Biotech researchers chart progress in fighting substance abuse

  • April 12, 2018

Scientists at the Medical University of South Carolina have discovered genetic factors in the brain that they believe increase the risk of relapse in drug addicts.  The culprit is actually epigenetics, or enzymes that change the behavior of genes but not the genes themselves.  The team focused on the enzyme histone deacetylase 5 (HDAC5), which in previous studies had been shown to slow down the process by which the rodent brain associates environmental cues with cocaine.

First, they trained rodents to press a lever to receive the drug, at which point a lamp turned on and a short sound was broadcast.  Then they gave some of the animals a dose of HDAC5 that targeted their neurons.  The enzyme did not reduce their urge to take cocaine.

However, when the researchers took the rodents off of cocaine for a week and then gave them HDAC5, they did not press the drug-dispensing lever as often in response to light and sound as did the animals that were only presented with the environmental cues.  The scientists even tried to tempt the rodents with a small dose of cocaine; however, the HDAC5 still lessened their drug-seeking behavior.

The scientists then did a search for all the genes inhibited by HDAC5 and hit upon NPAS4, a gene that has been linked to addiction-associated learning and memory.  The research was published in the journal Neuron.  “We might have tapped into a mechanism with relevance to multiple substance use disorders,” said MUSC professor and senior researcher Christopher W. Cowan, Ph.D., in a press release. HDAC5 is prevalent in reward centers of the brain that react to alcohol, cocaine and opioids.

In fact, addiction and relapse behaviors are strongly influenced by environmental cues — like positive memories of taking drugs or, in the case of the rodents, lights and sounds associated with addictive substances.  That is why many biotech approaches are focused on lessening the power of environmental cues that drive addiction.

On 26 SEP 2017, scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) received a three-year, $10.8 million grant from the National Institutes of Health to develop a new class of drugs that they believe will lessen the impact of those environmental cues in the brain.  The drugs target metabotropic glutamate receptor 2 (mGlu2).

Cocaine and nicotine addiction have both been tied to an increase in glutamate in the brain, said Sanford Burnham researcher Nicholas Cosford, who will be leading the research, in a statement.  His team’s lead compound, SBP-0069330, is designed to interact with glutamate receptors in the brain, cutting down on signals that drive craving, withdrawal and relapse driven by environmental cues in addicts.  “We believe our medicine will treat all three components of this problem,” he said.

Cosford is confident his group will have a compound ready for human testing by the end of the three-year grant period.  And he believes the approach may prove useful in treating patients addicted to nicotine, methamphetamines, heroin and cocaine.

REFERENCE:  Fierce BioTech; 27 SEP 2017; Arlene Weintraub

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