Is Darwin Threatened by Cocaine-Addicted Rats?

Using experimental systems where male rats can self-administer cocaine, researchers found that the sons of the cocaine-using fathers were resistant to the allure of cocaine. These results seem counterintuitive from a scientific viewpoint.
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Picture the scenario. A cocaine addict, ready to do almost anything for his next fix, has a one-night stand. He never contacts the woman again and doesn't even realize he has fathered a son. The son grows up, is offered cocaine and tries it. I bet I know what you're thinking: History will repeat itself. But it doesn't. The son is actually relatively resistant to cocaine and doesn't find it either as exciting or as addictive as his dad did. And this pattern -- the sons of cocaine addicts being less susceptible to the drug than their fathers -- is found repeatedly.

This is the rather surprising finding reported recently in the journal Nature Neuroscience by groups headed by Ghazaleh Sadri-Vakili (Massachusetts General Hospital) and Christopher Pierce (University of Pennsylvania). Admittedly, their findings were in rats, not humans, but the results are pretty startling nonetheless.

Using experimental systems where male rats can self-administer cocaine, they found the phenomenon described at the start of this blog. The sons of the cocaine-using fathers were resistant to the allure of cocaine, but the daughters were just as susceptible as most rats.

These results seem very counterintuitive from a sociological viewpoint, because in humans drug abuse and addiction seem to run in families. But in humans it's very difficult to unravel the various ways in which biology and environment interact, whereas it's possible to get much "cleaner" results in model systems like rodents.

But these results are also counterintuitive from a scientific viewpoint, because they suggest that an environmental event that took place in the parent had a lasting effect on his offspring. A different example would be a blacksmith developing large muscles by working all day at his forge and then passing on large muscles to his son. And as soon as you think of it in those terms, it's time to take a deep breath, because we are into that heretical field of Lamarckism, the idea that acquired characteristics can be inherited. That galloping sound you hear? It's the four horsemen of Richard Dawkins' apocalypse coming to mow me down for being anti-Darwinian.

Except I'm not anything of the kind. I think the Darwinian model of the evolution of species by means of natural selection is the most beautiful, profound and fundamental principle in all of biology. But I also think there are plenty of data now that suggest that sometimes biology tries to give offspring a head start by pre-adapting them for the environment they are likely to encounter. These data come from systems as diverse as water fleas exposed to predators, and humans who have too many or too few calories at key points in their development.

These changes in offspring in response to a parent's environment aren't caused by mutations in DNA, the fundamental genetic script. We know the usual rate of DNA mutations, and they are far too low to cause the size of effects we see in systems like the addicted rats. But DNA is not the only information passed on from parent to offspring. Our genetic material is not the naked DNA double helix that is such an iconic image in modern biology. It's wrapped around protein molecules, like a liquorice whip wrapped around marshmallows. Both the proteins and the DNA are modified in cells by the addition of a whole range of tiny chemical groups. These are called epigenetic modifications. These modifications don't change what a gene codes for, but they do change how genes are expressed. The modifications themselves change in response to all sorts of environmental factors, including cocaine.

The authors of the recent paper have shown that some of the epigenetic modifications at a specific gene involved in responses to cocaine are altered in the sperm of the addicted males. Their sons inherit these same epigenetic modifications via the sperm, and these alterations seem to get "set" as the male offspring develop, resulting in their brains being relatively resistant to cocaine.

Researchers suspect that this passing on of altered epigenetic modifications is the basis behind most, if not all, of the increasing number of examples we now have of so-called neo-Lamarckian inheritance. It's an attractive explanation and makes good evolutionary sense in many ways. It allows organisms to stack the odds for their offspring in terms of preparing them for the immediate environment. But it does this without disrupting the underlying genetic code. And that's important, because the basic DNA script has developed over a staggeringly long period of time, and in evolutionary terms most fluctuations in the environment are just that, fluctuations. Inheritance of epigenetic modifications is a relatively safe mechanism for reacting to relatively transient alterations in the local environment without mucking about with the real source code.

There's a lot we still don't understand about this process. In the cocaine-addicted rats we have no idea why only their male offspring are relatively resistant to cocaine, and not their daughters. We don't know why the effects of cocaine on offspring are different from those of other drugs such as morphine or amphetamines, but we do know that this isn't just restricted to drugs of abuse. Male rats fed very abnormal diets produce daughters who are metabolically similar to people with type 2 diabetes, even though the daughters themselves have been fed a standard, healthful diet. It will take many years and a huge amount of work before we can truly claim to understand these processes and the mechanisms behind them. But then again, for scientists that's the addictive part.

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