CELLULAR (membrane) receptor activation, deactivation and pharmacokinetics of Ibogaine... and I am working under the pretext that this is shaky, 'un-scientific' science because it assumes that ibogaine works in the first place... something that has yet to be actually proven. However, there are many convincing tales of antecdotal evidence to say that Ibogaine actually works.
-Dick