Transgenerational effects of exogenous cannabinoid exposure

September 11, 2012

A paper in the October issue of the Journal of Psychopharmacology will be of interest to my readership. It looks at the consequences of exposure to an exogenous cannabinoid agonist

Byrnes JJ, Johnson NL, Schenk ME, Byrnes EM. Cannabinoid exposure in adolescent female rats induces transgenerational effects on morphine conditioned place preference in male offspring.J Psychopharmacol October 2012 26: 1348-1354, first published on April 19, 2012 doi:10.1177/0269881112443745 [ PubMed ]

In this study the authors exposed 23 day old (adolescent) female Sprague-Dawley rats to a three day, twice per day regimen of WIN 55,212-2 which is a full agonist at the CB1 receptor. The more familiar exogenous cannabinoid, Δ9-tetrahydrocannabinol (THC) is a partial agonist at the same site. The authors waited until the animals were adult (60 days), bred them and then examined the subsequent male off-spring of these mothers. They assay of interest was the Conditioned Place Preference test which is one common method to assess subjective drug liking in rats and mice.

The idea is to take a chamber which is divided into two or there sections by dividers and doors (in this case it was a three-chamber apparatus). The chambers are differentiated by salient stimuli such as the floor texture or type, wall stripes (horizontal vs vertical), etc. You let the subject explore at will in pre-conditioning baseline studies. Then, you conduct a series of conditioning sessions in which the animal is injected with a drug and then confined in one of the chambers. On other sessions the animal is injected with the drug vehicle only and confined to the other chamber. In this case, there were three active drug and saline conditioning sessions. Finally, on a later test day the animal is allowed once again to freely explore all of the chambers. The amount of time it spends in each chamber is recorded and the relative preference for the drug-paired chamber over the saline-paired chamber can be expressed, typically as a difference in amount of time, or the percentage of the total time, spent exploring the drug-paired chamber.

The figure presents Conditioned Place Preference data for the adult male offspring (WIN-F1) of mothers which were exposed to WIN 55,212-2 in adolescence and in the control group (VEH-F1) of adult male offspring of mothers treated twice a day for three days with the drug vehicle. There were three different place conditioning levels with groups of animals from the VEH and WIN treated dams place conditioned (in adulthood) with saline, 1 or 5 mg/kg of morphine. As expected, the chamber preferences of animals “conditioned” with vehicle were indistinguishable, i.e., they spent approximately equal time in each chamber. Animals conditioned with morphine, however, spent more time in the drug-paired chamber than in the vehicle-paired chamber.

Interestingly, there was a group difference which depended on the maternal treatment. The offspring of the WIN treated mothers appeared more sensitive to the rewarding effects of morphine because they expressed a conditioned place preference after 1 mg/kg training, unlike the adult offspring of VEH exposed dams. Although I’m not showing it here, the study also looked at adolescent male offspring and found a similar enhancement of morphine place-preference conditioning in the offspring of WIN exposed dams.

The translational take-away is pretty clear and fairly frightening. It suggests that one of the reasons for familial patterns of substance abuse may not simply be down to genetic legacy but may have something to do with drug exposures of the mother.

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No Responses Yet to “Transgenerational effects of exogenous cannabinoid exposure”

  1. dr_mho Says:

    The data are suggestive, but far from overwhelming. For the adolescents, there was no main effect of drug history and no significant difference between VEH and WIN at any dose (the statement of a “trend” with p=0.07 is ridiculous and belies a poor understanding of statistical significance). For the adults, there is a main effect of drug history, but only a difference between VEH and WIN for the 1mg/kg dose.

    Your statement that the take-away is “pretty clear and fairly frightening” is melodramatic nonsense.

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  2. drugmonkey Says:

    Oh, do tell how any rat study that you could possibly imagine would be “overwhelming”.

    but only a difference between VEH and WIN for the 1mg/kg dose.

    yeah, that’s kind of the point. Dose-response function. If you had an experiment that didn’t produce any CPP in the control group, that’d be a problem for interpreatation. and for any assay like this, there are going to be ceiling and floor effects, therefore the presumption is that at some dose you should be able to produce equivalent effects. They did. So rather than this being a weakness, it is in fact a strength of the design.

    the statement of a “trend” with p=0.07 is ridiculous and belies a poor understanding of statistical significance

    Running around thinking that a p value that falls short of traditional thresholds for significance magically confers the absence of an effect visible in the data is what constitutes a poor understanding of inferential analysis of a dataset.

    melodramatic nonsense
    Really? “translational takeaway” means given that we assume this result is a good reflection of what obtains in human users. If so, you don’t think a lasting liability for drug abuse that is associated with your mother’s adolescent drug use is pretty damn interesting? no? I think that is pretty damn interesting.

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  3. miko Says:

    This happens in lab meeting all the time… student proudly shows of some p=0.04 result and hangs their head in shame at their p=0.06 failure. what are we teaching these kids?

    That said, every time I see a transgenerational behavioral result, it seems like I never see it again.

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  4. Jekka Says:

    I imagine the Nestler lab will have a transgenerational addiction paper in Science within the year.

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  5. dr_mho Says:

    “Oh, do tell how any rat study that you could possibly imagine would be overwhelming”

    well – error bars that weren’t 25% of the total effect and more consistent results across groups would be a start.

    “Dose-response function”

    I agree with you that your description is a potentially valid explanation. I also think that a different and potentially valid explanation is that the results are messy as shit, leaving it impossible to come up with any strong conclusions.

    “magically confers the absence of an effect”

    don’t be silly – that’s the point of p-values, you have to decide for yourself – if something is likely to happen by chance 1 in 20 times, do you think it’s actually real? Calling something a “statistical trend” just means that you are willing to say that something that might happen 7 in 100 times is likely to be real. it isn’t a trend – it’s a different arbitrary cut-off.

    i didn’t say it wasn’t interesting, i said that calling it “pretty clear and frightening” is nonsense.

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  6. drugmonkey Says:

    every time I see a transgenerational behavioral result, it seems like I never see it again.

    Of course. Replication is everything. The authors reference prior papers using the same regimen, btw. So this doesn’t appear to be the very first one in this area.

    error bars that weren’t 25% of the total effect and more consistent results across groups would be a start.

    First of all, bs that would convince you and second of all, why do we need “more consistent” results? why is this superior to inferential statistics? How do you set your personal standards and why?

    I also think that a different and potentially valid explanation is that the results are messy as shit, leaving it impossible to come up with any strong conclusions.

    Right…except my explanation has roots in a vast literature and you are just sneering at data for a conclusion that you apparently have an a priori position to dislike.

    i said that calling it “pretty clear and frightening” is nonsense.
    Why is that?

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  7. drugmonkey Says:

    it isn’t a trend – it’s a different arbitrary cut-off.

    uh-huh. right. But the point is why you said:

    the statement of a “trend” with p=0.07 is ridiculous and belies a poor understanding of statistical significance

    in the first place. You may dislike the word “trend” to refer to “close but no cigar”* but unfortunately this is a very well entrenched practice. it is therefore not “ridiculous” nor, as you second comment quoted here attests evidence of “poor understanding”. In fact quite the contrary, it shows they understand the p<0.06 vs p<0.04 situation quite well.

    *as do I, as it happens

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  8. drugmonkey Says:

    I imagine the Nestler lab will have a transgenerational addiction paper in Science within the year.

    I continue to assert that any fancy pants molecular folks that want to get a J.O.B. should take their toys over to the substance abuse fields because there are only a few labs to compete with. It’s getting slightly more crowded than when it was #literally two labs but still……

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  9. dr_mho Says:

    ok – last procrastinating post, then back to my grant…

    “first of all, bs that would convince you ” “you apparently have an a priori position to dislike”

    sigh…resorting to inference about the poster…

    “my explanation has roots in a vast literature”
    waving around “dose response curve” does not suddenly paint their results in a clear light – there is a clear monotonically increasing effect of morphine (bigger place pref for higher dose), so you have to posit that the dose response curve specifically refers only to the putative difference between treatment history. so… you asked what would make me happier, do a larger range of doses, plot out a well-fit dose response curve for both groups, and show me that the actual fit curve is shifted due to past treatment.

    “Why is that?”
    because i don’t think their results even strongly support their own conclusions, let alone yield a case for sounding the alarm bell…

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  10. dr_mho Says:

    ok, i lied, last comment…

    “You may dislike the word “trend” to refer to “close but no cigar”* ”

    this is the entire point, calling it a trend implies that 0.05 is more significant than 0.06 is more significant than 0.07, is more…. when in actuality, you have to pick your cutoff, then, it’s either significant or not…

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  11. drugmonkey Says:

    because i don’t think their results even strongly support their own conclusions

    so you are agreeing with me. IF these results translate, then it is alarming. You only are disagreeing with the possibility, entertained by me, that these results are valid and could apply to the human situation.

    resorting to inference about the poster

    I have never yet been incorrect about the a priori position of a person commenting critically and at length on my cannabis-related threads, as it happens.

    then back to my grant.

    best of luck.

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  12. Isis the Scientist Says:

    Where are the Hispanic rats?

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  13. Dude, you’re seriously having a high-school debate teem throwdown with your own commenters? Act like you’ve been here before, for fuck’s sake. You’re embarrassing yourself.

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  14. becca Says:

    Honest question from someone who never had to design rat studies- what is 23-26 days of age the equivalent of??? (random internet article- http://psychcentral.com/news/2012/08/23/rat-study-shows-early-mental-training-may-aid-later-brain-function/43598.html, put 35 days of age as equivalent to 13 years in humans, so I’m thinking 23-26 days would be a pretty early drug exposure). I know it’s hard to figure consistent equivalencies, because neural-development and reproductive-development may not be exactly in synch, but it strikes me as a pretty key factor if you’re going to talk about the potential translational implications.

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  15. whimple Says:

    Of course. Replication is everything. The authors reference prior papers using the same regimen, btw. So this doesn’t appear to be the very first one in this area.

    Only positive studies get published. If the p value isn’t overwheming in the literature, it’s probably garbage.

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  16. Grumble Says:

    Grumble’s First Rule of Behavioral Neuroscience: Never trust any CPP result until it’s been replicated by at least three labs. If this particular one is independently replicated, I’ll eat my hat.

    Like

  17. dr_mho Says:

    “I have never yet been incorrect about the a priori position of a person commenting critically and at length on my cannabis-related threads, as it happens.”

    well, there’s always a first…
    i’m a synaptic physiologist and biophysicist – i have no particular background or interest in behavioral pharm – i was just procrastinating and thought it would be fun to read the paper you mentioned…

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  18. Hagbard Says:

    What about a priori position of the blog author?

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  19. Drugmonky Says:

    It’s “I like scientific papers”, Hagbard. Why?

    Like

  20. Isabel Says:

    More like “I am a loyal follower of the Czar.”

    Like

  21. Funky Fresh Says:

    Calling him the czar is very racist against russians.

    Like

  22. Isabel Says:

    Well, cannabis prohibition was motivated by racism, and still is, so the racist terminology doesn’t surprise me.

    “I have never yet been incorrect about the a priori position of a person commenting critically and at length on my cannabis-related threads, as it happens.”

    Another outrageous lie. DM, you are a pathological liar. Seriously, you need help.

    As just one example, you have intentionally misquoted me, repeatedly accused me of saying pot was magical and harmless, repeated the accusation even after I corrected you (I never said anything even close to that) called me a pothead and a stoner who just wants a convenient source….I could go on. All lies.

    I haven’t had a drink or a hit of pot since approximately six weeks ago, and I’ve told you over and over I am a pretty moderate user.

    Yet next week you will be declaring that the reason I support the end of prohibition is that I am a “pothead” who thinks pot is “magical” and I want a cheaper source.

    “I have never yet been incorrect about the a priori position of a person commenting critically and at length on my cannabis-related threads, as it happens” my ass. You have your own fucked-up, biased, a priori ideas about peoples’ a priori positions and you stick them is more accurate.

    It’s very disturbing that a federally funded drug researcher is so biased against one particular drug, and so hostile to users and supporters of users of that drug. Also, you cannot seem to separate support of the users from support for the drug. You have a lot of issues, dude.

    Anyone who claims to support social justice causes who is not actively with me on this topic (i.e. we need to end prohibition NOW) is equally fucked up. Well maybe not quite as fucked up as you, but certainly severely hypocritical. I’m really losing patience with people!

    Like

  23. Grumble Says:

    Yes, yes, Isabel, but what did you think of the paper DM described?

    Like

  24. Drugmonky Says:

    Are you saying your personal desire to smoke weed unfettered by legal concerns has nothing to do with your rather fervent attitudes, and intractable science denialism, Isabel? Nothing at all?

    Like

  25. Isabel Says:

    Only to the degree that it may have initially made me aware of the tragic effects of prohibition, DM. It isn’t an issue at all these days. But people in jail, 800, 000 arrested yearly, creeping police state, racism and classism and prison populations through the roof, and all the other equally horrible effects I have repeatedly tried to draw your attention to are my concerns for nearly two decades.

    Grumble, I am no expert on the subject so no opinion. But your dismissal of my real concerns (the drug war, and on a personal level being lied about repeatedly here) is insulting. Calling me a science denier? Fucking asshole cherry picks his papers and worse, thinks they have something to do with prohibition.

    Like

  26. Isabel Says:

    ” It isn’t an issue at all these days. ”

    Well, on second thought: I should say, on behalf of the millions of users as well as myself, that it would be great to be able to “come out of the closet” and to be treated with respect, and to not be subjected to threats from law enforcement and constant mockery and disparagement from people such as yourself. To not be portrayed as some kind of low-life compared to the culturally normative alcohol users, to not always be seen as a drug abuser, a danger to children, or a perpetual adolescent. To not be subjected to these thoughtless, damaging and untrue stereotypes would be a positive for sure.

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  27. antagonista Says:

    driveby commentary:

    that is *incredibly* early for adolescence, especially considering most breeders wean at p21. not that it’s unheard of, but generally you’re looking p28 or older if you wanna call em adolescents… and p60 is also very early for adulthood. i stick to at least p70, preferably 75.

    that said, i haven’t read the paper. it’s been a shitty week.

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  28. onlyforlulz Says:

    Exposing psychoactive substances to a developing brain will fuck it up, impact factor=blah.

    Like


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