Side Effects of Pramipexole on Mesolimbic and Mesocortical Pathways

Parkinson’s Disease is a long-term neurodegenerative disease that mainly affects the substantia nigra of the basal ganglia. The substantia nigra is part of the nigrostriatal pathway, which originates from the basal ganglia and projects to the dorsal striatum; it produces dopamine for the central nervous system and is responsible for motor movement regulation. Degeneration of the substantia nigra reduces the quantity of dopaminergic neurons, and eventually leads to dopamine depletion. This insufficient dopamine supply in the nigrostriatal pathway is accountable for symptoms such as resting tremors, rigidity, autonomic dysfunction and neuropsychiatric problems seen in Parkinson’s Disease.

One of the pharmaceutical agents that treat Parkinson’s Disease is pramipexole, which targets dopaminergic receptors in the central nervous system. Ideally, it acts as an agonist and restores the neurochemical imbalance in the nigrostriatal pathway. By doing so, pramipexole could potentially manage the motor symptoms of the disease. However, the nigrostriatal pathway is not the only dopaminergic center in the brain; the mesolimbic and mesocortical pathways also house receptors of the neurotransmitter and regulate important neuronal functions. The mesolimbic pathway originates from the ventral tegmental area, and projects to the ventral striatum, specifically the nucleus accumbens. Upon stimulation of dopamine, the nucleus accumbens signals motivation for incentive salience and perception of pleasure. As a result, this region has significant involvement in reward and addiction formation. The mesocortical pathway, just like the mesolimbic pathway, originates from the ventral tegmental area, but projects to the dorsolateral prefrontal cortex. The dorsolateral prefrontal cortex is responsible for decision making and impulse control. Lesions to this region could lead to poor insight and impulsivity.

Although the nigrostriatal, mesolimbic and mesocortical pathways all have dopaminergic receptors, the subtype of the receptors is different in each pathway. D3-like dopaminergic receptors are abundant in the nucleus accumbens of the mesolimbic pathway, as well as the dorsolateral prefrontal cortex of the mesocortical pathway; however, their density is negligible in the dorsal striatum. On the contrary, the nigrostriatal pathway has a dense population of D2-like dopaminergic receptors.

As a dopaminergic agonist, pramipexole has differential affinities to the two subtypes of dopaminergic receptors. Experiments have shown that the molecule has a stronger affinity to D3-like receptors. In fact, the dissociation constant for this subtype is only 0.5nM, but could be as high as 3.9nM for D2-like receptors. In other words, pramipexole activates pathways that have abundant D3-like receptors, such as the mesolimbic and mesocortical pathways, more than the ones with D2-like receptors, such as the nigrostriatal pathway.

Clinically, the unintended activation of the mesolimbic and mesocortical pathways could cause disturbance in reward, decision making and impulse control functions of the central nervous system. Contingent administration of pramipexole could sensitize the nucleus accumbens, and lead to extreme incentive salience of rewarding stimuli. At the same time, the repeated exposure could inhibit the dorsolateral prefrontal cortex, and impair decision making. Extreme incentive salience and impaired decision making are critical premises for addiction development. A real life example of this is pathological gambling caused by pramipexole. Individuals with pathological gambling are not able to curb their compulsive urge to gamble, despite the negative financial and social consequences. When a Parkinson’s patient starts pramipexole treatment, the sensitized mesolimbic pathway and the inhibited mesocortical pathway work synergistically on cultivating addictive behaviors. This is why some Parkinson’s patients develop pathological gambling after taking pramipexole. Notably, Parkinson’s Disease usually has very late age of onset. Although these individuals are theoretically equally susceptible to other forms of addiction, gambling is more readily available and therefore becomes their “drug of choice.”