Methamphetamine, or Meth, is a nasty drug. It’s long been known that long-term meth use can cause cognitive problems and neuronal death through a myriad of ways, such as increases in free radicals in the brain and inflammation. However, meth use can also lead to liver damage. Liver is one of the most important organs involved in detoxification – a decrease in liver function can cause the build up of toxic metabolites, such as ammonia from protein digestion. The researchers set out to test if this buildup of ammonia in the brain may also contribute to meth-induced neurotoxicity.
They first showed that a meth-binge of 4 injections in a day was enough to induce liver toxicity, and that this correlated with an increase in ammonia measured from both blood and the brain. They then showed that lactulose, a drug that can help the excretion of ammonia out of the body, can inhibit the increase in ammonia, but not the amount of meth that eventually ends up in the brain.
So is the ammonia actually doing anything? Meth is known to specifically damage the nerve terminals that have dopamine and serotonin. The extent of damage can be measured by how much each of those neurotransmitters are left in the brain – the more damage, the less chemicals. Indeed, a meth binge caused rats to have much lower levels of both dopamine and serotonin. However, if the rats were pre-treated with lactulose (and hence have lower levels of ammonia after meth-injections), the serotonin levels could be completely restored, while dopamine levels could be partially rescues. This seems to hint that peripheral ammonia is causing a loss in both dopamine and serotonin neuron function.
To further test this idea, researchers locally infused meth, ammonia, or both into the brain, and 7 days later, checked for brain damage. Surprisingly, neither meth nor ammonia alone produced significant dopamine and serotonin loss; however, when both were given together, the rats lost a significant amount of these nerve terminals.
The researchers next went to test how the combination of meth and ammonia is killing monoaminergic cells, and pointed to glutamate as the main culprit. Glutamate in the brain activates a type of receptor called AMPA; excessive AMPA receptor activation can lead to many intracellular processes that eventually kills the cells – this is called excitotoxicity. To see if glutamate is involved, the researchers added an AMPA receptor blocker to the meth and ammonia mix, and infused all three directly into the brain. Inhibiting the AMPA receptor was enough rescue the toxic effects of meth/ammonia given directly to the brain.
So what happens after a meth injection? The researchers binge-dosed rats on meth, and showed that this indeed leads not only to elevation of ammonia in the brain, but also an increase in glutamate levels, albeit slightly later. Furthermore, increased glutamate propelled activation of another protein called calpain, which is indicative of excitotoxicity. Finally, by pre-treating the rats with lactulose and lowering ammonia levels, the rats also showed lower glutamate levels and reduced neurotoxicity.
From these results, it’s clear that methamphetamine packs a one-two punch. Upon administration of the drug, meth goes to the brain where it injures dopamine and serotonin terminals directly. However, meth also goes to the liver for metabolism where it injures the liver and induces an acute increase in both blood and brain ammonia levels. Ammonia then works together with meth through increased glutamate and AMPA receptor activation to cause neuronal damage.
What this suggests is that if we can inhibit the liver damage caused by meth, we can reduce ammonia levels and at least partially reduce some of the damage to the brain. This is important as the liver is much more readily accessible to drug treatments than is the brain. While the precise mechanisms behind meth-induced liver damage is not yet known, the researchers think that pathways involved in hyperthermia-induced liver damage may be involved.
