Title: Fighting Addiction One Pill at a Time

A new compound that effectively blocks dopamine can help tackle addiction

In America today, almost one in two adults knows a relative or close friend who has suffered from drug addiction. Whether a brother, daughter, uncle or colleague, 46 percent of Americans have a personal story to tell about someone battling addiction.

The American Psychiatric Association defines addiction as a brain disease in which people develop dependency on substances such as drugs or alcohol. Those afflicted with addiction are unable to stop using the addictive substances even if they want to, and suffer from withdrawal symptoms if and when they do stop. An estimated 21.5 million American adults suffer from some kind of substance addiction, making it one of the most severe health crises in the nation. While there are many forms of addiction, the neurobiology is generally similar across the board: an intake of addictive substances triggers a rapid release of a neurotransmitter, or neural signaling molecule, called dopamine.  One feels a temporary high because dopamine floods the ventral striatum—the reward control center of our brains—and then dissipates, which leaves the addict craving more. At normal levels, dopamine is essential in learning and motivating behavior, as well as regulating motor control. At elevated dopamine levels, however, such as after ingesting an addictive drug, our brain learns to associate the drug with greater neurochemical reward. This results in a more intense desire for the next hit of the drug and withdrawal symptoms when dopamine levels ultimately dip back to normal.

Researchers have investigated the possibility of treating addiction by regulating dopamine level in the brain using γ-aminobutyric acid (GABA), a neurotransmitter that can directly inhibit the binding of dopamine receptors. GABA is naturally synthesized in the brain but is actively degraded by enzymes called GABA aminotransferases (GABA-AT). Vigabatrin is currently the only FDA-approved drug that takes advantage of this pathway and inhibits the degradation of GABA by inactivating GABA-TA. This medication has been found to be an effective treatment for epilepsy and cocaine addiction in humans, but there is a 25-40% risk of vision loss due to off-target binding. This significant risk makes vigabatrin an unappealing choice. Recently, however, the Silverman Group at Northwestern University synthesized a drug that regulates dopamine levels as effectively as vigabatrin at 1/1000th the dosage. This finding has the potential to pave the way for much more efficient treatment for addiction.

This yet-to-be-named GABA-inhibitor is an improved version of the (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) GABA-AT inactivator, which was designed by the same group in 2013 and found to be 186 times more efficient than vigabatrin. r d“We were not satisfied with just finding CPP-115—we want to understand the mechanism and improve on it,” said Professor Richard Silverman, who conducted the study. Hence, they developed the new compound, which is ten times more effective than CPP-115. This new GABA inhibitor and CPP-115 both work in the same way as vigabatrin in regulating dopamine levels. They react irreversibly with GABA-TA to form an inhibitor-enzyme complex that prevents GABA-TA from binding to and degrading GABA. This in turn allows GABA to block sharp increase in dopamine levels.

The Silverman group also found that the compound does not inactivate or inhibit off-target enzymes, which makes it a much safer option than vigabatrin. The new compound does not react with other aminotransferases or enzymes commonly involved in drug-drug interactions. A pharmaceutical screen revealed that the compound has no significant reactivity with 176 common pharmacological targets. “Vigabatrin has known side effects, such as serious retina damage,”  Silverman said. “CPP-115 and the new compound are much more effective and can be taken at smaller dosage. Hence, there is a good probability that there will be no side effects.”

sHaving obtained good results in ,cells, the next step was to show the compound was effective in sliving organisms. The Silverman group administered the GABA inhibitor to rats that were also given cocaine or nicotine, and the drug was found to regulate the drug-induced elevation in dopamine levels in the rats’ striatum. “Current methods of treating addiction involve giving addicts another addictive substance, but it is not sustainable to fight addiction with addiction,” Silverman said. “In our model, we can provide a drug that blocks dopamine release directly.”

Another problem that addicts face in fighting addiction is conditioned place preference. The hippocampus, which is associated with spatial learning, shows a sharp increase in activity after each hit of dopamine. It has been suggested that this increase in activation is responsible for the brain learning to associate the specific environment in which the drug was ingested with the rush of dopamine. Hence, the next time the addict encounters the environment, they will release dopamine even before the addictive substance is present. The researchers also showed that the compound can block hippocampus activation after intake of addictive substances. Taken together, these results suggest that the new GABA inhibitor compound can not only block the elevation in dopamine after taking addictive substances, but it can also help prevent the addictive behavior from forming in the first place.

Robert Malison, Professor of Psychiatry at Yale University, agrees that this method of treating addiction by moderating GABA levels has a lot of potential. “To date, most, but not all, treatments for addictive disorders are based on so-called ‘agonist replacement,’” Malison said. “Targeting GABA-AT to treat addiction represents a novel strategy that shows clear promise. If further clinical trials can ascertain that there are no adverse effects, then this could be a breakthrough insofar as it resurrects a previously promising strategic approach.”

eThe bigger concern of drug development has always been how well it can be applied to tackling disease in humans. This problem is especially relevant today as the United States is in the midst of the worst drug overdose epidemic in history. In October 2017, President Trump declared the nation’s opioid crisis a public health emergency. Over the past few decades, there has been a precipitous increase in opioid-related overdose deathd; each year, billions of dollars go towards costs associated with treating addiction. Like other forms of addictive substances, opioids create dependency through affecting the dopaminergic pathway, and this GABA-inhibitor could potentially help us fight such addiction.  “Dopamine function has been implicated as potentially important in the addictive properties of several addictive drug classes, including opiates. While this study does not present the efficacy of this strategy for opiates specifically, it is possible that its efficacy of the new compound might extend to other drugs of abuse,” Malison said.

Silverman revealed that the new compound is currently undergoing studies for FDA approval. “This compound needs to be tested in humans,” he said. “If it is successful, then this method should be a gold standard for future treatment of addiction.” However, there no such thing as a miracle pill. Silverman warned that it will take more than developing an effective drug to solve the problem; the success of the treatment also depends on the mindset of the addict. “If an addict does not want to be free, it will be very hard to help,” he said. Therefore, while it is important to look for solutions in science and medicine, this approach must be done in tandem with other types of interventions to achieve the best outcome and help addicts overcome their addictions.