What is the recreational mechanism of brivaracetam?

[theGirlWithBlueHair]

Diamorphine is preferred over morphine because the two acetyl rings allow it to penetrate the brain quicker, that is all really, since it is more fat soluble, and once there it is rapidly metabolized into morphine and 6 MAM Other than that, it is the exact same drug as morphine.

And kappa opioid agonism doesn't always cause dysphoria. Many people enjoy salvia divinorum and look at oxcycodone, for example.

And I am not sure about potentiating the euphoria of MOR agonism with KOR antagonists as you would also greatly antagonize their painkilling effects and potentiate their respiratory depressant effects.

 

[Limpet_Chicken]

Acetyl RINGS? The acetyl group is a 2-carbon group and as such isn't long enough to form a ring. Smallest cycloalkyl (not cyclo-acyl) group, is cyclopropane which forms a pyramidal shape. With only two carbons there is just insufficient numbers of C atoms
to join together in a cyclic structure.

Oxycodone is a KOR agonist? can you cite further details? I'm curious about that now. As I have always noticed that IV oxy is pretty much devoid of any rush whatsoever, compared to other opioids, especially morphine.
As for heroin, I thought it had some differential affinity/efficacy at MOR splice variants compared to morphine.

 

[theGirlWithBlueHair]

acetyl groups.... (i did not mean rings lol. acetyl rings...lol. I have to proof read before I post) limpet chicken please forgive me! i type these things out so fast often times i have to go back and edit up to 5 to 6 times. (proof permanent this baclofen cognitive damage is here to stay


I hate when that happens... damn. same thing for when I have to post on my phone and can't you italics to empathize and have to use uppercase and it seems like I'm just being a bitch and yelling, when I'm just trying to be stressful is all.

Sorry about the acetyl rings. I meant GROUPS

Yes, let me find you a good pdf.

Here is the one at the kappa:

https://www.thevespiary.org/rhodium...ppear-to-be-k-opiod-receptor-mediated6d99.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572564/pdf/bph0168-0375.pdf (Here is its activity at mu, compared to morphine)

You say it's devoid of a rush - I have never received it so I wouldn't know (I have received morphine with no results however) - what would be your hypothesis as to why it's one of the most abusable and most sought after recreational drugs, even though it agonizes and activates the most dyshporic, hated receptor subtypes the most?

EDIT: lol, third time on this one... :/

Oh btw, now that I even think about, is there even such a thing as an acetyl ring...?

 

[Ligaturd]

I can attest to the fact that Oxycodone is devoid of much of a rush but I can say that the high is quite unique and euphoric, stimulating. People who use opioids tend to have different preferences, those who shoot may value a rush over what oxycodone can provide but it definitely has a huge fan base and is highly sought after.

With Heroin I really believe it's activity is a bit more complex than just crossing the BBB twice as fast and turning into morphine. There isn't near the histamine reaction accompanying the rush and the rush is much warmer. It feels very distinct compared to morphine anytime I have tried it.

 

[Limpet_Chicken]

I can't say as I personally experience the same. I don't really find oxycodone euphoric very much at all, either IV, IM, SC, oral or plugged, it just...doesn't do it for me at all.

It DOES however, make me nod out in a sufficient dose. Currently, I am on a lower dose of oxy than I used to be, but IR rather than oxycontin, used to be on the 80s, but asked my doc to switch me to morphine for my main workhorse opiate, which he did, because it has far more of a rush for me, plus the kind chemistry to make the stuff better is something one can do in one's sleep, more or less. Although I'm pretty sure that my doc didn't take my (fairly well known by him, partly owing to having to explain some journal articles supporting things I want done, and partly because there had to be SOME explanation for turning up to an (completely unavoidable) appointment, unfortunately for me (and everybody else within about 50 meters of me at the time) (twice although one of them due to chlormethiazole and excessive use of same) carrying a truly foul, and extremely long-ranged, utterly unbearable stench of things sulfurous and abominable)

Quite hilarious, looking back on it,but it sure as shit was NOT a laughing matter at the time, christ, I even had to wait outside the waiting room (I hid in the bogs, fuck only knows what other patients must have thought someone had left unflushed in there
)

But something tells me he didn't switch me over for me to, well, do what comes naturally, with the morphine. But I use oxy (rx) as well. Thats for breakthrough, although I'd sooner be on more or less anything else to be honest, I don't like it at all. Well, its not unpleasant, as such, but theres fuck all good about it really. It isn't my LEAST favourite full MOR agonist though, that would have to be tramadol, tying for first place with remifentanil. And although its not a full agonist, meptazinol, and either the benzoyl or propionyl ester, made both, only tasted one, neither of them any good and meptazinol is brutal on my insides, first time I tried it I didn't connect the two, but second, jesus, never again, stuff had me doubled over in pain in the foetal position, I ended up knocking myself out with tizanidine and clonidine, a large dose of both plugged, because I just couldn't stand waiting for it to end on its own.




With regards to the difference between morphine and heroin, yes they are indeed different subjectively, Anyone give me a pointer on how to use the BLAST database to see how MOR1, MOR1D, MOR2, and MOR3, especially MOR1 and MOR3 gene sequences in the mouse and human genome align? because presumably since at least the MOR subtypes would show considerable homology considering that opioid receptors are extremely primal, although seemingly evolved twice, that is to say, afaik MOR, DOR and KOR evolved from a single progenitor which diverged twice during evolution whilst another, presumably ZOR and ORL/nociceptin receptors, or, and I am merely guessing here as I don't know too much about it, the epsilon receptor. My guess would be the zeta opioid receptor, since as expressed in humans it shows relatively little sequence homology with other ORs compared to each other (MOR, DOR, and KOR that is to say), and is somewhat related to fibroblast growth factor receptors IIRC, figures, as it functions very differently from other opioid receptors and acts, as I understand things, as a tumor-suppressor and to slow cellular proliferation.

But my guess as to why oxycodone is really sought after...well the best I can come up with to be honest, is its an opioid and a strong one. Thats about it. If there was nothing whatsoever on offer that was better I'd go for it, if it wasn't expensive. That and
when people need a fix, to suppress withdrawal. Otherwise fuck all if I know. Because I've had access to it for a considerable period and still do, and I've had access to it at a strong dose (enough to take at least a few doses as high as I could go without puking my guts out or blacking out totally, and that with an extant tolerance. Sure, there are crappier opioids, like fentanyl, remifentanil for example, but oxy, at least to ,me is right up there.

One thing I'd like to know, not that I expect its been researched since the drug in question is not one clinically used, at least I don't think so. If it is, probably not very often, but dipropionylmorphine, I'd love to know what if any splice variant selectivity it has at MOR1 and its isoforms and heterodimers, compared with H and morphine.

Because I like the stuff a LOT more than H, and morphine itself I prefer to heroin IV. 6-MAM and 6-MPM would be interesting to assay in that respect also.

Also can someone clear up for me in that latter paper posted by girlwithbluehair what the meaning of the GgammaS DECREASE in binding assay was? because everything I've read states that MOR agonists induce a switch between Gi/o coupling and UPregulate GgammaS, so that doesn't make sense to me measuring its negative regulation.

And no an acetyl ring is not possible. The smallest number of straight lines (links between carbon atoms) that can make a cyclic geometry, is three, in a pyramid. Impossible to connect two straight lines, and have them link up in an oroboros-esque manner.

 

[theGirlWithBlueHair]

Acetly groups, not rings.

Diacetylmorphine.

 

[MeDieViL]

Gaba increasing drugs like tiagabine have been shown to be helpfull in drug addiction, i compiled a list of studys showing tiagabines therapeutic potential for anxiety.

Prim Care Companion J Clin Psychiatry. 2009;11(3):123.
Gabapentin and tiagabine for social anxiety: a randomized, double-blind, crossover study of 8 adults.
Urbano MR, Spiegel DR, Laguerta N, Shrader CJ, Rowe DF, Hategan LF.

Department of Psychiatry, Eastern Virginia Medical School, Norfolk, Virginia.
PMID: 19617947 [PubMed - in process]PMCID: PMC2708011Free PMC Article
Quote:
J Clin Psychopharmacol. 2009 Jun;29(3):314.
Questionable tolerability of tiagabine in generalized anxiety disorder.
Spielmans GI.

PMID: 19440099 [PubMed - indexed for MEDLINE]
Quote:
Psychiatry Clin Neurosci. 2009 Feb;63(1):122.
For publication: Tiagabine in the discontinuation of long-term benzodiazepine use.
Oulis P, Masdrakis VG, Karapoulios E, Karakatsanis NA, Kouzoupis AV, Papadimitriou GN.

PMID: 19154218 [PubMed - indexed for MEDLINE]
Quote:
Neuropsychopharmacology. 2009 Jan;34(2):390-8. Epub 2008 Jun 4.
A PET study of tiagabine treatment implicates ventral medial prefrontal cortex in generalized social anxiety disorder.
Evans KC, Simon NM, Dougherty DD, Hoge EA, Worthington JJ, Chow C, Kaufman RE, Gold AL, Fischman AJ, Pollack MH, Rauch SL.

Department of Psychiatry, Psychiatric Neuroscience Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA. [email protected]
Abstract
Corticolimbic circuitry has been implicated in generalized social anxiety disorder (gSAD) by several neuroimaging symptom provocation studies. However, there are limited data regarding resting state or treatment effects on regional cerebral metabolic rate of glucose uptake (rCMRglu). Given evidence for anxiolytic effects conferred by tiagabine, a gamma-aminobutyric acid (GABA) reuptake inhibitor, the present [(1F] fluorodeoxyglucose-positron emission tomography ((1FDG-PET) study sought to (1) compare resting rCMRglu between healthy control (HC) and pretreatment gSAD cohorts, (2) examine pre- to post-tiagabine treatment rCMRglu changes in gSAD, and (3) determine rCMRglu predictors of tiagabine treatment response. Fifteen unmedicated individuals with gSAD and ten HCs underwent a baseline (pretreatment) resting-state (1FDG-PET scan. Twelve of the gSAD individuals completed an open, 6-week, flexible dose trial of tiagabine, and underwent a second (posttreatment) resting-state (1FDG-PET scan. Compared to the HC subjects, individuals with gSAD demonstrated less pretreatment rCMRglu within the anterior cingulate cortex and ventral medial prefrontal cortex (vmPFC) at baseline. Following tiagabine treatment, vmPFC rCMRglu increased significantly in the gSAD group. Further, the magnitude of treatment response was inversely correlated with pretreatment rCMRglu within vmPFC. Taken together the present findings converge with neuroimaging findings from studies of social cognition in healthy individuals and symptom provocation in gSAD to support a role for the vmPFC in the pathophysiology of gSAD. Given the pharmacological profile of tiagabine, these findings suggest that its therapeutic effects in gSAD may be mediated by GABAergic modulation within the vmPFC.
Quote:
J Clin Psychopharmacol. 2008 Jun;28(3):308-16.
Tiagabine in adult patients with generalized anxiety disorder: results from 3 randomized, double-blind, placebo-controlled, parallel-group studies.
Pollack MH, Tiller J, Xie F, Trivedi MH.

Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA. [email protected]
Abstract
The objective of these studies was to evaluate the efficacy and tolerability of tiagabine, a selective gamma-aminobutyric acid reuptake inhibitor, in adult patients with generalized anxiety disorder (GAD). Patients with a diagnosis of GAD were enrolled in 1 of 3 randomized, placebo-controlled, 10-week studies. In each study, tiagabine was taken twice daily in divided doses--4, 8, or 12 mg/d in a fixed-dose study and 4-16 mg/d in two flexible-dose trials. The primary efficacy measure was the change from baseline in the 14-item Hamilton Rating Scale for Anxiety (HAM-A) total score at the final visit (last observation carried forward). Additional measures included change from baseline in the anxiety subscale of the Hospital Anxiety and Depression Scale, the Sheehan Disability Scale, and Clinical Global Impressions-Improvement scale. Tolerability was assessed via spontaneous reports as well as rating scales throughout the study period. In all 3 studies, there was no significant differentiation from placebo on the primary measure (change in HAM-A) for any tiagabine dose (P > 0.05). In the 2 flexible-dose studies, the tiagabine group showed improvements over time in the HAM-A that reached significance only in those patients who completed 10 weeks of treatment (study 2, P = 0.018; study 3, P = 0.03

Tolerance is reported to develop rapidly so it would only be properly therapeutic when combined with something like memantine.

Gaba reuptake inhibitors seem to be really weak compared to benzos or phenibut, also they dont show effects simular to baclofen, the recreational potential is minimal.

Valproic acids gaba increase is neglible.

Glutamata reduction or antaonism can be recreational in some cases, indeed glutamate downregulates gabab, its implicated and directly involved in tolerance to all drugs, which is why nmda antaonists like memantine work for drug tolerance.

The euphoria induced by opiates and all other drugs is induced by the mu opioid receptor, while da causes wanting and addiction, benzos are addictive without being euphoric, as they dont act on mu.

Kappa neates the dysphoria induced by mu, naltrexone is neutral with regards to reward, it bloks drug induced euphoria while leaving natural reward unaffected which indicates that drugs induce reward in a unique way

 

[theGirlWithBlueHair]

Tiagabine indirectly activate GABA B receptors.

Benzos can be euphoric as they indirectly release dopamine via alpha 1 subunit agonism, especially the z-drugs:

https://www.drugabuse.gov/news-even...nderlies-benzodiazepines-addictive-properties

Mu agonism isn't needed for euphoria.

Naltrexone only blocks euphoria caused by Mu opioid agonists. There are ALL SORTS of mechanisms by which dopamine can be released in the brain affecting reward, the mu opioid receptor nothwithstanding.

And mu opioid inhibition doesn't block D2 activation throughout the mesolimbic reward pathway. It just inhibits that receptor's activity.

That is just one pathway by which drugs can induce dopamine release and cause euphoria. The cannabinoid system and the alpha3beta4 nicotinic actetylcholine receptor, for example, also mediate reward.

And keep in mind, naltrexone, is a reversible antagonist and can be displaced by endorphine: it competes for the receptor site.


Valproic acid stimulates GABAergic neurogenesis: http://www.ncbi.nlm.nih.gov/pubmed/15379904

Can you give a source that valproic acid doesn't induce much increase in synaptic GABA levels? As it is a GABA T inhibitor, and it affects GAD activity as well.

These studies indicate otherwise:

http://www.ncbi.nlm.nih.gov/pubmed/6801254

http://www.sciencedirect.com/science/article/pii/002432058190504X

http://jpet.aspetjournals.org/content/220/3/654.short

http://link.springer.com/article/10.1007/BF00806585 (this supports the former link and the effect on GAD)

Delayed effects of GABA increase and GABA T inhibition: http://science.sciencemag.org/content/208/4441/288

Evidence that valproic acid is a weak, but still IS, a GABA T inhibitor: http://www.ncbi.nlm.nih.gov/pubmed/3092125

This is why it is used upwards of 1000mg, keep this in mind, at these dosages, it DOES have mild, but clinically relevant GABA T activity. Vigabatrin is used in similar dosages, but caused PRONOUNCED side effects typical of strong GABA T activity.

It's also possible that the metabolites are considerably more potent, as this article suggests:

http://www.sciencedirect.com/science/article/pii/0024320583900541

^This is similar to bupropion's weak NDRI activity, say compared to methylphenidate. It still has it, and it is still clinically relevant, but it doesn't display strong typical effects like you would expect from a really potent NDRI.

 

[aced126]

Tiagabine indirectly activate GABA B receptors.

Benzos can be euphoric as they indirectly release dopamine via alpha 1 subunit agonism, especially the z-drugs:

https://www.drugabuse.gov/news-even...nderlies-benzodiazepines-addictive-properties

Mu agonism isn't needed for euphoria.

Naltrexone only blocks euphoria caused by Mu opioid agonists. There are ALL SORTS of mechanisms by which dopamine can be released in the brain affecting reward, the mu opioid receptor nothwithstanding.

And mu opioid inhibition doesn't block D2 activation throughout the mesolimbic reward pathway. It just inhibits that receptor's activity.

That is just one pathway by which drugs can induce dopamine release and cause euphoria. The cannabinoid system and the alpha3beta4 nicotinic actetylcholine receptor, for example, also mediate reward.

And keep in mind, naltrexone, is a reversible antagonist and can be displaced by endorphine: it competes for the receptor site.


Valproic acid stimulates GABAergic neurogenesis: http://www.ncbi.nlm.nih.gov/pubmed/15379904

Can you give a source that valproic acid doesn't induce much increase in synaptic GABA levels? As it is a GABA T inhibitor, and it affects GAD activity as well.

These studies indicate otherwise:

http://www.ncbi.nlm.nih.gov/pubmed/6801254

http://www.sciencedirect.com/science/article/pii/002432058190504X

http://jpet.aspetjournals.org/content/220/3/654.short

http://link.springer.com/article/10.1007/BF00806585 (this supports the former link and the effect on GAD)

Delayed effects of GABA increase and GABA T inhibition: http://science.sciencemag.org/content/208/4441/288

Evidence that valproic acid is a weak, but still IS, a GABA T inhibitor: http://www.ncbi.nlm.nih.gov/pubmed/3092125

This is why it is used upwards of 1000mg, keep this in mind, at these dosages, it DOES have mild, but clinically relevant GABA T activity. Vigabatrin is used in similar dosages, but caused PRONOUNCED side effects typical of strong GABA T activity.

It's also possible that the metabolites are considerably more potent, as this article suggests:

http://www.sciencedirect.com/science/article/pii/0024320583900541

^This is similar to bupropion's weak NDRI activity, say compared to methylphenidate. It still has it, and it is still clinically relevant, but it doesn't display strong typical effects like you would expect from a really potent NDRI.

Bupropion doesn't seem to bind to DAT in the same way that MPH does.

http://www.ncbi.nlm.nih.gov/pubmed/24953830

There exist really potent NDRIs which do not produce rewarding effects (e.g mazindol), but instead are neutral and even aversive at high doses. The paper gives a hypothesis as to why this is so.

 

[theGirlWithBlueHair]

I have to disagree with that paper. Bupropion has definitely been shown to produce recreational and euphoric effects:

DRUG ABUSE AND DEPENDENCE

14 Humans: Controlled clinical studies conducted in normal volunteers, in subjects with a history15 of multiple drug abuse, and in depressed patients showed some increase in motor activity and16 agitation/excitement.17

In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of18 WELLBUTRIN produced mild amphetamine-like activity as compared to placebo on the19 Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a20 score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These21 scales measure general feelings of euphoria and drug desirability.22

Findings in clinical trials, however, are not known to predict the abuse potential of drugs23 reliably. Nonetheless, evidence from single-dose studies does suggest that the recommended24 daily dosage of bupropion when administered in divided doses is not likely to be especially25 reinforcing to amphetamine or stimulant abusers. However, higher doses, which could not be26 tested because of the risk of seizure, might be modestly attractive to those who abuse stimulant27 drugs.28

Animals: Studies in rodents have shown that bupropion exhibits some pharmacologic actions29 common to psychostimulants, including increases in locomotor activity and the production of a30 mild stereotyped behavior and increases in rates of responding in several schedule-controlled31 behavior paradigms. Drug discrimination studies in rats showed stimulus generalization between32 bupropion and amphetamine and other psychostimulants. Rhesus monkeys have been shown to33 self-administer bupropion intravenously.

I can vouch for this. Perhaps the nicotinic acetylcholine antagonism played a role. But that study is wrong.

http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-20-tab11A-Wellbutrin-Tabs-SLR028.pdf

Intranasal bupropion produces typical euphoric dopaminergic effects.


Also, I was referring to potency at binding, not mechanism. Such as the dosage needed and dissociation constant, for which bupropion is weak and in the mM range, whereas methylphenidate (which I used as an example since it is the only other prescription NDRI) is potent and in the nM range.

Binding differently doesn't mean it will produce different effects. Modafinil binds differently yet it still produces effects indistinguishable from methylphenidate at recreational dosages.

This is the only paper that exists on the subject, so really there is no evidence for this "inverse agonist" theory, and I really am inclined to disagree with it.

A negative allosteric modulator isn't going to somehow induce paradoxical effects.

Mazindol induces the releases of norepinephrine and serotonin as well, and the mechanism by which it does so (and who knows what other pharmacology it has) could be a reason for its dysphoria. And you stated at high dosages it is aversive. It's serotonergic properties could be prominent, which would definitely explain the dysphoria.

http://www.ncbi.nlm.nih.gov/pubmed/9253942

Naloxone reverses antinociception induced by mazindol, indicating it may have kappa opioid activity

https://www.google.com/patents/US20160136135

This suggest it antagonizes the dopamine transporter and agonizes the mu receptor (it's typical activity, well the DAT inhibition anyway, but the opioid activity means it definitely could bind to the kappa with high affinity, giving its propensity to cause dysphoria validity)


Reuptake inhibitors, keep in mind, are different than releasing agents, in that they HALT neurotransmitter release by causing IMMEDIATE activation of presynaptic inhibitory autoreceptors, so D2 activation will shut off dopamine release, as more dopamine is released.

This, taken into account with all of the above, may explaine its unique profile.

 

[aced126]

I have to disagree with that paper. Bupropion has definitely been shown to produce recreational and euphoric effects:

DRUG ABUSE AND DEPENDENCE

14 Humans: Controlled clinical studies conducted in normal volunteers, in subjects with a history15 of multiple drug abuse, and in depressed patients showed some increase in motor activity and16 agitation/excitement.17

In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of18 WELLBUTRIN produced mild amphetamine-like activity as compared to placebo on the19 Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a20 score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These21 scales measure general feelings of euphoria and drug desirability.22

Findings in clinical trials, however, are not known to predict the abuse potential of drugs23 reliably. Nonetheless, evidence from single-dose studies does suggest that the recommended24 daily dosage of bupropion when administered in divided doses is not likely to be especially25 reinforcing to amphetamine or stimulant abusers. However, higher doses, which could not be26 tested because of the risk of seizure, might be modestly attractive to those who abuse stimulant27 drugs.28

Animals: Studies in rodents have shown that bupropion exhibits some pharmacologic actions29 common to psychostimulants, including increases in locomotor activity and the production of a30 mild stereotyped behavior and increases in rates of responding in several schedule-controlled31 behavior paradigms. Drug discrimination studies in rats showed stimulus generalization between32 bupropion and amphetamine and other psychostimulants. Rhesus monkeys have been shown to33 self-administer bupropion intravenously.

I can vouch for this. Perhaps the nicotinic acetylcholine antagonism played a role. But that study is wrong.

http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-20-tab11A-Wellbutrin-Tabs-SLR028.pdf

Intranasal bupropion produces typical euphoric dopaminergic effects.


Also, I was referring to potency at binding, not mechanism. Such as the dosage needed and dissociation constant, for which bupropion is weak and in the mM range, whereas methylphenidate (which I used as an example since it is the only other prescription NDRI) is potent and in the nM range.

Binding differently doesn't mean it will produce different effects. Modafinil binds differently yet it still produces effects indistinguishable from methylphenidate at recreational dosages.

This is the only paper that exists on the subject, so really there is no evidence for this "inverse agonist" theory, and I really am inclined to disagree with it.

A negative allosteric modulator isn't going to somehow induce paradoxical effects.

Mazindol induces the releases of norepinephrine and serotonin as well, and the mechanism by which it does so (and who knows what other pharmacology it has) could be a reason for its dysphoria. And you stated at high dosages it is aversive. It's serotonergic properties could be prominent, which would definitely explain the dysphoria.

http://www.ncbi.nlm.nih.gov/pubmed/9253942

Naloxone reverses antinociception induced by mazindol, indicating it may have kappa opioid activity

Modafinil is not known to be euphoric and reinforcing, even at super-gram doses.

Mazindol is one example. Other examples include bupropion, nomifensine, tesofensine, sibutramine, GBR12909, modafinil etc.

There are several studies indicating that bupropion is not rewarding, even in psychostimulant abusers.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1983.tb01512.x/pdf
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1429582/
http://www.ncbi.nlm.nih.gov/pubmed/6406459
http://www.ncbi.nlm.nih.gov/pubmed/20520602

The point I'm trying to make (which the paper exemplifies clearly) is that NDRI potency does not correlate to subjective rewarding and reinforcing effects. Just because a compound binds really well to DAT does not necessarily mean it will be reinforcing. Cocaine inhibition of dopamine uptake is around 500nM, around the same as bupropion, and significantly less than e.g mazindol (around 50nM), but cocaine is much more euphoric, reinforcing and rewarding than the other two drugs, which in fact both become aversive given a sufficiently high dose.

 

[Cotcha Yankinov]

Route of administration is known to be important for many drugs euphoric effects.

"a subsequent study looked at the actual extracellular concentrations of dopamine in the human brain after an acute oral treatment of bupropion and failed to observe any increase, concluding that the weak DAT occupancy was not sufficient to increase dopamine levels.^[12][13] In contrast, the same study also looked at dopamine levels in the rat brain after administration of bupropion via intraperitoneal injection and did see an increase, which could have been related to species differences.^[12] However, an alternative explanation is that the difference had to do with the different routes of administration employed (i.e., oral vs. i.p.) and the associated differences in pharmacokinetics and metabolism, namely, the bypassing of first-past metabolism with the latter route, that resulted.^[12] Although oral bupropion at clinical doses does not appear to have a significant potential for abuse, there are many isolated case reports of bupropion abuse and "cocaine-like" effects in humans who ingested the drug via a non-oral route (e.g., injection, insufflation, etc.).^[76] Notably, awareness of the abuse potential of bupropion via non-conventional routes appears to be especially prominent in correctional facilities.^[77]"

 

[theGirlWithBlueHair]

Modafinil is not known to be euphoric and reinforcing, even at super-gram doses.

Mazindol is one example. Other examples include bupropion, nomifensine, tesofensine, sibutramine, GBR12909, modafinil etc.

There are several studies indicating that bupropion is not rewarding, even in psychostimulant abusers.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1983.tb01512.x/pdf
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1429582/
http://www.ncbi.nlm.nih.gov/pubmed/6406459
http://www.ncbi.nlm.nih.gov/pubmed/20520602

The point I'm trying to make (which the paper exemplifies clearly) is that NDRI potency does not correlate to subjective rewarding and reinforcing effects. Just because a compound binds really well to DAT does not necessarily mean it will be reinforcing. Cocaine inhibition of dopamine uptake is around 500nM, around the same as bupropion, and significantly less than e.g mazindol (around 50nM), but cocaine is much more euphoric, reinforcing and rewarding than the other two drugs, which in fact both become aversive given a sufficiently high dose.

Bupropion is unique in that it is metabolized into a NRI orally and has the nAChR antagonism that INHIBITS dopamine release. Intranasally, where the ACTUAL bupropion molecule is maintained, it is euphoric and reinforcing.

And modafinil does produce euphoric effects, similar to methylphenidate:

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled SubstancePROVIGIL contains modafinil, a Schedule IV controlled substance.9.2 AbuseIn humans, modafinil produces psychoactive and euphoric effects, alterations in mood,perception, thinking, and feelings typical of other CNS stimulants. In in vitro bindingstudies, modafinil binds to the dopamine reuptake site and causes an increase in extracellulardopamine, but no increase in dopamine release. Modafinil is reinforcing, asevidenced by its self-administration in monkeys previously trained to self-administercocaine. In some studies, modafinil was also partially discriminated as stimulant-like.Physicians should follow patients closely, especially those with a history of drugand/or stimulant (e.g., methylphenidate, amphetamine, or cocaine) abuse. Patientsshould be observed for signs of misuse or abuse (e.g., incrementation of doses ordrug-seeking behavior).The abuse potential of modafinil (200, 400, and 800 mg) was assessed relative tomethylphenidate (45 and 90 mg) in an inpatient study in individuals experienced withdrugs of abuse. Results from this clinical study demonstrated that modafinil producedpsychoactive and euphoric effects and feelings consistent with other scheduledCNS stimulants (methylphenidate

It just happens to also be a D2 partial agonist at higher dosages, which cuts off dopamine release - which is counter productive - as the D2 receptor is also a presynaptic inhibitory autoreceptor, so its abuse is greatly limited.

And the potencies of cocaine and bupropion are far from similar - look at the dosages needed and the occupancy of the receptor at the dosages. Even at optimal dosages, bupropion - which isn't even bupropion to be technical - achieves, what is it, 22% receptor occupancy? You need MUCH higher for euphoria. And at those dosages nAChR antagonism comes into play. The dysphoria from large dosages of bupropion some people experience is NOT from DAT inhibition; it's from the nicotinic antagonism.

Other mechanisms of action as well metabolism and whatnot need to be take into account with these drugs.

Bupropion is abusable and does produce reinforcing effects when administered intranasally or intravenously. It's metabolism negates much of its abuse potential orally.

But the original study done by the manufacturer does show that it does have some abuse potential, and the pharmacy packets do come with warnings with people with drug abuse problems, and I personally have gotten favorable psychostimulant properties.

I think it largely depends on a person's response to the nACh effects.

The same with modafanil: dosing has to be gotten right, otherwise you're going to be essentially turning it into an abilify, due to the D2 partial agonism

 

[aced126]

My original point was simply to point out that your analogy might not be suitable as NDRI activity does not necessarily correlate with rewarding and reinforcing effects. The original paper I linked clearly shows several strong DRIs which do not induce typical amphetamine like locomotor activity, and are neither reinforcing nor rewarding, suggesting cocaine-type DRIs have a fundamentally different mechanism of action than non-reinforcing DRIs.

 

[theGirlWithBlueHair]

But I wasn't pointing that out. I was simply pointing out the correlation between the potency of bupropion and methylphenidate for NET and DAT and the correlation to clinical effects which is similar to the potency of vigabatrin and valproic acid for GABA T and the correlation for clinical effects.

Not anything about pharmacological activity.

A lot of the dopamine reuptake inhibitors you pointed out also have conflicting pharmacological mechanisms that would prevent them from having reinforicing effects, such as bupropion, mazindol, and modafinil, though. (Albeit, bupropion and modafinil have demonstrated recreational activity, as modafinil is a controlled substance and bupropion in its original study did produce effects similar to d-amphetamine and did induce increases in locomotor activity)

I think some non-reinforcing DRIs may have additional action at the D2 receptor, causing them to shut off dopamine release. I think one of the papers I read on mazindol, the one mentioning naloxone, indicated it might have some D2 activity.

 

[aced126]

But I wasn't pointing that out. I was simply pointing out the correlation between the potency of bupropion and methylphenidate for NET and DAT and the correlation to clinical effects which is similar to the potency of vigabatrin and valproic acid for GABA T and the correlation for clinical effects.

Not anything about pharmacological activity.

A lot of the dopamine reuptake inhibitors you pointed out also have conflicting pharmacological mechanisms that would prevent them from having reinforicing effects, such as bupropion, mazindol, and modafinil, though. (Albeit, bupropion and modafinil have demonstrated recreational activity, as modafinil is a controlled substance and bupropion in its original study did produce effects similar to d-amphetamine and did induce increases in locomotor activity)

I think some non-reinforcing DRIs may have additional action at the D2 receptor, causing them to shut off dopamine release. I think one of the papers I read on mazindol, the one mentioning naloxone, indicated it might have some D2 activity.

This was what I originally intended to bring up: the fact that potency at DAT does not correlate to clinical effects in several cases. The way neurotransmitter sodium symporters like DAT, NET and SERT function seems to be much more complex than how most enzymes. In DAT, there are at least 2 binding sites (S1 and S2) to which substrates can bind to, and a putative S3 site as well, and there are many low energy states of DAT, any of which could be stabilised by a ligand causing different effects (e.g ligands could stabilise an open-to-out conformation, closed-to-out etc). A ligand that stabilises an open-to-in conformation could result in DAT spontaneously reverse transporting DA into the synaptic cleft. Some ideas like this are explained in the original review I posted, and many other studies on DAT indicate evidence like multiple binding sites. Measuring reuptake inhibition misses out on information like this, which is one of the reasons why several of the compounds with high DAT potency do not show "expected" physiological effects.

 

[theGirlWithBlueHair]

http://pubs.acs.org/doi/abs/10.1021/jm401754x

Yeah, modafinil binds differently than cocaine, which could explain it's diminished abuse potential.

I wasn't debating the pharmacology of DAT, I was just stating that the some of the compounds you stated do in fact possess some recreational effects, and that some of their other pharmacological activity - other than DAT inhibition - could be contributing to their lack of expected effects.

Such as bupropion's nAChR antagonism, which decreases dopamine release. Or modafinil's D2 partial agonism, which inhibits presynaptic dopamine release and blocks dopamine from activating D2 receptors postsynaptically. These effects would cause aversion and dysphoria.

But receptor occupancy does play a role too. Bupropion does only occupy (and this is hydroxybupropion) 22% orally. Intranasally it hits the receptors quickly and fully and produces recreational effects. Modafinil has high receptor occupancy, which explains its higher abuse potential and controlled substance status.

In the case of these two drugs, in my opinion at least, receptor occupancy plays a role, maybe not potency, but occupancy.

 

[aced126]

http://pubs.acs.org/doi/abs/10.1021/jm401754x

Yeah, modafinil binds differently than cocaine, which could explain it's diminished abuse potential.

I wasn't debating the pharmacology of DAT, I was just stating that the some of the compounds you stated do in fact possess some recreational effects, and that some of their other pharmacological activity - other than DAT inhibition - could be contributing to their lack of expected effects.

Such as bupropion's nAChR antagonism, which decreases dopamine release. Or modafinil's D2 partial agonism, which inhibits presynaptic dopamine release and blocks dopamine from activating D2 receptors postsynaptically. These effects would cause aversion and dysphoria.

But receptor occupancy does play a role too. Bupropion does only occupy (and this is hydroxybupropion) 22% orally. Intranasally it hits the receptors quickly and fully and produces recreational effects. Modafinil has high receptor occupancy, which explains its higher abuse potential and controlled substance status.

In the case of these two drugs, in my opinion at least, receptor occupancy plays a role, maybe not potency, but occupancy.

Is this receptor occupancy constant even if the concentration of the drug is increased? Surely you can get more receptor occupancy just by taking more bupropion?

 

[theGirlWithBlueHair]

I'm sure. But hydroxybupropion doesn't have the affinity that bupropion does. That is why bupropion really needs a different ROA

It circulates 1000 fold higher than bupropion

But damn if I can't tell the difference between 900mg of bupropion and 120mg of vyvanse.

 

[Cotcha Yankinov]

GWBH, what about the difference between bupropion and dextroamphetamine for you subjectively?

Also, just thought I'd point out modafinil is a strange one (histamine etc.)