Heritability of Substance Abuse Meets Epigenetics?

Virginia Hughes has a nice piece out on generational transmission of……experiences. In this case she focuses on a paper by Dias and Ressler (2014) showing that if you do fear conditioning to a novel odor in mice, the next two generations of offspring of these mice retain sensitivity to that odor.

This led me to mention that there is a story in substance abuse that has been presented at meetings in the past couple of years that is fascinating. Poking around I found out that the group of Yasmin Hurd (this Yasmin Hurd, yes) has a new paper out. I’ve been eagerly awaiting this story, to say the least.

Szutorisz H, Dinieri JA, Sweet E, Egervari G, Michaelides M, Carter JM, Ren Y, Miller ML, Blitzer RD, Hurd YL. Parental THC Exposure Leads to Compulsive Heroin-Seeking and Altered Striatal Synaptic Plasticity in the Subsequent Generation.Neuropsychopharmacology. 2014 Jan 2. doi: 10.1038/npp.2013.352. [Epub ahead of print] [PubMed, Neuropsychopharmacology]

This study was conducted with Long-Evans rats. The first step was to expose both male and female rats, during adolescence, to Δ⁹tetrahydrocannabinol (THC) at a dose of 1.5 mg/kg, i.p. every third day from Post Natal Day 28-49. No detectable THC was still present in the animals 16 (and 28) days later. The animals were bred at PND 64-68. Parallel Vehicle exposed rats were the comparison.

The resulting pups were fostered out to surrogate mothers in new “litters” consisting of approximately equal male/female pubs and an equal number from the THC-exposed and Vehicle-exposed parents. So this rules out any effects the adolescent THC might have on parenting behavior (that would affect the pups) and mutes any effect of littermates who are offspring of the experimental or control parents.

The paper shows a number of phenotypes expressed by the offspring of parents exposed to THC in adolescence. I’ve picked the one that is of greatest interest to me to show. Figure 1d from the paper depicts behavioral data for a heroin intravenous self-administration study conducted when the offspring had reached adulthood. As you can see, under Fixed-Ratio 5 (5 presses per drug infusion) the animals with parents who were exposed to THC pressed more for heroin than did the control group. They were equal in presses directed at the inactive lever and exhibited equal locomotor activity during the self-administration session. This latter shows that the drug-lever pressing was not likely due to a generalized activation or other nonspecific effect.

The paper contains some additional work- electrophysiology showing altered Long Term Depression in the dorsal striatum, differential behavior during heroin withdrawal and alterations in glutamate and dopamine-related gene expression. I’ll let you read the details for yourself.

But the implications here are stunning and much more work needs to be completed post-haste.

We’ve known for some time (centuries?) that substance abuse runs in families. The best studied case is perhaps alcoholism. The heritability of alcoholism has been established using human twin studies, family studies in which degree of relatedness is used and adoption studies. Establishing that alcoholism has a heritable component led to attempts to identify genetic variations that might confer increased risk.

The findings of Szutorisz and colleagues throws a new wrinkle into the usual human study designs. It may be possible to identify another factor- parental drug exposure- which explains additional variability in family outcomes. This would probably help to narrow the focus on the genetic variants that are important and also help to identify epigenetic mechanism that change in response to actual drug use.

On the pre-clinical research side…..wow. Is it via the male or female…or is it both? Does the specific developmental window of exposure (this was adolescent) matter? Does the specific drug matter? Is the downstream effect limited to some substances but not others? Is there a general liability for affective disorder being wrought? Does the effect continue off into subsequent generations? Can it be amped up in magnitude for the F2 generation (and onward) if the F0 and F1 generations are both exposed?

I think if this finding holds up it will help to substantially advance understanding of how An Old Family Tradition can become established. As I posted before:

In his classic song the great philosopher and student of addictive disorders, Hank Williams, Jr., blames a traditional source for increasing the probability of developing substance abuse:

….Hank why do you drink?
(Hank) why do you roll smoke?
Why must you live out the songs you wrote?
Stop and think it over
Try and put yourself in my unique position
If I get stoned and sing all night long
It’s a family tradition!