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Angela Shuback November 20, 2014 Physiology Lab (Thursday 1-4) Parkinson’s Disease Background Parkinson’s disease (PD) is a chronic, degenerative disorder of the central nervous system that usually affects older individuals between the ages of 50 and 65 (Nutan 2005). Over time the disease increases in severity and is not known to regress or go away. It results from the gradual degeneration of nerve cells in a portion of the midbrain that ultimately leads to the loss of control of body movements. In the U.S. it is estimated that over one million people are affected by this disease and each year around 50,000 new cases are diagnosed (Nutan 2005). PD is not fatal, but it can cause debilitating symptoms that impact everyday movement and motility. The core symptoms seen with this disorder include tremors, rigidity, bradykinesia (slowness of movements), and postural instability. Secondary symptoms can also occur, for example, loss of facial expression, dysarthric speech, micrographia (small handwriting), dysphagia (difficulty swallowing), drooling, GI complications, and mental health (depression). However, signs and symptoms vary from each individual. These symptoms can develop slowly or in some cases they progress quickly. Some symptoms may also be minor while others are debilitating. This just shows that each individual case of PD is unique (Weiner et al 2002). Furthermore, the main cause of PD is still unknown. However, several factors have been found to be associated with the disease. Environmental factors may play a role and some examples include exposure to pesticides, head injuries, and living in the country or farming (Nutan 2005). Rural environments and the drinking of well water may be risks since these are indirect ways to be exposed to pesticides. Also, heavy metals have been proposed as a possible risk factor through the accumulation in the substantia nigra. Additionally, genetic factors may have an association with PD and mutations in specific genes have been shown to cause it (Nutan 2005). Researchers suspect that it is a combination of genetic and environmental factors that cause Parkinson’s (Nutan 2005). Dopamine and the Dopamine Pathways A vast number of neurotransmitters are present within the brain and allow for many different functions. However, in Parkinson’s Disease, dopamine (DA) is the main neurotransmitter at play. Dopamine is one of five neurotransmitters that make up the family known as the monoamines--the other four neurotransmitters being norepinephrine, epinephrine, serotonin, and histamine (Carlson, 2013). Dopamine, along with norepinephrine and serotonin, is also part of the subclass known as the catecholamines (Carlson, 2013). Tyrosine, an amino acid, is the precursor for dopamine production and is mainly obtained through our diet (Carlson, 2013), Dopamine has the ability to produce both excitatory and inhibitory postsynaptic potentials depending on the postsynaptic receptor it is binding to (Carlson, 2013). Humans rely on dopamine for many functions, including movement, attention, learning, and the reinforcing effects of certain abusive drugs (Carlson, 2013). Many systems of dopaminergic neurons exist throughout the brain, but perhaps the most important systems are the ones that originate in the substantia nigra and the ventral tegmental area (VTA); both of these brain areas are part of the midbrain (Carlson, 2013). The three main dopamine systems are the nigrostriatal system, the mesolimbic system, and the mesocortical system (Carlson, 2013). In each of the systems, cell bodies of the neurons originate in the substantia nigra or VTA and project to different surrounding areas. In the nigrostriatal system, the cell bodies originate in the substantia nigra and project their axons to the caudate nucleus and putamen, areas involved in motor control (Carlson, 2013). In the mesolimbic system, cell bodies originate in the VTA and project their axons to the nucleus accumbens, hippocampus, and amygdala, the main structures involved in the limbic system (Carlson, 2013); the nucleus accumbens plays a large role in reinforcement for rewarding stimuli, such as abusive drugs (Carlson, 2013). Finally, the mesocortical system has cell bodies that originate in the VTA and project their axons to the prefrontal cortex (PFC), thus having an excitatory effect on the PFC (Carlson, 2013). These excitatory neurons in the PFC play a crucial role in planning, formation of short-term memories, and strategies for problem-solving (Carlson, 2013). The behavioral functions that these three dopamine systems elicit clearly illustrate their importance within the brain and how detrimental it can be to an individual if these systems go awry, like in Parkinson’s Disease. Pathology of Parkinson’s Disease In a person without Parkinson’s Disease, the dopamine systems described above would be functioning normally, with the cell bodies projecting to their appropriate brain areas. However, in individuals with Parkinson’s Disease, degeneration of these neural projections in the nigrostriatal system occurs (Carlson, 2013). As a result of this degeneration, an individual may experience tremors, poor balance, rigidity of the limbs, and have great trouble initiating movements (Carlson, 2013). Additionally, in non-demented individuals, the substantia nigra appears black in color, due to the presence of a compound called melanin (a compound responsible for one’s skin color; Carlson, 2013). Melanin is produced by the breakdown of dopamine, so the substantia nigra appears pale instead of black in patients with Parkinson’s Disease (Carlson, 2013). Prevention/Management Environmental toxins were first implicated in correlation to PD pathology in 1983. Intravenous injection of illicit drugs containing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed selective damage to the dopaminergic cells of the substantia nigra (Lau & Breteler 2006). Avoiding and limiting exposure to harmful environmental chemicals, drugs, and certain dietary habits has shown a decrease in prevalence of PD in patients involved in both retrospective case studies and cohort studies (Lau & Breteler 2006). The herbicide paraquat, the pesticide rotenone, as well as MPTP all act to induce dopamine depletion via complex-I inhibition of the substantia nigra (Wang et al. 2006). Heavy metals such as iron, manganese, copper, lead, amalgam, aluminium, and zinc have been inconclusively implicated in PD pathology possible due to increased oxidative stress of neurons (Lai et al. 2002) Other cohort studies have observed reduced risk and onset of PD with consistent caffeine intake to reduce risk of PD (Lau & Breteler 2006). Increased dietary intake of antioxidants such as vitamin E and C has shown to slightly reduce risk of onset of PD possibly by reducing the number of free radicals and reactive oxygen species (ROS) in the brain (Lau & Breteler 2006). Treatment There is not yet a cure for PD, but increasing the amount of exercise disease has been implicated in suppressing the symptomatology of the disease in patients. Drug therapies usually prove better treatment options due to the geriatric nature of the disease and inability of those afflicted to exercise regularly. The prevalence of dopamine associated motor symptoms have decreased with the use deep brain stimulation (DBS) as well as drug therapies such as: levodopa, dopamine agonists, N-methyl-D-aspartic acid (NMDA) antagonists, and monoamine oxidase B inhibitors (MAO-B) (Muller 2012). These drug therapies may result in side effects amplifying the non-motor symptoms of the disease or act synergistically causing other problems. Levodopa (LD), a natural precursor molecule of dopamine, is administered with a dopadecarboxylase inhibitor (DDI i.e. ) that prevents conversion of LD into until it reaches the brain (Muller 2012). Dopamine agonists act mechanistically similar to LD treatments, but only mimic the effects of dopamine as compared to the conversion of LD to dopamine. MAO-B inhibitors prevent the breakdown of dopamine in the brain by inhibiting the enzyme monoamine oxidase B (Muller 2012). NMDA antagonists such as amantadine improve motor symptoms by indirect dopamine stimulation, but is usually used in conjunction with LD and DDI treatments (Muller 2012). DBS of the subthalamic nuclei does not prevent the progression of PD, but provides beneficial motor symptom improvement for those affected with advanced PD progression. It is usually only administered when LD therapies are ineffective and may cause behavioral and cognitive side effects (Muller 2012). References Carlson, N.R. (2013). Physiology of Behavior (11th ed.). Upper Saddle River, New Jersey: Pearson Education, Inc. Lai, B.C., Marion, S.A., Teschke, K., Tsui, J.K. (2002). Occupational and environmental risk factors for Parkinson’s disease. Parkinsonism & Related Disorders, 8, 297–309. Lau, L.M., Breteler, M.M.B. (2006). Epidemiology of Parkinson’s Disease. The Lancet Neurology, 5, 525-535. Muller, T. (2012). Drug therapy in patients with Parkinson’s Disease. Translational Neurodegeneration, 1, 10. Nutan, S. (2005). Parkinson's disease and the family : a new guide. Cambridge, Massachusetts: Harvard University Press. Wang, Y.S., Shi, Y.M., Wu, Z.Y., He, Y.X., Zhang, B.Z. (1991). Parkinson’s disease in China. Coordinational Group of Neuroepidemiology, PLA.ChinMed J (Engl), 104, 960–64. Weiner, W., Shulman, L., Lang, A.. (2002). Parkinson's Disease : A Complete Guide For Patients And Families. Baltimore: Johns Hopkins University Press.