Concerned about your vole's amphetamine habit? Get them a wife!

Jul 27 2011 Published by under Addiction, Neuroscience, Physiology/Pharmacology

Sci's been meaning to cover this paper for a while, honestly. There is really so much to blog and so little time, you know? I saw this paper make a minor splash when it came out back in June, and I've been wanting to read it myself. And what better way to really READ a paper than to blog it?

So let me introduce the subject of today's paper, the monogamous prairie vole.


(D'awww. Source)

The prairie vole is kind of a darling of the research vole. I mean, it's got nothing on mus musculus, but we do tend to like our voles. They're monogamous! Isn't that sweet! It's cute and easy to breed, and...monogamous! Really, that's the defining feature that makes them interesting, because there really are relatively few species out there other than primates that ARE monogamous. Only 3% of mammals, in fact. So some research has gone in to what it is that MAKES them monogamous, especially when compared to their extremely close cousins the mountain voles.

And then of course, once you've got through all the monogamy issues with the oxytocin and the vasopressin, you start to look at other aspects of this rare kind of social behavior. Things that can be affected by it and things that can affect it.

Things like drugs.

Liu et al. "Social Bonding Decreases the Rewarding Properties of Amphetamine through a Dopamine D1 Receptor-Mediated Mechanism" J. Neuroscience, 2011.

So, drug abuse. Drug abuse is something that, socially speaking, is often defined by what it affects rather than what it IS. Drug use becomes ABUSE when it starts interfering with aspects of your normal daily life, like keeping a job, getting food, keeping a roof over your head, etc. And one of the big things affected by drug abuse is your social relationships. Drug use is very hard on your social relationships...but social relationships are reciprocally hard on drug use. People with strong social bonds, especially to parents or spouses, are less likely to abuse drugs. For people who are already addicted to drug, strong social ties often predict success in staying clean.

But the question is: what is the mechanism? HOW do social bonds help prevent drug abuse? For this particular paper, the authors turned to the neurotransmitter dopamine. When most people hear about dopamine, they think of drugs, as well as feelings of "high" or pleasure. Certainly there's more to dopamine than that (movement, for example, you get Parkinson's without it), but for this paper, the idea of dopamine as predicting feelings of reward or pleasure will do. Drugs of abuse (including cocaine, amphetamine, MDMA, ethanol, etc, etc) increase dopamine in an area of the brain called the Nucleus Accumbens, and changes in dopamine signaling in the nucleus accumbens go along with drug abuse, addiction, and withdrawal, and can be present even following a single instance of drug use.

But drugs aren't the only things that influence dopamine. In fact, so do social bonds. The presence of dopamine in the nucleus accumbens determines the formation and maintenance of pair bonding in voles. So since they both come down to dopamine, it seems like the vole is a good model to examine the effects social bonds on things like drugs.

So they took a bunch of voles, they raised them up. Half the male voles were placed in pair groups with a buddy male vole. The other half were allowed to form pair bonds with a female vole. Once the paired voles were all established and having long conversations about where the relationship was heading, they took both the lonely voles (these voles did have male buddies, but I'm gonna call them "lonely" anyway, just for ease of use. The authors called them sexually naive, but I feel bad making fun of a poor vole's virginity) and the paired voles and ran them through a protocol called conditioned place preference.

Conditioned place preference is a test that used to measure drug reward in rodents. Since a rodent can't really tell you that it's SOOOO high right now, you give it a chamber with two different options. The two options are the same size, the same lighting, the same all over really. There's nothing all that interesting about them to the rodent, but they are distinguishable, so the rodent can tell which side he's in. You then give an injection of amphetamine, and place the vole (in this case) in one side. The next day, give an injection of saline, and put the vole in the OTHER side. Wash, rinse, repeat. After a few days of this, you put the vole in between the two chambers, and ask it which one it likes. If it finds the drug injections it was getting NICER than the saline, it will hang out in the drug chamber. If it finds the drug injections WORSE than the saline, it will hang out in the saline chamber. This is called conditioned place preference.

You can see up there that the lonely voles liked the amphetamine (the set of bars second from the left). They spent more time in the amphetamine paired chamber. But the paired voles (the set of bars on the far right) didn't really seem to find anything particularly special about the amphetamine. They didn't show place preference at all.

Of course, then you have to check and see if your amphetamine is WORKING.

Yup.

That's a microdialysis measure in the nucleus accumbens. Microdialysis is where you push a small amount of cerebrospinal fluid through a little probe in an animal's (or a human's, I suppose) brain. As the CSF flows through the brain, it will run into more CSF which contains things it doesn't, things like dopamine. As it comes into contact with this, the dopamine will diffuse into the area where it's not, and you end up with a measure of the dopamine in the brain when the sample comes out. And this means, whatever's going on in the brain will happen in your sample. In this case, the measures are from the nucleus accumbens. You can see that the amphetamine injection increased dopamine in the brains of both sets of voles regardless of pairing or loneliness. But still, the pair bonded voles preferred the amphetamine LESS.

WTF.

The authors of this study hypothesized that the receptors in the nucleus accumbens were to blame. Yes, dopamine is a neurotransmitter and is responsible for signaling. But a chemical is only as good as its receptor. And when receptors change, so do the effects of drugs.

In this case, we are looking at D1 type receptors (for dopamine, there are D1 like and D2 like, D1 tend to be what we call stimulatory, and D2 tend to be inhibitory). And this is where it gets a little odd to me. The lonely saline voles on the far left, fine. The lonely amphetamine voles second from left show an increase in D1 receptors. What's interesting here is that the pair bonded voles had an increase in D1 receptors at baseline! This was then REDUCED by amphetamine exposure. Really, it kind of looks like the pair bonded voles had the opposite response to the lonely voles.

To look into this further, they tried to block the conditioned place preference response to amphetamine with a D1 antagonist in the lonely voles.

Check. You can see that both doses of the D1 antagonist blocked the place preference behavior.

So what about the paired voles?

In this one, you can see that the paired voles showed no preference for amphetamine. Ok, we had that from before. But when they pre-treated the paired voles with a D1 agonist, stimulating the receptors, they got the place preference that had been lacking before.

The authors conclude that the pair bonded voles showed decreased rewarding properties of amphetamine (ok), and that this was mediated by a D1 receptor mechanism.

Yeah. That seems fine. But I'm not really sure they went far enough. WHAT D1 receptor mechanism? The D1 receptors are high in pair bonded voles at the beginning, and then lower after amphetamine, so...how is this working? They suggest that the decrease in D1 expression is to blame, but I can't help but think that with fewer receptors, you might end up with a stronger signaling response to amphetamine...and I'm at a loss for how this is working. And I think they are, too. If I had to guess I'd bet on differences in other aspects of dopamine neurotransmission, like dopamine transporters (they did look at D2 changes but didn't see anything). But if there WERE changes in dopamine transporters, wouldn't you see that in the dopamine microdialysis response up there in figure 2? DANGIT WHAT IS GOING ON.

The authors also posit that this, along with other data on drug abuse in pregnant rats, nursing rats, and socially housed animals shows that "social" factors change the way animals react to drugs. I would go further than that and say that probably there are hormones and other signals at play here that act as the mechanism of these "social" factors.

So this paper shows that pair bonding changes the rewarding effects of amphetamine in voles. That's cool. But I don't think it really addresses HOW. I mean, yes, the D1 receptors are different. But why?! We know it changes the reward related behaviors of amphetamine, but this is more than just sensitization or tolerance, this looks like basically a complete reversal of D1 receptor actions here. Since a receptor really can only do one thing one way, this really makes me wonder what else about these voles changes when they get with the ladies. And what does this D1 receptor change mean for other functions?

And there's something I'd like to see (which wasn't done in this study, but the authors appear to be looking at all sorts of different angles, so they may get there): we know that social bonds, in this case pair bonds specifically, change how rewarding the voles consider amphetamine to be. They show less place preference. Ok. We also know that giving amphetamine BEFORE letting the voles form pair bonds impairs the forming of the bond. My question now is...how does the bond affect withdrawal? What about relapse? Can we get these voles to self-administer amphetamine, and then look at pair bonded and non-bonded voles in withdrawal and relapse and see how they differ? Is the pair bond protective and through what mechanism? Social studies in humans and other species would say is social bonds are protective, is this protection mediated through the dopamine system?

But what we can conclude from this paper is this: social bonds, particularly strong social bonds between pairs, are effective in reducing the reward-related properties of drugs like amphetamine. This adds to previous literature looking at mother/pup relationships and drug abuse (maternal separation can increase drug taking in adulthood), and really makes it clear how important strong social bonds can be when it comes to drugs.

But HOW it all happens? Well that's still a mystery.

Liu, Y., Young, K., Curtis, J., Aragona, B., & Wang, Z. (2011). Social Bonding Decreases the Rewarding Properties of Amphetamine through a Dopamine D1 Receptor-Mediated Mechanism Journal of Neuroscience, 31 (22), 7960-7966 DOI: 10.1523/JNEUROSCI.1006-11.2011

8 responses so far

  • becca says:

    Best blog post title I have read in many moons.

  • BigTex says:

    Anacker et al Addict Biol 2011 show that socially bonded 'lonely' male voles like their alcohol too. The 'frat party' model of addiction-like behavior?

  • One of my comics is about a lonely vole... maybe he attended too many rave parties in his misspent youth?

    http://ataraxiatheatre.com/2010/10/15/the-vole-page-one/

  • Gary Wilson says:

    From your post: "D1 tend to be what we call stimulatory, and D2 tend to be inhibitory".

    I'm confused. I've read that activation of D2 facilitates pairbond formation, whereas, D1 inhibits it. And upregulation of D1 prevents pairbond formation with another vole.

    from
    "Dopamine Regulation of Social Choice in a Monogamous Rodent Species"

    Within the NAc shell, DA regulation of partner preference formation is highly specific. Mating-induced DA release selectively activates D2-like receptors and decreases cAMP signaling to promote pair bond formation (Figure (Figure6B).6B). Conversely, activation of D1-like receptors and increased activation of cAMP signaling prevents pair bond formation (Figure (Figure6C).6C). These data indicate that, under natural circumstances, DA transmission is not uniformly increased as it is under certainly laboratory conditionings (Schultz, 2002). Rather, the pair bonding studies suggest that prairie vole social interactions result in modest increases in extracellular DA concentration that selectively activate high affinity D2-like receptors while not activating low affinity D1-like receptors.

    • scicurious says:

      Hi Gary, I'm sorry I should have been more clear. D1 receptors tend to be stimulatory to the cells they are ON, while D2 receptors tend inhibitory to the cells they are on, increasing and decreasing the likelihood of cell firing, respectively. So the studies don't conflict at all, the D2 activation there decreases cAMP signaling (a supposed decrease in cell activity) to promote pair bonding, while D1 receptors increase cAMP and prevented bond formation. In the context of THIS paper, D1 receptors appear to mediate the rewarding effects of amphetamine in the vole (as blocked by the antagonist). So pair bond formation and amphetamine reward are both mediated by dopamine, just in different ways and via different receptor signaling pathways. Does that help?

      • Gary Wilson says:

        OK, thanks. I see the intracellular differences in the studies.

        What's confusing to me is this - I thought of D2 receptors being associated with the rewarding aspects of drugs & natural reiforcers. Many studies point to a downregulation of D2 rceptors as an indicator of addiction processes - desensitization and anhedonia. Wouldn't less activity of D2 containing neurons be experienced as less rewarding?

  • ro says:

    great post on interesting topic.
    and i also want to know HOW all that stuff works on molecular and organismal levels, because cool observations are not enough in biology.

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