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  • Parkinson ’s disease, Alcoholic addiction  – a new perspective

    And understanding working of Neurotransmitters

    Contact : Narayanan/ Mob: +91-9840687593

    Email: siliconlabs@gmail.com

    Abstract

    Deficiency of active inhibitory neurotransmitter, dopamine, produces the symptoms of Parkinson’s disease and in Alcoholic addiction. It is due to Push-Pull nature of the neuro system and depending on the deficiency of active inhibitory neurotransmitter, excitation of the muscles happens even at resting state ranging from tremor to rigidity. Deficiency of active dopamine is due to its binding with excess free estrogen increasing its molecular size. This binding is due to molecular plasticity and makes dopamine useless and inactive. 

    Neurotransmitters Overview

    Neurotransmitters are body’s chemical messengers. They carry messages from one nerve cell across a space to the next nerve, muscle or gland cell. These messages help one to move limbs, feel sensations, keep one’s heart beating, and take in and respond to all information body receives from other internal parts of body and environment. Without neurotransmitters, body can’t function. Too high of a level or too low of a level of specific neurotransmitters results in specific health problems [1].

    Neurotransmitters are located in a part of the neuron called the axon terminal. They’re stored within thin-walled sacs called synaptic vesicles. Each vesicle can contain thousands of neurotransmitter molecules.

    As a message or signal travels along a nerve cell, the electrical charge of the signal causes the vesicles of neurotransmitters to fuse with the nerve cell membrane at the very edge of the cell. The neurotransmitters, which now carry the message, are then released from the axon terminal into a fluid-filled space that’s between one nerve cell and the next target cell (another nerve cell, muscle cell or gland).

    In this space, called the synaptic junction, the neurotransmitters carry the message across less than 40 nanometers (nm) wide (by comparison, the width of a human hair is about 75,000 nm). Each type of neurotransmitter lands on and binds to a specific receptor on the target cell (like a key that can only fit and work in its partner lock). After binding, the neurotransmitter then triggers a change or action in the target cell, like an electrical signal in another nerve cell, a muscle contraction or the release of hormones from a cell in a gland.

    Neurotransmitters transmit one of three possible actions in their messages, depending on the specific neurotransmitter.

    Excitatory – Excitatory neurotransmitters “excite” the neuron and cause it to “fire off the message,” meaning, the message continues to be passed along to the next cell. Examples of excitatory neurotransmitters include glutamate, epinephrine and norepinephrine.

    Inhibitory – Inhibitory neurotransmitters block or prevent the chemical message from being passed along any farther. Gamma-aminobutyric acid (GABA), glycine, dopamine and serotonin are examples of inhibitory neurotransmitters.

    In practice the network of neural connections are very complex. Dendrites primarily form connections through a process of receiving chemical signals and converting them into electrical impulses. A single neuron may receive thousands of inputs across its “dendritic tree.” The dendrites collect and sum these excitatory and inhibitory signals to decide if the neuron should “fire” its own electrical impulse. Further to stress the point, some of the inputs of the dendrites are of excitatory and some of them are inhibitory. The total sum decides whether the neuron fires its own electrical impulse.  

    Push-Pull Logic in neural network

    Push-Pull Logic is followed in the neural network. For ease of understanding let take a neuron with one axon and two dendrites. Here one input of dendrite is excitatory (+) and other input inhibitory   (-). If both inputs have equal level of signal as shown in Fig.1(a) then there will no impulse produced (output) in the axon.  This neuron will be under resting state.

    Similarly, if excitatory input is higher than the inhibitory input as shown in Fig 1(b) then there will impulses in the axon and its strength will be difference of the input signals.

    On the contrary if inhibitory input is higher than the excitatory as shown in Fig 1(c) then there will be no impulses in the axon.

    This type of control is called push-pull type which is very widely employed in neural network in every motor neuron activity. This Push-Pull theory is the key to understanding many disorders of nervous system which involve abnormalities of monoamine neurotransmitters. It is important to note that every resting neuron (effector neuron) needs equal excitation from both excitatory and inhibitory inputs. This is how always balance established in the system.

    Further if due to some reason overall excitatory signal is more than inhibitory signal then the sum up will make the neural network of the subject in an alert waking state. Opposite of this is sleeping state. Amount of alertness or level of sleep depends on the level of difference between excitatory and inhibitory inputs. This is applied to mental tensions, muscle movement and co-ordination etc.,

    This Push-pull logic thus needs both inhibitory and excitatory inputs.

    Deficiency in particular type of Neurotransmitter

    Suppose let say there is deficiency in the amount of inhibitory neurotransmitter then the sum output will be always positive in the push-pull logic even at resting state which means that particular motor neuron unnecessarily activates the effector muscle even at rest state.

    This is what exactly happens in Parkinson’s disease. Here dopamine is an inhibitory neurotransmitter and its deficiency leads to less excitation on inhibitory side and thus it results in continuous excitation of motor neuron of limbs. The twitching of the limbs is due to excitation of motor neurons and it is not getting shut in resting state.  This is illustrated in Fig. 2. When the deficiency is more it results in larger gap resulting muscle stiffness or rigidity.

    Today’s literature says that the main reason for Parkinson’s disease is the deficiency of dopamine but it is unable to explain the resulting symptoms of the disease.  This Push-Pull theory adequately explains the theory behind resulting symptoms.

    Parkinson’s disease explained as on today

    Parkinson’s disease is a progressive movement disorder of the nervous system. It causes nerve cells (neurons) in parts of the brain to weaken, become damaged, and dies, (without much proof is believed) leading to symptoms that include problems with movement, tremor, stiffness, and impaired balance. As symptoms progress, people with Parkinson’s disease (PD) may have difficulty walking, talking, or completing other simple tasks. 

    While the exact cause of PD is unknown today, some cases are hereditary and can be traced to specific genetic mutations. . Most cases are sporadic, meaning they arise with no known cause. Researchers think  that PD likely results from a combination of genetics and exposure to one or more (mostly unknown) environmental factors that trigger the disease [2].

    Parkinson’s disease Real Scenario

    Parkinson’s disease is a disorder due to deficiency of active inhibitory neurotransmitter, in particular dopamine. This is because some of the dopamine turns inactive. Disease progresses as the deficiency also progresses. Symptoms include problems with movement, tremor, stiffness, and impaired balance. As symptoms progress, people with Parkinson’s disease (PD) may have difficulty walking, talking, or completing other simple tasks.

    Symptoms of Parkinson’s disease

    1. Tremor (shaking) often begins in a person’s hand, although sometimes the person’s foot or jaw is affected first. The particular tremor associated with PD has a rhythmic back-and-forth motion. Often, the tremor will cause the person to rub their thumb and forefinger together, which may appear as  “pill rolling.” It is most obvious when the hand is at rest or when a person is under stress.
    2. Rigidity (muscle stiffness), or resistance to movement, affects most people with PD. The muscles stay tense and tight so the person aches or feels stiff. If another person tries to move the individual’s arm, it will move only in short, jerky movements ( known as “cogwheel” rigidity).
    3. Bradykinesia is a slowing down of spontaneous and some automatic movement. It can make simple tasks more difficult, and activities the person could once perform quickly and easily—such as washing or dressing—may take much longer. The person’s face may be less expressive (known as “masked face”).
    4. Postural instability, such as balance problems and changes in posture, can increase the risk of falls.

    The above symptoms all can be reasoned well with push-pull theory said in this article. Following are very important logic to prove Push-Pull theory.

    1. This tremor usually disappears during sleep.  This is because during sleep inhibitory signal is much higher than the excitatory signal.
    2. This tremor improves when the person makes a purposeful, intended movement. During voluntary movement excitatory is much higher than the inhibitory.
    3. When dopamine is administered, it is found to reduce the heat rate and also blood pressure because in sum it reduces the excitatory impulse which is acting on the heart.

    Dopamine is a Happy Hormone

    Dopamine is inhibitory neurotransmitter.  At increased levels it subtracts the (world) noisy excitatory signals which makes mind calm and happy. All the limb muscle goes in to relaxed resting state. Nothing to get disturbed altitude which produce happiness (example is Sleep gives the best happiness). This is constituted as an inbuilt reward program by Today’s existing theory.

    Dopamine Deficiency

    Today’s theory points to Dopamine deficiency related to the destruction of the substantia nigra.  There is no substantial proof to show that indeed dopamine deficiency has occurred.

    This theory has a drawback that, motor symptoms may significantly improve at first with medication of dopamine, but can reappear over time as PD worsens and the medications become less effective. There is serious repeatability problem as the Dopamine dosage increases with time.

    Real Cause for Dopamine Deficiency

    Real cause for Dopamine deficiency is the free circulating estrogen. Estrogen binds to some of the Dopamine and gets locked making it useless or inactive to activate synaptic site due to combined mass. In other words these inactive Dopamine are available, increase in molecular size makes it useless to do its purpose. As a steroid hormone, estrogen readily diffuses across the lipid-rich plasma membrane of cells and possess a highly hydrophobic binding pocket (LBD – Ligand Binding Domain) composed of 12 alpha-helices. This ligand-binding domain (LBD) is flexible and can accommodate various estrogenic compounds, including natural hormones (molecular plasticity). Another important point to be noted is this free estrogen determined by Sex hormone-binding globulin (SHBG). SHBG hormones always ensure the level of free estrogen. Hence although initially medication significantly improves symptoms, it reappears, as the free estrogen level is increased. Hence the root cause is, above the normal level of free estrogen is to be noted.

    Alcohol Addiction

    Alcohol contains inhibitory neurotransmitter chemicals which on consumption boosts brain calmness, happiness and sedation. Once these temporarily substances got cleared naturally over time, the subject will experience shaking, sweating, anxiety and restlessness due to deficiency of inhibitory neurotransmitter.  Similar to Parkinson ’s disease, shaking, tremor of limbs occurs due to deficiency in inhibitory neurotransmitter. Hence the root cause for addiction and post symptoms are due to inhibitory neurotransmitter.

    To prove otherwise, some studies also have suggested a potential link between moderate regular alcohol consumption and a reduced risk of developing Parkinson’s. This proves the potential role played by the inhibitory neurotransmitter. Further similarity of shaking, tremor in both PD as well as alcohol withdrawal clearly proves the role played by Push-pull logic of neuro systems. 

    Conclusion

    Parkinson’s disease and Alcoholic addiction symptoms are due to impairment of dopamine molecules, an inhibitory neurotransmitter, making deficiency at the synaptic receptor. Hence balance between inhibitory and excitatory is offsetted resulting  in the symptoms. Free estrogens bond with affinity to dopamine resulting in impairment of dopamine action.

    References:

    1. Cleveland Clinic
    2. NIH National Institute of Neurological Disorders and Strokea component of the National Institutes of Health – https://www.ninds.nih.gov/
    3. Alcohol and Risk of Parkinson Disease in a Large Prospective Cohort of Men and Women Palacios  Mov Disord. 2012 Jun 19;27(8):980–987. doi: 10.1002/mds.25050