If you watch network television on occasion, you've probably seen advertisements for medications like Requip or Mirapex that are marketed as a treatment for Restless Leg Syndrome (RLS), a weird, creepy-crawling feeling that usually occurs at night and makes sufferers feel as though they must constantly move their legs to attain comfort. Particularly severe cases can greatly disrupt sleep cycles or even lead to insomnia. Now, if you're like me (shut up), while watching these commercials you've probably wondered why some of the side effects listed include "intense gambling or sexual urges or other impulsive behaviors." What could these things possibly have to do with disorders involving involuntary motor-functions? My first reaction to encountering these weird side effects was a vague sort of dread regarding our forays into altering brain chemistry. Just what exactly is Mirapex tweaking deep within our cortices?Turns out ropinirole (Requip) and pramipexole (Mirapex) are members of a class of drugs known as dopamine agonists, which means that they attach to dopamine receptors on various brain structures and mimic the effects of the neurotransmitter dopamine. (As an interesting aside, these drugs are specifically non-ergoline dopamine agonists, which means they do not involve ergoline alkaloids, a class of drugs that includes the infamous LSD and other hallucinogenics). Now, dopamine agonists are primarily used to treat Parkinson's disease, and ropinirole and pramipexole are no exceptions. In fact, they were originally created to treat Parkinson's disease, and are merely provided in smaller doses to treat RLS. Apparently, the roots of RLS may be very similar to those of Parkinson's disease, although on a much smaller (and apparently non-progressive) level. Here's where the fun brain science begins.
Parkinson's disease is caused by a decrease in dopamine production in the substantia nigra, a portion of the basal ganglia. The basal ganglia is an extremely important deep-brain structure and is responsible for far more brain activity that can be discussed here. What's important is that the dopamine that is normally produced by the substantia nigra usually binds with dopamine receptors on the striatum, another portion of the basal ganglia. There are four types of dopamine receptors, and it seems that D2 and D3 are the most directly related to Parkinson's symptoms (this info will be important in a minute). Though it regulates other things (which we'll touch upon shortly), one of the main functions of the striatum is the planning and regulation of movement. A Parkinson's afflicted brain isn't producing enough dopamine to activate the striatum sufficiently, which in turn results in decreased activation of the motor cortex, producing erratic, unintentional tremors, muscle rigidity and a variety of other motor problems. So on a smaller level, a similar dopamine disruption is responsible for RLS, and the dopamine agonist medications act to stimulate the receptors in the striatum that aren't being activated through normal brain chemistry.
Ok. So the striatum is also involved in some other sneaky stuff that is really pretty far removed from motor function, and this is where dopamine agonists can start to alter behavior in ways that at first seem quite random. It seems that the striatum also regulates a lot of processes related to something called "executive function." Executive function involves things such as planning, abstract thinking, selecting sensory information, and, getting closer to the core of our inquiry, selecting appropriate actions and inhibiting inappropriate ones. It is also largely involved with processing stimuli involved in reward. It seems that the striatum is activated when a person is presented with stimuli that are new, aversive, unexpected or particularly intense. We can now start to see how sexual compulsions, strange gambling urges and things like overeating are related to subtleties in chemistry in this particular region of the brain. Problems with impulse control are also frequently exhibited in people with Parkinson's disease. These issues are clearly related to feelings of reward (the extreme gratification of orgasm, the experience of winning or the exhilaration of taking risks, the pleasure of indulging in certain foods) and are also highly likely to involve stimuli that could be classified as "novel," "intense," or (depending on how depraved you are) "aversive." These functions appear to be closely related to the D3 receptors on the striatum. And of the two related receptors that Requip and Mirapex bind to, guess which one they like the best? You got it. D3.
So it would appear that if you screw with the dopamine receptors on the striatum, some sort of weird, screwy feedback loop can result, where people have less ability to inhibit their actions, which frequently results in the sorts of behavior that actually greatly stimulate the striatum in the end. This seems to be due to the fact that dopamine agonists like Requip and Mirapex actually decrease the sensitivity of the dopamine receptors over time. Logically, this increases the symptoms associated with the striatum. A really sucky situation can develop where an individual not only cannot produce the required dopamine, but also cannot accept dopamine (or agonist medications) in areas that it is required. It seems likely that, in the cases where an individual is taking a dopamine agonist for RLS and experiences odd compulsions, the medication might actually be altering the dopamine receptors' ability to bind with neurotransmitters, including what dopamine they are still naturally producing. Ah, the joy of medication!
Some other uncommon side effects also tie in closely with the functions of the striatum: hallucinations, confusion, paranoia, memory loss, abnormal thinking, abnormal dreams, and decreased sex drive.
And that's pretty much it. Does it ease my feeling of dread? No, not really. But it is interesting to see how trying to target one problem in the brain can inadvertently effect so many other areas of cognitive function. It also speaks to the mystery of our own brains when investigations such as these show how one small part of the brain can be responsible for such a diverse array of functions. Immensely cool stuff.
Anyway, I think I'm going to stick with aspirin for now. My brain doesn't need any more help being bizarre.
