on chickens, eggs, and meth

I have previously mentioned predisposing factors and brain adaptations following drug use that contribute to personality traits some may, at first pass, consider part of a "weak mind."  This paper, published a few months ago in the Journal of Neuroscience by my rockstar former office neighbor Bruce Lee (no lie -- he changed his name before he left, and to this day we can't figure out if he knew), illustrates what I'm talking about.  The title, "Striatal Dopamine D2/D3 Receptor Availability Is Reduced in Methamphetamine Dependence and Is Linked to Impulsivity," kind of says it all, but click here for more details and thoughts.

(image credit NIDA)

before i get started, i should say that i'm stunned to find my former advisor's name on this paper, considering she rides everyone about the use of "reduce" in studies that compare groups (things can be lower in one group than another, but "reduction" implies a within-subjects longitudinal design), and makes everyone use super-awkward language to avoid saying "abuser" (for good reason) - yet it managed to slip into the text here and there.

but that aside, bruce lee's paper makes some important points.

- people who use meth are impulsive
this is no surprise, and has been shown before, but it's nice to show in your particular sample. this study used the Barratt Impulsiveness Scale, which consists of 3 subscales of impulsiveness: cognitive, motor, and nonplanning. meth-using subjects scored higher than healthy control subjects on all three.

- people who use meth have low dopamine receptor availability in the striatum
this, too, has been shown before, but replication = good science. the finding is kind of a big deal in general because dopamine in the striatum is one of the cornerstones of addiction neuroscience. dopamine transmission in the striatum (specifically, a part of it named the nucleus accumbens) is what makes things feel good, and is common to all drugs of abuse, regardless of their initial mechanism of action. if a drug is rewarding or reinforcing, it somehow managed to get dopamine released in the nucleus accumbens.  the striatum also coordinates movements, and is important for habit formation, so it's not surprising that the changes that occur there with repeated drug use result in a "drug habit."  anyway, once dopamine is released there, it has to bind to a dopamine receptor before anything else can happen.  bruce lee shows that meth-dependent subjects have fewer of those receptors than control subjects do. 

i should mention, this is a PET imaging study - they injected subjects with a radioactive tracer (called F18-Fallypride) that binds to dopamine receptors, and then measured levels of radioactivity across the brain, giving a measure of receptors available for fallypride binding -- more radioactivity, more receptors (unbound fallypride washes out). D2/D3 just refers to specific subtypes of dopamine receptor, of the 5 we know about.

ok -- but what do fewer available receptors mean in terms of behavior? that's where the 3rd point comes in.

- across all subjects, there is a relationship between dopamine receptors and impulsiveness: those people with lowest receptor availability are the most impulsive ones.

although we don't know how yet, dopamine receptor availability in the striatum seems to contribute to personality traits like impulsivity -- and this is normal! there's a spectrum of striatal dopamine receptor availability across people, and if you're on the low side, you're likely impulsive;  folks who are meth-dependent just happen to find themselves on the extreme low end.
or, in bruce lee's words:

"As the negative relationship between striatal D2/D3 receptor availability and impulsivity extends to healthy control subjects, it appears to be fundamental (albeit exaggerated in subjects who self-administer methamphetamine)."

hooray!  we have evidence for a specific biological mechanism that explains some of the behaviors likely contributing to meth addiction, and that we can maybe target for intervention or prevention strategies.

the next point, though, kind of rubs me the wrong way.  it refers to the last finding of the study: 


- across meth-dependent subjects, there is a relationship between the amount of meth taken in their lifetime and receptor availability (more meth, fewer receptors), as well as impulsiveness (more meth, more impulsive).
take it away, bruce lee.

In addition, the association between duration of methamphetamine abuse and striatal D2/D3 receptor availability suggests that methamphetamine exposure has a negative impact on the D2/D3 receptor system, thereby promoting impulsivity. [...] Nonetheless, we cannot exclude the possibility that lower D2/D3 receptor availability (with attendant greater impulsivity) contributes to the self-administration of methamphetamine.

it's not that he did or said anything wrong. it just fundamentally bugs me that neurobiology/addiction is a chicken/egg situation that can be spun to anyone's liking, leaving alternative views offered as an afterthought.

with this paper, for example, if you want to make the case that meth rots your brain, you can. meth either killed the brain cells on which the dopamine receptors reside, or the receptors have retreated or closed up as an adaptation to constant dopamine bombardment. either way, meth has changed the brain, and as a result, people who use it have been knocked down to the low end of the spectrum of receptor availability -- and are thus more impulsive/likely to use again.  and on top of it, those people who have done more meth show more of this effect because more meth means more damage. 

but the argument can be made just as easily in reverse.  it could be that someone who is born with fewer receptors/more impulsive personality is just more likely to wind up using meth, precisely because they are so impulsive, or because they are trying to compensate for low naturally-occuring dopamine transmission (fewer receptors, fewer signals get across).  when you compare their brains to those of people who didn't wind up using meth (because they're chock full of dopamine receptors), of course you'll measure a difference.  as for the correlations with lifetime meth exposure, what if the lowest receptor availability compelled a person to take the most meth, or to start the earliest?  the correlation across people would be the same.  so, if you were dying to make the case that meth is entirely harmless, and that meth-dependent folks have just been dealt a particularly unfortunate molecular hand, you could do that, too.

as is the case with most things in life, the truth is probably somewhere in the middle. in animals, evidence exists for both sides of the argument. impulsive animals take more drugs, and animals that have been exposed to drugs become more impulsive.  the two views are of course not mutually exclusive, but the nature of their combination is hella tricky to disentangle (in humans, anyway).  in most human studies of this kind, we only learn the "that" of a situation (the study showed THAT there are fewer sites for radioactive fake-dopamine to bind to), but the "how" and "why" are left up to interpretation -- and it's frustrating that many in the field seem to have already made up their mind as to which way it goes.  as a prelude to a future rant, this is why we have to turn to animal research for answers.  but sadly that gets your car firebombed.

in any event, we're lucky that bruce lee is a mighty good guy, and his conclusion appropriately neutral:

Our results provide direct empirical evidence that striatal D2/D3 receptor availability is associated with impulsiveness in humans, suggesting an important link between a striatal dopaminergic system and cortical influence on a wide variety of disorders that involve uninhibited maladaptive behavior.

 "decreased?"  or just lower?  (image NIDA)