Cocaine Flaws in DAT Hypothesis?

[Smyth]

Here is an interesting paper.

In it they do lots of genetic changes to rats brains to see how it affects their enjoyment of cocaine.

While it is clearly shown that DAT is responsible for the locomotor activity of the drug, it is shown that DAT alone is not responsible for the cocaine reward.

I still think the results show that dopamine is chiefly responsible for the reinforcing effects but it might help explain why people prefer coke to ritalin, and also why mazindol is not very popular.

 

[Smyth]

http://www.annalsnyas.org/cgi/content/abstract/1025/1/47

Also the above link contains a slightly more recent article bt the same author if anybody can get it.

 

[5-HT2]

It is important to note that all of the studies indicating a role for SERT and NET in cocaine reward involve ablation/blockade of the DAT. This raises dopamine levels to the point where it is likely that significant amounts are taken up by other monoamine transporters. Thus, in these cases, cocaine may be acting by mechanisms that are not shared with its mode of action in the normal brain. This view was recently bolstered by a very recent paper in which the generation and characterization of mice with a cocaine insensitive DAT was described:

Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter

Rong Chen*, Michael R. Tilley*, Hua Wei*, Fuwen Zhou{dagger}, Fu-Ming Zhou{dagger}, San Ching{ddagger}, Ning Quan{ddagger}, Robert L. Stephens§, Erik R. Hill*, Timothy Nottoli¶, Dawn D. Han*, and Howard H. Gu*,||,**

Departments of *Pharmacology, ||Psychiatry, {ddagger}Oral Biology, and §Physiology, Ohio State University, 5184b Graves Hall, 333 West 10th Avenue, Columbus, OH 43210; {dagger}Department of Pharmacology, University of Tennessee College of Medicine, Memphis, TN 38163; and ¶Section of Comparative Medicine, Yale University, 375 Congress Avenue, New Haven, CT 06520

Edited by Susan G. Amara, University of Pittsburgh School of Medicine, Pittsburgh, PA, and approved May 2, 2006 (received for review February 2, 2006)

There are three known high-affinity targets for cocaine: the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Decades of studies support the dopamine (DA) hypothesis that the blockade of DAT and the subsequent increase in extracellular DA primarily mediate cocaine reward and reinforcement. Contrary to expectations, DAT knockout (DAT-KO) mice and SERT or NET knockout mice still self-administer cocaine and/or display conditioned place preference (CPP) to cocaine, which led to the reevaluation of the DA hypothesis and the proposal of redundant reward pathways. To study the role of DAT in cocaine reward, we have generated a knockin mouse line carrying a functional DAT that is insensitive to cocaine. In these mice, cocaine suppressed locomotor activity, did not elevate extracellular DA in the nucleus accumbens, and did not produce reward as measured by CPP. This result suggests that blockade of DAT is necessary for cocaine reward in mice with a functional DAT. This mouse model is unique in that it is specifically designed to differentiate the role of DAT from the roles of NET and SERT in cocaine-induced biochemical and behavioral effects.

This model, though an improvement on the previous knockouts, is not perfect, and is incompletely characterized. If they can show that these mice do not self-administer cocaine, that finding will probably shift the field back towards more classical views of cocaine action at the DAT.

 

[BilZ0r]

Pharmacokinetics can also explain why bupropion and methylphenidate aren't quite as fun...

^ Good paper 5-HT2... I hadn't actually thought of what you said, but in retrospect, it is painfully obvious.

 

[Smyth]

Yes this latter study has been a useful contribution. I understand the principle perfectly well. I guess what im really trying to figure out is if there is anyway of knowing if mixed uptake inhibitor (eg cocaine) is anymore desirable than a pure DAT inhibitor (eg RTI-113). I was just thinking out loud but on this occasion it churned out a good response which im pleased about.

The fact that a suitably chosen DAT specific inhibitor can produce euphoria/reinforcment/pleasure etc seems obvious.

However what u have highlighted is that in the absence of DAT affinity, cocaine lacks the ability to cause heightened arousal.

I guess the take-home message is that pure DAT blocker is all that is needed for cocaine substitute therapy and that the role of serotonin and noradrenaline in the descriminative response can be neglected.

 

[BilZ0r]

^ Well as I say, whether or not it is addictive will depend massively on the compounds pharmacokinetics; but I agree with your take home message.

 

[Smyth]

Found this whilst I was browsing google.