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!

Music lyrics poll: Drug Use

In a Twittersation today we arrived at the possibility that being a heroin user is a unique lyrical stimulus. The specific assertion is that while a lot of so-called ‘crack rap’ discusses *selling* crack cocaine, there are no lyrics about being a crack *user*.

So let’s broaden the call…can you think of songs that are about using drugs other than heroin? Let’s leave alcohol aside for the moment, there are a bajillion songs about drinking.

RIP: Joe Brady

A towering legendary figure of behavioral pharmacology and the drug abuse sciences has passed on.

photoJoseph V. Brady, Ph.D. [Department, PubMed, Neurotree] died Friday July 29, 2011 at the age of 89. He earned his doctorate in 1951 from the University of Chicago, worked at Walter Reed Institute from 1951 to 1970 and spent the balance of his career at Johns Hopkins University.
His most recent paper listed in PubMed was on the effects of gamma-radiation,

Hienz RD, Brady JV, Gooden VL, Vazquez ME, Weed MR. Neurobehavioral effects of head-only gamma-radiation exposure in rats.Radiat Res. 2008 Sep;170(3):292-8.

is a continuation of his longstanding association with NASA and spaceflight. Oh yes, Joe Brady trained the first space chimps.

R.I.P. Charles Robert Schuster, Ph.D.

sourceAn towering figure of the substance abuse research fields has passed away. According to a note posted to an ASPET mailing list, Charles Robert Schuster, Ph.D. suffered a fatal stroke on Feb 21 in Houston Texas. NIDA Director Nora Volkow has also posted a notice to the NIDA-grantees mailing list.
The CPDD biography of Dr. Schuster is a brief overview of his career.

After six years in the Department of Pharmacology at the University of Michigan, he joined the Departments of Psychiatry, Pharmacology, and Behavioral Sciences and founded the University of Chicago´s Drug Abuse Research Center. In 1986, Dr. Schuster was appointed the Director of the National Institute on Drug Abuse, a position he held until 1992. In January of 1995, Dr. Schuster was appointed as a Professor in the Department of Psychiatry and Behavioral Neurosciences at Wayne State School of Medicine and the Director of the Substance Abuse Research Division.

One of the most fundamental and lasting advances of Dr. Schuster was the development of the self-administration model of drug reinforcement. Bob Schuster was one of the first to demonstrate that animals would work to receive intravenous infusions of drug and he was a major player in several of the initial observations on the reinforcing properties of recreational drugs through the 1960s and 1970s.
James R. Weeks published in 1962 that female rats would press a lever to receive intravenous infusions of morphine. Schuster and his colleagues were the first to adapt this method to nonhuman primates, getting started at approximately the same time as Weeks (there are references to Abstract presentations from Weeks as early as 1960 or 1961).

An Opiate Antagonist Precipitates Withdrawal…From Exercise.

In my prior post, I overviewed a pair of papers which suggested the possibility that rats provided with running wheels might be used to model exercise addiction. The application hinged on a finding that when rats are provided with longer term 4 or 24 hr access to a wheel they gradually escalate their running over the course of about three weeks; this effect is greater than any increases seen when rats have wheel access for only an hour or two. As I alluded to, however, confidence in wheel running as a model of human exercise addiction akin to substance dependence is going to require a lot more converging evidence.

Kanarek and colleagues have provided some of this converging evidence. The authors examined the effects of challenge with the opiate antagonist naloxone in groups of male and female rats which had been permitted to run on an activity wheel.

This study relies on an effect* which has been known for quite some time, namely that the acute administration of low doses of drugs which block mu opiate receptors can rapidly precipitate withdrawal signs in rats or mice which have been treated chronically with morphine, heroin or other mu opiate agonists. Withdrawal signs that are similar in appearance to those that emerge with spontaneous withdrawal of the animal from chronic exposure to opiates. As Marshall and Weinstock observed in 1969, withdrawal symptoms could be quantified as an index of opiate dependence.

The purpose was to determine whether the number of jumps elicited by nalorphine in groups of mice could be used as a method of measuring the intensity of the withdrawal syndrome…The number of jumps was a monotonic increasing function of both the number of injections and the total dose [of morphine-DM] injected…In conclusion it is suggested that the number of jumps elicited by an antagonist in chronically narcotized mice can be used as a quantitative measure of the withdrawal syndrome.

Kanarek and colleagues were thus not just hypothesizing that they could precipitate withdrawal differentially in exercised animals, but also that the neuropharmacological change associated with exercise involved endogenous opioids. To wit, the endorphins which have been speculated in common use to underlie the so-called runner’s high.

The study is a bit complicated because it includes a manipulation termed Activity-Based Anorexia. Apparently if you give rats access to food for only an hour a day, they can survive with approximately normal maintenance of weight but if you also provide them with an activity wheel, they stop eating and drop weight-even to the point of death. This is a mere distraction for the present purpose, however, since the effect of challenge with the opiate antagonist was not qualitatively changed by the feeding condition. Nevertheless, the designs were between groups with factors of wheel access and feeding condition (24 hr food vs 1 hr food). There was also an additional yoked-pair feeding group which was inactive but fed the same amount of food consumed by the 1-hr / wheel access animals. This is by way of explaining the graphs, but the key effect for today’s discussion lies in the main effect of exercise condition.

The first experiment was conducted in female rats permitted wheel access for 7 days (plus sedentary groups) and then initiated on the 1 hr / 24 hr / yoked feeding conditions. The naloxone challenge (1 mg/kg) was initiated after 3-6 days when the 1 hr / activity group had dropped to 80% of their initial bodyweight. Since individuals took different numbers of days to reach this criterion, matched numbers of animals from the other groups were challenged with naloxone on the days over which the critical group reached criterion. Traditional withdrawal symptoms were scored.

As you can see in the Figure, withdrawal was precipitated more robustly in the group which had been permitted to exercise on the wheel and received 1 hr access to food, relative to the remaining groups. The authors also reported a correlation between total withdrawal signs exhibited by an individual and the wheel activity on the day before naloxone challenge in all activity rats but this was attributable to the food restricted subgroup. Similar results were found when they assessed the number of rats expressing a given withdrawal symptom, instead of the overall withdrawal score, as shown in the Table.

The second experiment was conducted in males with similar wheel access and feeding groups. In this case, however, the males in the exercise groups were permitted 25 days of wheel access (instead of the 7 used for the females) prior to initiation of the feeding conditions. Again, naloxone challenges were conducted when the 1-hr feeding / Wheel access group dropped to 80% of their prior weight.

Effects of naloxone challenge were most pronounced in exercised rats however in this case the effect did not depend on feeding condition. The graph of the mean total withdrawal scores shows that naloxone precipitated more signs of withdrawal in the 24-hr feeding / Wheel access group than in the sedentary groups.

So why the difference in the 24-hr feeding / wheel access condition between the experiments? I think the most likely issue is the difference in wheel access duration prior to the food conditions. The males, although they ran less than the females, escalated their running through about 16 days of access and had plateaued by the start of the food-access manipulation at day 25. The females were still increasing their running at the end of 7 days and into the food manipulation condition, but very likely had not completely expressed the commonly observed increase in daily running associated with 24 hr access over ~3-4 weeks duration.

In some senses these two experiments are not discordant but rather complement each other. Together they point out that the amount of activity on a wheel is not sufficient to increase liability for precipitated withdrawal. The females in the 24-hr feeding condition peaked at about 21,000 revolutions per day whereas the males in the 1-hr feeding condition peaked at about 8,500 revolutions per day. Only the latter exhibited increased withdrawal signs after naloxone when compared with their inactive control group. This suggests that it is the relative increase from baseline activity levels that is most important, rather than the spontaneous difference in baseline running.

And that interpretation, DearReader, is consistent with the idea that repeatedly engaging in physical activity can disrupt the neuronal mechanisms that subserve the rewarding aspects of that exercise. This disruption can then be observed as withdrawal signs, given acute administration of an opiate antagonist. This further suggests that endogenous opioids may be critically involved in the rewarding, and therefore addictive, aspects of repetitive exercise.

As with the behavioral escalation papers I previously discussed, this is not in and of itself proof that rats are addicted to, or become dependent on, wheel running.
__
A PubMed search for naloxone precipitated withdrawal finds 1135 references.

Kanarek RB, D’Anci KE, Jurdak N, & Mathes WF (2009). Running and addiction: precipitated withdrawal in a rat model of activity-based anorexia. Behavioral neuroscience, 123 (4), 905-12 PMID: 19634951

Marshall I, & Weinstock M (1969). A quantitative method for the assessment of physical dependence on narcotic analgesics in mice. British journal of pharmacology, 37 (2) PMID: 5388579

Why Pain Research Matters

Our good blogfriend JuniorProf has launched a campaign to explain why pain research matters. I am already learning lots of stuff from his older posts. Also from observations such as this one at Almost Diamonds and this one from Zuska.
The thing that caught my eye recently, though, was this post:
Drug discovery in academia and NIH, a new type of U01

This brings us to the bane of drug discovery: absorption, distribution, metabolism and excretion (ADME). This is something that industry does very well.
…
ADME in academia, well, let’s just say, not so much. The reasons for this are likely pretty simple: its an important area of drug development but not the most exciting, by any stretch of the imagination (sorry you ADME specialists), and it often requires all sorts of rather expensive testing in model organisms that aren’t used often in academic labs. Its also highly compound-specific and this makes grant writing very hard (or so I hear).

JuniorProf then goes on to make an argument for why drug development should be done in academia and how that might work best. He then describes a recent NIH initiative that is trying to support some academic drug development effort.
Go read. Follow @juniorprofblog on Twitter or perhaps just the #painresearchmatters hashtag.

Great-Gran's elixir

I have been waiting and waiting for this post.

This is a page from my great-grandmother’s cookery notebook. She was a cook in England in the late nineteenth century (yes, we have long generation times in my family). Elsewhere in the notebook she seems to be planning a menu for a visit by Lord Roberts of Kandahar, so her employers were clearly very, very posh. And, whenever they got a cold, very, very high.

Go Read.

Great-Gran’s elixir

I have been waiting and waiting for this post.

This is a page from my great-grandmother’s cookery notebook. She was a cook in England in the late nineteenth century (yes, we have long generation times in my family). Elsewhere in the notebook she seems to be planning a menu for a visit by Lord Roberts of Kandahar, so her employers were clearly very, very posh. And, whenever they got a cold, very, very high.

Go Read.

Does one drug cause the user to be more annoying?

As a bit of a followup to the poll we ran on whether or not cigarettes make you high, I offer context and my thoughts. As of this writing, btw, the votes are running 44% “Yes”, 47% “No”, the balance “other” with a fair bit of commentary to the effect that “high” is not exactly the right description for nicotine.
For the background, we might as well start with the comment from SurgPA:

This started with an email from PalMD asking why doctors react much more negatively to narcotics abusers than alcohol or nicotine abusers. I hypothesized that most people view acute use of the various drugs differently. Specifically I suspected that most doctors’ gut reactions when seeing someone light a cigarette are qualitatively (and vastly) different from seeing someone shoot heroin (or snort crushed oxycontin). In short that we don’t see the act of smoking as an acute intoxication by a neuroactive substance, even if we understand it intellectually.

Vaccination against cocaine: Incremental advance

I last broached the topic of immunization against drug use some time ago and I concentrated more on the ethical implications of vaccinating. I was being ever so slightly disingenuous because the current state of progress is not such that we need to consider such questions as:

Would you recommend it broad-spectrum for all children much like MMR?
Would you recommend parents be permitted to subject their drug abusing teen against his or her will?
Allow the courts to mandate inoculation?
Suppose it were made a condition of employment?

A recent paper by Martell and colleagues provides a nice opportunity to review the promise and limitations of immunopharmacotherapy for drugs of abuse. The rationale for such studies is pretty easy to grasp, although at present the results fall short of the lasting immunity you associate with childhood vaccines and even the seasonal flu shot. Drugs of abuse are molecules that do not generate any immune response because they are too small. The starting rationale is that if you create a drug mimic and attach it to something that will attract the attention of the immune system you might be able to generate antibodies that recognize the target drug.

Another death in the tribe and this one is…close to home.

The initial news reporting from Baltimore led with “Post-Doctoral Fellow Charged After Girlfriend’s Death”. Oh Christ.

A post-doctoral fellow at the University of Maryland School of Medicine has been charged with illegal drug possession after his live-in girlfriend, also a fellow, died.

Not. Good. Not good in the least.

According to investigators, Dr. Carrie Elisabeth John injected herself Monday with a drug known as “bupe” in the house she and McCracken shared.
Bupe is intended to help addicts break their dependency on heroin.
Court documents said John stopped breathing and was pronounced dead in the university hospital emergency room.

“Bupe” or buprenorphine [Wikipedia] is an mu opioid receptor partial-agonist used as agonist therapy for opiate dependency under trade names such as Subutex® and Suboxone®.

Another Poppy Tea Death

Damn. A Twitt from @abelpharmboy alerted me to this article in the Denver Post.

A 19-year-old man was found dead in Boulder on Tuesday morning, and authorities suspect poppy tea as the cause.
If so, it would be the second death in five months of a young person in Boulder who drank opium tea, police said.
Jeffrey Joseph Bohan, a 2008 graduate of Fairview High School in Boulder, drank the powerful psychoactive brew with his older brother about midnight, authorities said.
His brother found him unresponsive at 6 a.m. in a home

Abel Pharmboy had written some comments about that first death of a young man in Boulder. In the first post, Able overviewed a bit of the history of the medicinal (and recreational) preparation of products from the opium poppy.

Another Poppy Tea Death

Damn. A Twitt from @abelpharmboy alerted me to this article in the Denver Post.

A 19-year-old man was found dead in Boulder on Tuesday morning, and authorities suspect poppy tea as the cause.

If so, it would be the second death in five months of a young person in Boulder who drank opium tea, police said.

Jeffrey Joseph Bohan, a 2008 graduate of Fairview High School in Boulder, drank the powerful psychoactive brew with his older brother about midnight, authorities said.

His brother found him unresponsive at 6 a.m. in a home

Abel Pharmboy had written some comments about that first death of a young man in Boulder. In the first post, Able overviewed a bit of the history of the medicinal  (and recreational) preparation of products from the opium poppy.

The sad fact is that we’ve known for over 200 years that this is a bad idea: based upon growing conditions, harvest time, and extraction method, the resulting concoction can provide an extremely variable dose of these compounds. Used medicinally as one of the strongest analgesics (“painkillers”) we know, in higher doses the opiates can impart a warming sense of euphoria but, at even higher doses, suppresses the respiratory control center of the brain stem, resulting in death.

Abel also mentioned a website created by a father of yet another kid who overdosed on poppy tea. The point of Poppy Seed Tea Can Kill is, quite obviously, to educate people on the risks of home-brewed poppy tea. It includes a redacted version of the drug panels run on his son postmortem which is a great thing. I wish all the parents / closest relative of the folks who die from “Ecstasy” would do similar- this kind of information goes a long way toward addressing controversy over what did and did not kill the individual.

At any rate, it is very sad that this seeming fad in recreational drug use is resulting in fatalities. It seems that it is doing so almost entirely because the dose is so hard to control / appreciate under the typical use circumstances. Perhaps publicizing this hypothesis widely would go a long way toward harm reduction by inducing a bit of caution in the user population. I can hope, anyway.

NIDA requests information on minimizing risks with pain meds

The National Institute on Drug Abuse has issued a notice requesting help in developing a new research strategy (NOT-DA-09-006). They are after:

Public Comment on Development of a Funding Opportunity Announcement on Translational Research on Minimizing Risks of Managing Pain with Opioids in General and Specialty Medical Settings

Post done, right? No, no, that’s just the title. What they are working up to is issuing a “funding opportunity announcement”. Although a Program Announcement qualifies, we are probably talking about an eventual Request For Applications. RFAs are the things we are looking for because they come with set aside money, a limited application window and an assurance that at least one or three projects will be funded. For anyone who thinks that IC research priorities are detached from real world interests or are developed a little to self-referentially (say by calling up a couple of already-funded investigators and asking them what is important to fund), well, this RFI is a cool thing. They want feedback from you.
So, why is NIDA interested in this topic?

Repost: Musty Must-Read: "Mrs. Winslow's Soothing Syrup"

I originally posted this Jan 09, 2008 on the old blog (this version has been lightly improved from the prior version). It has been one of my more popular posts when it comes to Google hits.

---

The US Food and Drug Administration (FDA) began sending warning letters to sellers of so called “bio-identical hormone replacement therapy” today according to an AP report. Apparently the claims for alleviating menopausal symptoms are

not supported by medical evidence and are considered false and misleading.

Needless to say, these “compounded” products are being sold without FDA approval. It’s all a conspiracy man! Dang FDA is a tool of BigPharma trying to keep cheap and effective remedies from the public. Noted tool of TheMan_{(BigPharmaDivision)} Abel Pharmboy has a recent post in which he touches on “cosmeceutical” marketing of drugs and the FDA’s authority to regulate cosmetics under

their regulatory authority is in part ordered by the Federal Food, Drug, and Cosmetic Act of 1938 (and subsequent legislation).

source
This reminds me of the glory days of the quack remedy / patent medicine era and today, from the mouldering archives, we take up a Case Report published by A. B. Hirsch, M.D. [“Mrs. Winslow’s Soothing Syrup. American Medical Journal, 1884, 12(11):504-506] which is available from Google Books here. A footnote indicates that this Abstract was read before the Philadelphia County Medical Society on Sept 17, 1884. Ahh, Mrs. Winslow’s . Used for over 60 years by mothers for their teething children.