Will a dual sigma receptor antagonist / dopamine transporter inhibitor treat stimulant abuse?

This post covers a platform presentation in symposium 222. Molecular Basis of Addiction: Neurocognitive Deficits and Memory (Mon, Apr 28, 9:55 AM - 12:10 PM) at the 2014 Experimental Biology meeting.

803.3/D382 - Preclinical efficacy of the dual sigma receptor antagonist dopamine uptake inhibitor, CM699, as a medication for stimulant abuse

Johnathan Katz of the NIDA Intramural Research program presented an overview of the data and findings that led up to the creation of a new molecule (CM699) that functions a both a dopamine transporter (DAT) inhibitor and a sigma receptor antagonist. As a bit of background, NIDA has spent a tremendous amount of effort trying to use dopamine transporter inhibitors as agonist therapy for stimulant abuse. The theory of agonist therapy is familiar from the nicotine patch and methadone. The outline is that if you have a drug which mimics the abused drug in effect but has different time-course of effect, you may be able to blunt the acute high of the preferred drug and/or method of use. The nicotine patch supplies the identical drug but in a more sustained, slower and less-peaky manner. Methadone is relatively long acting at endogenous opioid receptors, apparently providing relief without the acute euphoric high. A similar strategy has governed attempts to identify compounds which would confer protection against stimulant abuse.

Since the acute reinforcing effect of stimulants such as cocaine and methamphetamine is mediated through the DAT, this was the target of considerable NIDA effort over decades. It has not been a successful effort.

First off, Katz pointed out that calling sigma a "receptor" is bit of a misnomer as it functions as an intracelluar chaperone protein. This molecule hangs out in association with the endoplasmic reticulum but under ligand activation can migrate to modulate the function of membrane bound proteins. One of those is apparently the dopamine transporter.

Another background consideration for the presentation is that cocaine, as Katz noted, blocks the DAT but also has some sigma affinity. The significance of this agonist activity was not made entirely clear in the talk and we should keep in mind that any antagonism of the sigma receptor will also likely remove the sigma-mediated effects of cocaine. This part was not well explicated in the talk.

At any rate, sigma antagonist compounds block the effects of cocaine. Katz described data indicating that the acute locomotor stimulant effect of cocaine can be prevented and that sigma antagonists can attenuate lethality from an otherwise toxic dose of cocaine.

An initial study from Remi Martin-Fardon, however, found that one sigma antagonist (BD1047) did not reduce cocaine self-administration. Katz then tested several additional sigma antagonists to rigorously determine that no, sigma antagonist compounds by themselves did not reduce cocaine self-administration, even cross a wide range of cocaine doses.

Katz next presented data to remind us that the DAT inhibitor methylphenidate (aka Ritalin) not only fails to reduce cocaine self-administration but that it can increase the self-administration of lower per-infusion doses of cocaine.

However, the combination of methylphenidate with any of several sigma antagonists produced an "insurmountable antagonism" of cocaine self-administration. Meaning that across a wide range of per-infusion doses of cocaine, the rats now failed to self-administer. Importantly, these combinations had no effect on food maintained operant responding, no effect on self administration of opioids or direct dopamine D1 or D2 like receptor agonists but did work to suppress methamphetamine self-administration. This indicates the effect is specific to DAT mediated reinforcing effects.

This all led up to the creation of a compound (CM699) that had the ability to both antagonize sigma receptors and to inhibit the DAT. It was found to blunt the dopamine response to acute cocaine, as measured with intracerebral microdialysis. Furthermore, this single compound produced the "insurmountable antagonism" of cocaine self-administration that had been found for the two-drug combinations.

The talk ended with a proposal that the mechanism of action is that sigma antagonism depletes cholesterol from the membrane which promotes an inward-facing conformation of the DAT.

Obviously, Katz is optimistic that this combined-action CM699 compound proves the concept for a stimulant abuse treatment medication. The half-life of this particular compound was only about 4 and a half hours, thus their immediate goal is to get a longer acting compound which both antagonizes sigma and blocks the dopamine transporter. Nevertheless, the chance that it can completely remove the rewarding properties of cocaine supports the idea that combined activity at DAT and sigma is the route to effective agonist therapy for stimulant abuse.

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