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Cocaine-like neurochemical effects of antihistaminic medications

BilZ0r

BilZ0r

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The pattern of activation of dopamine (DA) neurotransmission in the nucleus accumbens (NAc) of rats produced by H1 histamine antagonists which have behavioral effects like those of psychostimulant drugs was examined. Diphenhydramine and (+)-chlorpheniramine were compared with triprolidine, a potent and selective H1 antagonist and (−)-chlorpheniramine which is less active than its enantiomer at H1 receptors. Affinities of the drugs to DA, serotonin, and norepinephrine transporters at H1 receptors and potencies for DA uptake inhibition in striatal synaptosomes were determined to assess mechanisms by which the compounds increased DA levels. Intravenous diphenhydramine (1.0–3.0 mg/kg) (+)- and (−)-chlorpheniramine (1.0–5.6 mg/kg) but not triprolidine (1.0–3.0 mg/kg) elicited a cocaine-like pattern of stimulation of DA transmission with larger effects in the NAc shell than core. The absence of stereospecific effects with chlorpheniramine enantiomers along with the lack of an effect with triprolidine suggest that the effects on DA transmission were not related to H1 receptor antagonism. Although in vivo potencies were not directly related to DA transporter affinities, it is hypothesized that actions at that site modulated by other actions, possibly those at the serotonin transporter, are primarily responsible for the neurochemical actions of the drugs on DA neurotransmission and might underlie the occasional misuse of these medications.
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Compound...............H1 Affinity(nM).....DAT affinity(nM)
Cocaine................1040................71
Diphenhydramine........96..................581
(+)Chlorpheniramine....27.9................203
(-)Chlorpheniramine....506.................383

Looks like not going that much above clinical chlorpheniramine dose should get you some significant DAT inhibition; meanwhile you'd have to go 10x clinical dose to get that from diphenhyramine. Which is what some people do when they try to 'trip' on it.
 
I was under the impression that IV diphenhydramine produced more of a rush than chlorpheniramine, though I don't believe there are any stereospecific products. Would (-)Chlorpheniramine, with it's decrease in both affinitys (but massively greater decrease in H1 affinity) be better suited for abuse, or is the decrease in DAT affinity too much to make it worth it? It has such a high h1 affinity that I'd be worried to even consider it.
 
I put my bet on (-)Chlorpheniramine if I was going to; because at least with it, you'd be awake. But fuck knows what other kind of non-selective effects you'd get.

I just thought it was interesting. IVing 400mg of (-)Chlor doesn't sound to hot.
 
Have other antihistamines been tested to assess their potential DAT inhibitory action? I'd be particularly curious about cyclizine and pyribenzamine seeing as those are the two that are most prominently associated with opioid co-administration by IV injection. DAT inhibition would certainly explain the increased rush that people report with these combinations.
 
don't forget that diphenhydramine is the grandfather to the invention of SSRIs.

Chlorpheniramine does contain the PEA skeleton within it (how will the resonating double bonds effect binding though?)
 
Ham-milton said:
don't forget that diphenhydramine is the grandfather to the invention of SSRIs.
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That is something I had in mind while reading this thread. Didn't we already know that most antihistamines have an affinity for blocking monoamine reuptake, and through that, they exhibit antidepressant effects (in chronic administration)? Or is the DA craze sweeping across BL getting the best of you, Bill? :)
 
^ As far as I am aware, we didn't know diphenhydramine or chlorpheniramine messed with dopamine transporters. We already knew Diphenylpyraline probably did though.

It wasn't diphenhydramine that was used to create SSRIs, it was chlorpheniramine, by way of brompheniramine. Comapire:
Zimelidine (the first SSRI)http://upload.wikimedia.org/wikipedia/en/thumb/a/a9/Zimelidine.png/120px-Zimelidine.png

Brompheniramine
http://upload.wikimedia.org/wikiped...e.svg/160px-Brompheniramine_structure.svg.png

And Diphenhydramine
http://upload.wikimedia.org/wikiped...e.svg/220px-Diphenhydramine_Structure.svg.png
 
I'm aware that Zimelidine was the first marketed, but it is my understanding that SSRIs were developed after discovering that diphenhydramine selectively reinhibited the reuptake of serotonin.
 
a search for thephorin brings me this:

imgsrv.fcgi
 
Nah, sorry Ham-milton, diphenhydramine doesn't really hit the SERT (1-10uM). And clearly, if you look at the structures, someone messing with a structure activity relationship is going to look at Brompheniramine/chlorpheniramine and synthesise Zimelidine in their first batch of test compounds. That jump is not going to happen from diphenhydramine.

And finally, if you want to go down to the library, you can get the publication by the guy who made zimelidine, and see that I am right.
A. Carlsson (1981) Acta Psychiatrica Scandinavica 63 (s290) , 63–66
 
Hydroxyzine... thats a complicated one because it's metabolized in cetirizine.. I'm not sure if hydroxyzine is a prodrug perse, but cetirizine is a potent drug in its own right.

Both Hydroxyzine and cetirizine will bind at the H1 histamine receptor with low nM affinities (1-10nM). I'll have to look up any dopamine effects. Nah, I can't find anything.
 
That's too bad. The reason I asked is because Hydroxyzine in particular seems to have wider applications than other antihistamines.

As for its metabolite, according to the wiki entry, it does not cross the BBB. Does this mean that some of the hydroxyzine will be metabolized in the brain causing the resulting citrizine to become centrally-active for a while?
 
Oh, sorry, I was being dumb. Cetirizine is a 2nd generation antihistamine. Its used because it DOESN'T get into the brain, i.e. "non-sedating antihistamine"
 
Nah, sorry Ham-milton, diphenhydramine doesn't really hit the SERT (1-10uM). And clearly, if you look at the structures, someone messing with a structure activity relationship is going to look at Brompheniramine/chlorpheniramine and synthesise Zimelidine in their first batch of test compounds. That jump is not going to happen from diphenhydramine.
Click to expand...

Huh, I guess the internet mislead me. That's what you get, though ;)

But was Zimelidine the first synthesized or only the first marketed?
 
First to the clinic, I think. I'm not sure. Its actually quite funny. In that paper I cited above, they made a Serotonin-noradrenaline reuptake inhibitor (the other isomer of zimelidine), but they ignore it because at that time everyone wanted a SSRI. 2 decades later they were busting their balls to make duloxetine.
 
chlorpheniramine has been shown to inhibit the reuptake of SERT and NA, i didn't realize it affected DAT as well. however, i heard that for a DRI to have recreational potiential it's affinity(nM) had to be less than 100.

but this still does interest me. i assume oral administration would not have desired effects related to DAT reuptake inhibition(as ritalin, a much more potent DRI, isn't too recreational oraly) and i don't want to I.V. chlorpheniramine, so would intranasal administration of the "right" amount of chlorpheniramine cause any DRI related euphoric effects?

*even though chlorpheniramine isn't a strong DRI, it also is a SRI and increased DAT and SERT are to synergize in euphoria(ex. MDMA isn't a strong DAT releaser, but the combination of SERT and DAT release causes greater euphoria) as well as increased SERT reducing the anxiety of increased NA(ex. cocaine is a SDNRI and ritalin is just a DRI, and while ritalin is more potent at stopping DAT reuptake, cocaine is still often prefered over ritalin regardless of ROA- intranasal and I.V. causes rapid effects for both but cocaine's SRI effect is said to synergize in a euphoric way with the DRI effect and reduce anxiety caused by increased NA).
 
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