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Ask a Neuroscientist: Can dopamine release become addicting?

by Talia Lerner

Graduate students take questions from the public and answer them on the blog Neuwrite West as part of their Ask the Expert series.



Peter Senavallis writes:  Because dopamine is identified as a neurotransmitter in which is released in certain amounts depending on actions, can its affects on the brain (rewarding/pleasurable emotion) ever become addicting?



Excellent question. Essentially, you’ve just summarized the dopamine hypothesis of drug addiction, which has been a driving force in addiction research ever since people noticed that addictive drugs all seem to act in one way or another on dopamine regulation. Some drugs, like cocaine, methamphetamine and ecstasy act fairly directly on the dopamine system by changing dopamine transport mechanisms in cells, flooding synapses with the neurotransmitter in larger quantities and for longer than would happen normally. Nicotine, the addictive drug in cigarettes, increases the firing of dopamine neurons by activating receptors that normally respond to the neurotransmitter acetylcholine. Other drugs, like opioids (e.g. heroine, morphine, codeine) and benzodiazepines, act less directly (though not necessarily less powerfully) on the dopamine system by inhibiting inhibition of dopamine neurons (thus increasing dopamine neuron firing). It’s also worth noting that behaviors we do that are sometimes considered addictive, like gambling, having sex and eating junk food, can also provoke large dopamine release events.

So why not just cut to the chase and directly stimulate your dopamine neurons? Neuroscientists have known for decades now that sticking an electrode in certain parts of a rat’s brain and then allowing that rat to perform some action (e.g. press a lever) to send current through the electrode will cause the rat to perform the action. Rats will self-stimulate (as this behavior is called) various parts of their brains, but one part that works especially well is called the medial forebrain bundle. It’s a bundle of dopamine axons. Rats will self-stimulate their medial forebrain bundle A LOT. Like, thousands of times an hour. If you let it, the rat will keep performing the action to the exclusion of other important activities, like eating. This striking observation led to the question: Is dopamine necessary and sufficient to support self-stimulation?

The answer is yes. If you block a rat’s dopamine receptors so that it can no longer sense the presence of dopamine, the rat will no longer press a lever to self-stimulate (showing that dopamine is necessary). If you use a neat bioengineering technique called optogenetics to allow a rat to stimulate only dopamine neurons and no other neighboring neurons or axons that might be in the medial forebrain bundle, the rat still self-stimulates like crazy (showing that dopamine, or at least dopamine cell firing, is sufficient).

But to get back to your precise question, what about addiction? Just because a rat will stimulate its own dopamine neurons doesn’t mean it’s addicted to doing so. Addiction is usually identified in people using criteria like escalating use, withdrawal, craving, and continued drug use or drug seeking behavior in the face of adverse consequences. In the brains of human addicts, we find reductions in dopamine release and dopamine receptor expression, which may help explain why addicts are always seeking more ways of stimulating their dopamine system harder and harder. The tendency to get addicted may have to do with how susceptible your dopamine system is to being downregulated by initial drug use. In rats, the loss of dopamine signaling over time as they are given access to cocaine predicts escalating cocaine use. This finding calls into question the idea that dopamine neuron stimulation would be sufficient to induce and sustain all the classic hallmarks of addiction, both behavioral and molecular. It might not be – continued direct dopamine neuron stimulation might actually prevent escalation, the particular type of dopamine neurons being stimulated might matter a lot*, and other neurotransmitters or patterns of brain network activity might also be required to form the long-term drug habits that take over addicts’ lives – or it might be – excessive dopamine release might trigger all the necessary downstream events that cause progression from use to addiction. Here is the boundary of our current knowledge, the place where future research is always needed. Although the questions may seem esoteric now, the answers will have great import for the rational design of a cure for addiction.

*As discussed in my previous post on dopamine neuron diversity, “Are you there, God? It’s me, dopamine neuron,” not all dopamine neurons are created equal. Differences in dopamine neuron subtypes defined by inputs and outputs or by co-transmitters could be very important. A neurotransmitter by itself is just a molecule, and has no meaning when removed from the brain circuit it operates within.