What do the dopamine reward system and Parkinson's disease have to do with one another?
The topic for discussion this week came about because of the serendipitous connection between two events. The first: listening to a discussion regarding how the analysis of video game behavior can provide insight into enhancing learning. The second moment: while attending a neurology conference at Tulane University, a talk on movement disorders, given by Dr. Jayaraman Rao, mentioned the phenomenon of pathological gambling in Parkinson’s disease patients who were taking dopamine agonists. The latter mentioned the dopamine reward system, which was the same neurochemical mediator referred to in the video game lecture. If that doesn’t make you go “Hmmmm,” I don’t know what will.
By way of background, there have been several impulse control disorders (ICD) recognized in Parkinson’s disease patients, particularly those on dopamine agonists. ICDs are a heterogeneous group of conditions involving repetitive, excessive, and compulsive activities that interfere with life functioning. These represent a form of compulsive behavior that may have several forms of expression:
· Compulsive gambling
· Compulsive shopping
In addition, some patients develop a stereotypical, repetitive motor task called punding. This may have a relationship to previous occupation or hobbies. While engaging in these behaviors, the patient has some withdrawal into their own activity, apparently oblivious to the world around them.
If patients display the characteristic of addictive behavior to their dopamine medication, it is termed dopamine dysphoric syndrome. These patients, despite obvious dopamine toxicity with dyskinesias, will request increasing their dose of medication and will resist any attempts to reduce their Parkinson’s disease medicines. They frequently display other elements of ICDs. All of these disorders actually have a great deal of overlap with drug addict behaviors. As it turns out, there is likely a common biochemical basis for drug addictions, ICDs, and learning.
The Parkinson’s disease patients most at risk for the development of ICDs have these characteristics:
· Young onset
· Display novelty-seeking behavior
· History of alcoholism or other psychiatric comorbidities
· Taking a dopamine agonist
All of the phenomena mentioned above are thought to represent a disturbance in the so-called dopamine reward system. This dopamine pathway is separate from the nigrostriatal system involved in the motor complication of Parkinson’s disease. This other pathway is a mesocorticolimbic pathway with different afferent and efferent connections, as well a difference in predominant dopamine receptor type. The pathway originates in the ventral tegmentum and connects extensively to the nucleus accumbens, amygdala, and olfactory tubercle. The mesocortical pathways project to the septum and prefrontal cortex.
This pathway has a preference for the D3 receptor type. It has been postulated that there may be a differential degradation of pathway types in Parkinson’s disease, with relative preservation of the mesolimbic system. Therefore, treatment earlier in Parkinson’s disease with pramipexole or ropinorole may have more influence in the relatively preserved dompaminergic neurons in this pathway.
The dopamine neurons are thought to encode the difference between an expected outcome and the actual outcome of an event. Therefore the
Reward Value X Probability = Expected Value.
The discrepancy between the actual event and its prediction is called an event prediction error. When a reward is better than predicted, it elicits an activation (positive prediction error). Negative reward prediction errors (eg, when an expected reward fails to arrive) are conveyed by pauses in dopamine neuron firing. A fully predicted reward draws no response, and a reward that is worse than predicted induces a depression (negative error). Thus, there is an increase in phasic dopamine firing when there is a greater-than-expected reward, and a decrease in the firing rate with a lower-than-anticipated reward.
The study of dopamine agonist-induced compulsive behaviors provides a unique opportunity to unravel the core biology of ‘‘behavioral addiction’’ in susceptible individuals. Somehow, expected results are perceived as rewards and are not influenced by adverse results. This alteration in the reward system could be the explanation for the compulsive gambling behavior seen in patients on dopamine agonists in both Parkinson’s disease and restless leg syndrome. The conceptual link between learning models and addiction has received further support from recent human and animal studies examining naturally occurring variations in dopamine function. As the neural mechanisms controlling dopamine reward pathways are further understood, not only will chemical and behavioral addictions be more controlled, but our ability to influence learning will be greatly enhanced.
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