Researchers have received a rare insight into the brains fight against substance abuse, boosting the possibilities of developing better medicines to combat drug addiction.
The study, that involved many Indian scientists working in the US, has identified several brain mechanisms that underlie addiction-related structural changes. To their surprise, the researchers found that these mechanisms are an attempt by the brain to defend itself against excessive drug use.
The structural changes that appeared in the brain after chronic cocaine exposure, at critical points of communication between cells in the nucleus accumbens — the reward or pleasure centres — might actually function to limit addiction rather than support it, says Suprabha Pulipparacharuvil, the first author of the study. The findings appear in the August 28 issue of the journal Neuron. They tend slow the process or minimise the long-lasting behavioural changes associated with addiction, she told KnowHow.
Previous studies have shown that repeated use of drugs like cocaine, amphetamines and nicotine increases the number of anatomical structures called dendritic spines in the regions associated with pleasure and reward. These dendritic spines are the sites where brain cells communicate with one another. Many scientists believe that this long-lasting brain rewiring underlies similarly persistent drug taking and drug seeking behaviours associated with addiction and relapse. The mechanism that controls this brain rewiring and its relationship to addiction-related behaviour was not known previously.
In the new study involving laboratory mice, the researchers found that cocaine suppresses the activity of a set of proteins called MEF2 proteins. As MEF2 normally reduces the number of brain connections, suppressing it leads to an increase in dendritic spine density. The researchers also found that enhanced MEF2 activity in the brain blocked a drug-induced increase in dendritic spine density and increased addiction-related behavioural responses to cocaine.
This seems to be the brains natural response to cocaine. It may not be important for the process of addiction but may limit it, says Christopher Cowan, who led the research. The brain adapts to the effects of cocaine, and some of these changes may actually oppose addiction, he says.
Cowan is hopeful that by identifying a gene family that modulates the behavioural responses to cocaine, the study may generate new potential protein targets for drug companies to pursue.
Relapse, or the resumption of active drug taking and drug seeking, is very common in drug addicts, says Cowan. Addiction-related brain changes and behaviours seem to be hardwired and semi-permanent, and treatment options are limited. Our data suggest that rather than trying to block the process of increasing dendritic spine density, we may actually want to look at treatments that try to enhance this.
MEF2 is activated in response to brain activity. It actually tells the brain to eliminate the potential growth of too many communication sites between nerve cells. But repeated exposure to cocaine disrupts this function of MEF2, resulting in new brain connections.
To investigate the relationship between MEF2 and spine density changes, the researchers varied the level of the protein in the nucleus accumbens. Brain imaging done after administration of cocaine to the lab animals showed that it prevented MEF2 from limiting dendritic spine increase.
To test MEF2s relationship to behaviour, the researchers monitored the movement of the mice after daily exposure to the same amount of cocaine. The same dose of cocaine produced a larger behavioural response after repeated days of drug injections, resulting in a sensitised response. This sensitised behavioural response to the drug is very stable, lasting for months after the drug is discontinued.
When the researchers manipulated the animals so that their MEF2 levels remained high in the presence of cocaine, they turned out to be more sensitive to the drug. This suggested that an increase in the number of communication sites might help combat the addiction process.
This suggests the exciting possibility that MEF2 proteins may control the expression of key genes that modulate drug-related brain changes and behaviour, says Cowan. If we understand which genes are influenced by MEF2, we can intervene and try to help the system resist or reverse these sensitisation processes.