Researchers from the University of Minho in Portugal have discovered that rats exposed before birth to glucocorticoids (GC) not only show several brain abnormalities similar to those found in addicts, but become themselves susceptible to addiction (the glucorticoids, which are stress hormones, were used to mimic pre-natal stress).  But even more remarkable, Ana João Rodrigues, Nuno Sousa and colleagues were able to reverse all the abnormalities  (including the addictive behavior) by giving the animals dopamine (a neurotransmitter/ brain chemical). 

The study has several implications – for a start it alerts for the dangers of high levels of stress during pregnancy, but - since GC are often prescribed as an anti-inflammatory or to help organ maturation during pregnancy - it also calls for an urgent investigation on the effects of this drug in pregnant women. But it is what we learn about addiction that is most interesting - the work not only unveils stress as a new susceptibility factor for the disease, but  also a very simple treatment that, if translated into humans, could one day mean an effective treatment, and maybe even the prevention of human addiction. 

Drug addiction was for a long time a character flaw, a moral problem. Now, instead,  is accepted as the complex brain disease that is with the addict a patient in need of treatment. After all many people try drugs, but only a few become addicts

And it is in these few that lays the key to the disease and its treatment.

So what do we know about these patients and the disease? First although the psychological and social contexts in which the drug is taken are important,  as much as 50% of the compulsion is in the  individual’s genetic makeup. We know that addiction is linked to the mesolimbic system - the brain area that evolved to provide feelings of pleasure to actions that increase our survival chances, such as eat, sex and social stimulation.

In fact, drugs activate the mesolimbic circuit too, only far stronger than any physiologic stimulus.  This leads to the production of very high quantities of dopamine – the brain chemical linked to pleasure – creating the euphoria that brings users back. After while, though, the brain no longer can cope with the constant ” high” and adapts by becoming desensitised to dopamine (produced by any type of stimulus) what leads users to consume more in order to “feel” again and trapping those more susceptible in addiction. And with the brain changes induced by drugs being apparently long-lasting - since both cravings and relapses don’t disappear with time – it is not easy to escape once trapped.

Adding another piece to the puzzle, recently the disease was also linked to stress during crucial developmental periods, such as feotal life. In fact, high levels of prenatal stress increase propensity to mental problems and now have been suggested also to substance abuse, with the effects being mediated by glucocorticoids (GC). 

Rodrigues and Sousa’s group have a long history of interest in stress and have seen before that  rats from mothers injected with GC while pregnant (mimicking pre-natal stress) show changes in their mesolimbic area and in the dopamine response. So in the study now published, following these results and the addiction-stress link, the researchers investigated the responses to drugs in rats exposed to GC while in the uterus. These rats were found to have a susceptibility to addiction not present in control (non-exposed) rats.

When their mesolimbic system was examined they also showed several structural and molecular abnormalities,  including less dopamine. The levels of their dopamine receptor Drd2, despite initially being very high, once they experimented drugs, went to abnormally low levels . So why is this important? Because reduced dopamine and Drd2 levels are typical of addicts suggesting that stress and long-term exposure to drugs affect the brain in very similar ways what could explain why the first could lead to the second. 

The good news is that low levels of dopamine can be treated so Rodrigues and colleagues restored the rats’ dopamine levels to normal just to find,much to their surprise, that all the structural and molecular abnormalities induced by prenatal GC were reversed. Even more surprising, the addictive behavior also disappeared.

As Ana João Rodrigues explains, “This is a remarkable result because it suggests that with a relatively simple pharmacological approach- restoration of dopamine levels- we can eventually treat, and even more importantly, potentially prevent drug abuse in vulnerable individuals. Of course that we still have a long way to go but our results are quite promising. In fact, if we know where susceptibility to substance abuse lies – and low dopamine and altered Drd2 response seems to be it - then maybe we can find better ways to prevent/treat this disorder. “

Restoring dopamine levels has been used to treat cocaine cravings but the few trials looking at its effect on addiction were never very clear. One possible reason might be the length or the dosages used – in Rodrigues’ study, rats treated for 3 days reverted back to an addictive behavior 3 weeks after the end of the treatment,  but this no longer occurs if the treatment continues for 3 weeks

Now it will be necessary to test this new theory in humans what could be problematic with addicts as they are notoriously not the most cooperative or reliable research subjects. Large human studies on the effect of prenatal stress are also difficult to mount but there are a couple of them being run at the moment that could be tagged into such as “Project Ice Storm” in Canada.This study is following women pregnant n January 98 in southern Québec during an extreme ice storm that led to electrical power failures affecting more than 3 million people for as much as 6 weeks during the coldest month of the year(when temperatures can go to -18 C). 

It is still early for any studies on addiction(the children are only 13 years old after all) but it will be an interesting place to look, especially since abnormal levels of behavioral and cognitive problems have already been detected by scientists.

Drug abuse and addiction carry enormous social and financial costs to society, families and individuals.Only in the US, the National Institute for Drug Abuse calculates that more than600 billion dollars are being spent, annually, to combat the disease. Despite this,a steady increase of drug use among teenagers and in prescription drugs continues with treatments remaining as inefficient as ever.  Rodrigues and Sousa’s work might be the first step towards a solution if their remarkable results can be translated into humans.

Citation: AJ Rodrigues, P Leão, JM Pêgo, D Cardona, MM Carvalho, M Oliveira, BM Costa, AF Carvalho, P Morgado, D Araujo, JA Palha, OFX Almeida and N Sousa, “Mechanisms of initiation and reversal of drug-seekingbehavior induced by prenatal exposure to glucocorticoids, Molecular Psychiatry,(2011)  doi:10.1038/mp.2011.126