Damping the morphine high

BDNF is a neuroscience star. Known by its full name as “brain derived neurotropic factor”, it is secreted naturally in the brain, “feeds” neurons by acting at its receptor, TrkB, where it encourages new neurons to grow, improves the function of existing neurons, and protects them from various insults such as stress and stroke damage. Unfortunately, BDNF has its dark side – an increase in its levels in the mesolimbic dopamine system, a brain area deeply involved in drug addiction, has been shown to mediate addiction to various stimulants such as cocaine, and increase relapse vulnerability. So it makes sense to dampen BDNF signaling in addicts…right?

Not so fast. Like cocaine, morphine is also known promote signaling in the same system – specifically, in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). It changes the biochemical properties and shapes of neurons in those areas, which is believed to underlie its addictive properties. However, morphine’s a little different. For one, it deceases BDNF levels. For another, injecting BDNF counteracts the biochemical consequences of morphine, opposite of what’s seen in cocaine. So what, if anything, is BDNF doing in a morphine-addicted brain?

BDNF Is a Negative Modulator of Morphine Action. Ja Wook Koo et al.Science 338, 124 (2012).(Title kinda gives it away, huh?)

To tackle this problem, the authors first gave rats intermittent injections of morphine, and showed that this did in fact decrease levels of normally secreted BDNF. To show that the rats were hooked on morphine, they used a test called conditional place preference (CPP) – when a rat is given drugs in a specific location, it tends to associate the drug high with that particular place, and will voluntarily prefer to stay there given the opportunity (possibly like addicts hoping for another serendipitous hit).

The scientists next genetically deleted the BDNF gene specifically in dopamine neurons in the VTA, producing mice that did not have the protein. They dosed these BDNF- mice up with morphine and ran them through the test. Compared to normal rats, BDNF- showed stronger addictive behavior, spending significantly more time in the place where they were given morphine. A chemical signal is only as good as its receptor – in this case, the TrkB receptor. Knocking-out TrkB produced the same hyper-addictive effect. This suggests that BDNF, which normally present in the brain, functions as a gate blocking out the effects of morphine.

The VTA doesn’t exist in a vacuum – as part of the limbic system, it sends out projections to its neighbor in the reward processing system, the NAc (latin for “pleasure center”). Activation of the NAc has also been linked to addiction – so much in fact that there are clinical practices in removing chunks of the NAc to treat alcoholism.  So is it possible that BDNF is inhibiting the information transfer from VTA to the NAc? To test this, the researchers used a special type of transgenic mice whose neurons encode a channel activated by light (optogenetics). They then gave the mice a low dose of morphine (which usually cannot trigger addictive behaviors) while shining pulses of light in the brain to activate VTA dopamine terminals in the NAc. The combination was sufficient to promote morphine addiction – so much in fact, that giving these mice BDNF in the VTA no longer suppressed the onset of addiction. However, blocking dopamine receptors (D1) in the NAc allowed BDNF to re-exert its inhibitory effect on morphine addiction.

So what does this all mean? First, it shows that NAc neurons are also responsible for forming and triggering morphine addiction, since bypassing the front man VTA by direct light activation is enough to bring on addictive behavior. Second, it shows that ultimately, BDNF is affecting dopamine transmission. In the VTA, morphine lowers BDNF levels leading to hyperexcitable burst firing of neurons, which subsequently release their dopamine packets, active D1 receptors in the NAc, and promotes morphine addiction. Giving the BDNF-deprived neurons an extra dose of the protein blocks this chain of reaction and releases mice from the warm euphoric embrace of morphine.

As I mentioned before, BDNF is very well studied in the field of stimulant addiction. So this paper comes as a bit of a surprise, in that the same molecule can drive both a stimulant feed-forward loop and an opiate negative feed-back loop. This finding sheds light on the complexity of our reward system, and is something to keep in mind for the treatment of polydrug  (cocaine-like stims and opiate) users.

And no, snorting cocaine and injecting morphine at the same time will NOT balance each other out. The brain's tricky like that.