Sunday, March 14, 2010

The Cocaine Conundrum

Effective treatment remains elusive.

For addiction to cocaine, amphetamine, and other stimulants, the treatment picture has been complicated by the lack of any truly significant anti-craving medications. (See post, “No Pill for Stimulant Addiction"). The National Institute on Drug Abuse (NIDA) has yet to approve any medications for the treatment of either cocaine or amphetamine addiction.

Take the case of cocaine. Partly the problem stems from the direct effect cocaine has on dopamine transmission.  The hunt for a pharmaceutical approach to blunt that effect is complicated by the problematic nature of dopamine receptors.  Dopamine antagonist drugs like the antipsychotic drug haloperidol do not always block the stimulant rush. And their side effects, such as lethargy, emotional blunting, and tardive dyskinesia, make them unsuitable for ongoing addiction therapy. Conversely, some drugs that act as dopamine agonists turn out to be addictive in their own right. Many designer drugs are like that.

Because of all this, different approaches may be needed. The direct ride to the pleasure pathway provided by stimulants makes it difficult to tamper selectively with their effects. An antibody that would reduce cocaine consumption and sop up cocaine molecules in the brain, a kind of vaccine against cocaine, is one approach being pursued (See post, “Cocaine Vaccine Hits Snag”).

But other avenues of attack are being exploited.  Scientists in NIDA’s Intramural Research Program are testing compounds that target certain proteins known as dopamine transporters. Transporters move dopamine molecules in and out of the synaptic gap between neurons in the brain. Interfering with that transportation system is another way of altering dopamine uptake, and it represents one active avenue of approach to the treatment of cocaine addiction.

The researchers tested Benztropine Mesylate (BZT), brand name Cogentin, one of a class of drugs known as anticholinergic suppressants commonly used in the management of Parkinson’s disease. What exactly does benztropine do? It possesses both anticholinergic (acetylcholine-blocking) and antihistaminic effects. It has chemical similarities to atropine, which is used for Parkinson’s and for heart disease.

To begin with, the researchers wanted to establish that benztropine itself is non-addictive. By substituting different BZT analogs for cocaine during self-administration testing on addicted rats, “two of the three BZT analogs that were tested significantly reduced drug self-administration… which indicates that those BZT analogs themselves have low potential for abuse.”

Next, the cocaine-addicted rats were given different BZT analogs before they got their cocaine. “When given before rats had access to cocaine in the self-administration chambers,” the researchers reported in the Journal of Pharmacology and Experimental Therapeutics, “two BZT analogs also significantly reduced the number of times the rats would press a lever to receive cocaine.” Monoamine uptake inhibitors were used as a control. The authors conclude that “these compounds are promising candidates for the development of medications for cocaine addiction.”

Hiranita, T., Soto, P., Newman, A., & Katz, J. (2009). Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors Journal of Pharmacology and Experimental Therapeutics, 329 (2), 677-686 DOI: 10.1124/jpet.108.145813


Adi Jaffe said...

This is nice, but there are quite a few holes in their logic here: "which indicates that those BZT analogs themselves have low potential for abuse.” Cocaine-induced sensitization may account for this also since the animals would not be showing the heightened response they'd been showing for cocaine. Also, since rats are pretty good at being able to tell the effects of different drugs apart, they might require some more exposure to BZT to show equivalent responding.

I'm also not really sure that DAT interference would help anything since cocaine increased dopamine tone while essentially shutting down phasic DA release. Wouldn't interfering with DAT then exacerbate the problem?

Okay, off to actually read the paper...

Dirk Hanson said...

Excellent, come back and tell us what you learned if you get the chance.

Adi Jaffe said...

Okay, now I've actually taken the trouble to read the paper...

It seems that there BZT analogues are much more selective for DAT than for other receptors types and that they produce some, though reduced, pressing. The finding regarding their inability to produce place-preference are encouraging as well.

The findings regarding presses/second are a bit misleading when they're examined compared to total volume acquires, where results are less impressive. Also, it's important to note that my earlier notions about the possibility of additional testing days may indeed change this equation.

Lastly, the suggestion here seems to be that these would be good for treatment by reducing the pleasure received from cocaine in the case of relapse, though i'm not sure about its effect on reducing cravings and the probability for relapse itself. A different procedure will be necessary for that.

This seems to be promising in the buprenorphine for opiate addiction sort of way, though of course, that would be an amazing breakthrough for cocaine which has been kind of left behind in terms of pharmacological interventions.

Dirk Hanson said...

Thanks for the analysis. Cocaine has indeed lagged behind other drugs in this respect. Sounds like it would be better than nothing, as you have noted. But I still hold to the notion that the best pharmaceutical approach is to attack cravings instead of, or in addition to, blunting the drug's effect.

Anonymous said...

I am not going to be original this time, so all I am going to say that your blog rocks, sad that I don't have suck a writing skills

Anonymous said...

Thanks for an explanation, I too consider, that the easier, the better ?

Anonymous said...

Mike has left a new comment on your post "The Cocaine Conundrum":

Yes, Anonymous is correct..your blog does rock! I'm jealous of your writing skills! ;) as a recovering Crack-Cocaine/Heroin addict myself, I would say that anything that the science/medical community could come out with on this issue would be of great help. I have heard of there being a pill for this although cannot remember the details, any one else hear of it?

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