By David N. Leff

Science Editor

There’s a by-prescription antidepressant pill called Wellbutrin, which comes in two sizes and colors – one sapphire, the other light purple. The fine print on the smaller tablet faintly resembles a Have A Nice Day smiling face. Their chemical name is bupropion.

The same pharmaceutical company purveys another pill, the same bupropion, trademarked Zyban. It’s prescribed for people trying to kick nicotine addiction. Zyban’s package insert states that “its mechanism enhancing patient ability to abstain from smoking is unknown. It’s presumed mediated [in part] by dopaminergic mechanisms.”

Dopaminergic neurons secrete the multifunction brain neurotransmitter dopamine. “Dopamine is essential in processing all of the brain’s motor and driving motor movements,” observed neurobiologist Isabelle Mintz, at Boston University Medical Center. “But this process is through the targets and nuclei of dopaminergic neurons. So these cells send out message-carrying axons to a variety of centers in the brain, and there dopamine is absolutely crucial in the normal processing of information. The symptoms of Parkinson’s disease,” she explained, “are due to the fact that dopamine levels in failing neurons drop to 20 percent or less than the normal levels.”

Mintz is senior author of a paper in today’s Science, dated Sept. 28, 2001, titled: “Dendrodendritic inhibition through reversal of dopamine transport.”

“The main finding in this paper,” she told BioWorld Today, “is that we have identified the mechanism by which dopamine is released by neurons that degenerate in Parkinson’s disease [PD]. The dopamine cells use a very unusual mechanism to release dopamine by way of their dendrites.

“The classic mechanism for release in the brain,” she explained, “is exocytosis – the process by which secretory granules or droplets are released from a cell. In the context of PD, exocytosis is the package of transmitters in vesicles exiting into synapses. So here we have a dopamine transporter,” Mintz explained, “which normally functions to mop up excess dopamine that’s been released, and recycle it. We report a transporter that works abnormally from the opposite end of the synapse, and transports dopamine to the outside of the neurons, Also, there’s a very selective antagonist that blocks these transporters.”

Mopping Up Excess Dopamine Spillage

Mintz continued: “This is where our finding has clinical implications for PD, because these antagonists are compounds that have long been used clinically for treating depression. Our paper in Science identifies these agents as good candidate neuroprotective drugs, because they inhibit release through that transporter. One of the key ideas in PD is that hyperactive dopamine itself in the dendrites and cell bodies is neurotoxic. So by preventing its release locally, we may be able to slow down progression of the disease.

“The novel aspect,” she pointed out, “is that we identified a mechanism that is very unusual for release. The recognition that this is the mechanism involved is raising a new possibility for treatment. We can target these dopamine transporters with antagonists that are very selective compounds. The best-established agent is Wellbutrin – bupropion – made in Italy and marketed by Glaxo as an antidepressant. It’s also sold as Zyban as therapy for addiction to nicotine.

“The hypothesis is that by blocking the dopamine transporter,” Mintz pointed out, “these agents may alleviate the symptoms of PD by decreasing the release of dopamine in the brain’s substantia nigra. There this would have a beneficial effect in diminishing this neurotoxicity of excess, overexcited dopamine. And this should have a neuroprotective effect.”

She and her co-authors conducted electrophysiological experiments with rats. “What we did,” Mintz recounted, “was to excite the dendrites and produce the release of dopamine. We recorded the response of these cells to the dopamine that had been released, and showed that this response was completely abolished if we pretreated the slices with the dopamine transporter antagonist.

“In one set of experiments,” she said, “we exposed naove rats to the dopamine transporter inhibitor agents, then recorded electrical impulses of dopaminergic neurons, with their cell bodies, from slices of their brains containing the substantia nigra. The result is that when we blocked the dopamine transporter, inhibition disappeared. So we didn’t have the response to dopamine any more.”

This outcome suggested potential therapeutic applications in treating PD. “To be specific,” Mintz said, “there are two steps that need to be taken before this finding can develop new treatments for PD patients. In order to do that, we first need to show that our prediction is valid in an animal model of PD – rodents, primates or, hopefully, both. We’d use them to test our hypothesis that dopamine transporter antagonists, these bupropion agents, would prevent or slow progression of the disease.”

In Vivo: Animals First, Folks Second

“There are different ways by which one can mimic PD in animal models,” Mintz noted, “by using toxins or any kind of agent that will trigger a metabolic assault on dopamine neurons. These models are very well established, and it will be routine to test whether dopamine transporter inhibitors have any neuroprotective effect. We plan to begin these preclinical trials as soon as possible, in the next few months. It would take up to a year to get significant results.

“The second step,” she went on, “is to hold controlled clinical trials in human PD patients, to evaluate the efficacy of these antagonists. The promising aspect is that these compounds, used for so many years as antidepressants, have track records regarding their safety. So we would not be starting at day one.”

She explained why it will be necessary to wait a year for animal trials to end when these agents are of proven safety. “They are safe in patients with depression,” Mintz pointed out, “but we don’t know how safe they will be in patients with Parkinson’s disease. The dopamine system has been altered, and there is an issue as to whether it will be without adverse side effects. So I don’t think it should be recommended to use these compounds without controlled clinical trials.

“I am going to establish collaborations, hopefully, to be able to institute these studies,” she allowed. “But I know that different laboratories are geared up to do this immediately,” Mintz concluded, “so I expect that these experiments will be started very soon.”