TL neuro

November 17, 2010

Genetic engineering against stimulant dependence?

Filed under: Cocaine, MDMA, SfN Annual Meeting 2010 — Tags: , — mtaffe @ 5:59 pm

In the 1997 film Gattica, the human species had perfected itself through genetic engineering of its offspring. Well, the richer parts of the species had done so, anyway, creating a tiered society. A poster presented at the Society for Neuroscience Annual Meeting 2010 provided a clue towards engineering a more-perfect human. In this case, one that is resistant to developing dependence on stimulant class drugs of abuse.

Fontana and colleagues presented data (Abstract 545.15 “Why are some serotonin and dopamine transporters more promiscuous?“) that described a more-selective version of the dopamine transporter (DAT) and serotonin transporter (SERT).

The DAT, in particular, is a target of many stimulant class drugs of abuse such as cocaine and methamphetamine. This is considered to be a significant treatment target since the National Institutes on Drug Abuse has funded many a study attempting to create drugs which interact with the DAT and might therefore serve as agonist therapy for stimulant dependence.

The SERT is also affected by stimulant class drugs, although different drugs will have stronger or weaker effects at the SERT relative to their effects at the DAT. The amphetamine derivative drug 3,4-methylenedioxymethamphetamine (MDMA) is one that has more SERT activity than is typical for stimulants, and it is very likely this combined DAT/SERT activity that gives MDMA (known as ‘Ecstasy’ in street use) its special subjective character.

This promiscuity of these endogenous chemical signalling mechanisms are a common (perhaps inevitable) gateway for exogenous drugs that people find enjoyable. The drugs are able to interact with brain mechanisms that have an endogenous purpose, producing similar effects to those of a neurotransmitter made by the body in normal function. This includes the DAT and the SERT which are flexible enough to be activated and/or blocked by many molecules other than dopamine and serotonin. Naturally, they are not identical in effect- there are minor or even major differences in structure between dopamine and the exogenous drugs which also interact with the dopamine transporter. Likewise for serotonin and exogenous serotonergic drugs.

But what if the SERT and DAT were highly selective for their endogenous substrates?

Fontana and colleagues took SERT and DAT genes derived from a parasite, Schistosoma mansoni. This is a parasite which causes human disease including (from the Wikipedia entry):

This “acute schistosomiasis” is not, however, as important as the chronic forms of the disease. For S. mansoni and S. japonicum these are “intestinal” and “hepatic schistosomiasis”, associated with formation of granulomas around trapped eggs lodged in the intestinal wall or in the liver, respectively. The hepatic form of the disease is the most important, granulomas here giving rise to fibrosis of the liver and hepatosplenomegaly in severe cases. Symptoms and signs depend on the number and location of eggs trapped in the tissues. Initially, the inflammatory reaction is readily reversible. In the latter stages of the disease, the pathology is associated with collagen deposition and fibrosis resulting in organ damage that may be only partially reversible.

Nasty. It turns out that this parasite expresses SERT and DAT on the external membrane; the author informed me that if you deprive the S. mansoni of exogenous serotonin you can kill it so this is not a trivial feature of the organism. Yet S. mansoni also has tryptophan hydrolase which is essential in the synthesis of serotonin. So it apparently makes serotonin internally as well.

Fontana and colleagues performed binding experiments in which they expressed the human and S. mansoni versions of SERT and DAT in cell systems and evaluated their respective ability to bind serotonin, dopamine, d-amphetamine and MDMA (in addition to some other compounds). The authors found that the hSERT and SmSERT were nearly identical in their binding of serotonin and the hDAT and SmDAT were likewise identical in their binding of dopamine.

The interesting bit was that the affinities for recreational stimulant class drugs differed considerably. The binding affinity (Ki) for inhibiting serotonin transport at the hSERT was 2.7 and 27.1 micromolar for MDMA and d-amphetamine respectively. The binding to SmSERT required much higher concentrations (312.8 and 393 micromolar for MDMA and d-amphetamine).

A similar story was presented for d-amphetamine inhibition of dopamine transport via the hDAT (0.25 micromolar) and SmDAT (10 micromolar).

The rest of the poster focused on the extracellular loop 6 of the SERT and some mutation studies demonstrating that this was involved in conferring or blocking affinity of the SERT for MDMA and d-amphetamine. The presenting author of course was interested in using this type of information to learn more about designing therapeutic drugs that might interact with the SERT. For example, the most famous antidepressant drugs, the SSRI’s are Selective Serotonin Reuptake Inhibitors- i.e., they work through blocking the SERT. Ritalin, the most known treatment for Attention Deficit Hyperactivity Disorder works by blocking the DAT. The more we know about how these transport molecules work, the better we can design drugs to have a desired function while avoiding undesired function. That’s the drug-development theory anyway.

It is much more fun to speculate about the glorious genetic future in which we could engineer our offspring to lack the ability to respond positively to amphetamine or MDMA, though, isn’t it?

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