Researchers have shown that enzymes working at the synapses of medium spiny neurons (MSN) are associated with drug-seeking and extinction behaviors. These novel molecules, they say, may become potential targets for future treatments for drug addiction.
Researchers have previously found that plasticity at MSNs expressing the D1-type dopamine receptor in the nucleus accumbens part of the brain is associated with drug-seeking behavior. Meanwhile, activity at the D2-type dopamine receptors in the same brain region is linked to extinction behaviors. As such, the present study set out to find why this is the case.
For the study, the researchers trained rats to self-administer heroin by pushing a lever for ten days, followed by a ten-day withdrawal period. Afterward, they examined the rats’ brains under a microscope to identify enzymatic activity around their MSN synapses.
In particular, they focused on the activity of extracellular enzymes known as metalloproteinases (MMP). By breaking down proteins that constitute the extracellular matrix around nerve cells, they support synaptic connections. They also, however, make it harder for neurons to remodel synaptic connections from new experiences, which consequently impacts neuroplasticity.
All in all, the researchers found that drug cues increased MMP activity near D1-type MSNs in the nucleus accumbens and promoted plasticity in cells linked to addiction. Extinction training was, however, found to increase MMP activity around D2 receptor-containing MSNs (cells related to protection against addiction), as opposed to reducing MMP activity around D1 MSNs.
“This finding suggests that recovery from addiction is not simply a reversal of addiction-related changes in the brain, but rather it also involves the laying down of new anti-addiction changes that protect against substance use.” says Dr. John Krystal, MD, Editor of Biological Psychiatry.