OVERVIEW


Many Neuroleptic drugs induce severe extrapyramidal side effects that can last even when the drug is removed from the individual’s system. The effects can include Acute Dystonia, Drug-Induced Parkinsonism, and Tardive Dyskinesia. Chlorpromazine and Clozapine are among the list of neuroleptics that cause these side-effects and both act on inhibiting D2 receptors, although Chlorpromazine is shown to more commonly cause heavier extrapyramidal side effects. Both Chlorpromazine and Clozapine are used to treat individuals with Schizophrenia, delusions, and hallucination. Traditionally, it is thought that the effect of neuroleptics’ control of Dopamine receptors only affect behavior and an individual’s ability and desire to choose an action for a reward. But the obvious and heavy-handed nature of the extrapyramidal effects of these drugs has even larger implications for their impact on motor control and voluntary movements.


FUNCTIONAL ANATOMY

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Substantia Nigra: Clinically important dopamine pathway
Globus Pallidus: regulation of voluntary movement and subconscious movement
Basal Ganglia: Communication between the Striatum and Substantia Nigra, particularly in transmitting Dopamine
Striatum: a group of nuclei important in facilitating voluntary movement (includes the Caudate and the Putamen)
Dopamine: Dopamine is produced in the Substantia Nigra and is then projected to the Striatum and is received by either D1 or D2 receptors. D1 receptors are more characteristic of the direct pathway, and are responsible for opening chemically gated channels and depolarizing the membrane. D2 receptors are more important for facilitating the indirect pathway. Most important function as a Neurotransmitter
GABA: Binding sites that open the Cl- channels and decrease the influx of Ca2+, allowing for repolarization of the cell membrane



INDIRECT AND DIRECT PATHWAYS

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Cortico-striatal-thalamic circuits: http://image.slidesharecdn.com/movementdisorders-151013175717-lva1-app6892/95/movement-disorders-11-638.jpg?cb=1444759137
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Dopamine: Dopamine facilitates communication between the Substantia Nigra and the Striatum, where D2 autoreceptors receive pre-synaptic Dopamine.
GABA: facilitates output from the Striatum, and from the Globus Pallidus to the Subthalamic Nucleus and the Thalamus

Voluntary movement begins in the Primary Cortex, travels to the Cerebral Peduncle, to the midbrain, to the pons, and then through a Corticospinal Descending Tract, and finally to the Spinal Cord for designation of movement.

NEUROLEPTIC AFFECT ON MOTOR CONTROL


Neuroleptic drugs notoriously cause dangerous and severe extrapyramidal side effects. These large-scale damages can be caused by small-scale hiccups in communicative pathways between the Motor Cortex and the Thalamus. Clozapine and Chlorpromazine affect GABA receptors and Dopamine receptors respectively to achieve these effects.

Chlorpromazine
Chlorpromazine is prescribed to treat Schizophrenia and its positive symptoms. A positive symptom is a symptom that happens in addition to the “normal” span of functions of an individual’s mental health. Conversely, a negative symptom is one that is taken away from an individual’s normal breadth of mental health (i.e. prosopagnosia). Chlorpromazine has the most devastating effects to one’s extrapyramidal system with prolonged use. Chlorpromazine interferes with D2 receptors and their uptake of Dopamine in the Striatum. This acts mainly to deaden the excess amount of Dopamine allowed in the cortical and limbic areas of the brain. Chlorpromazine also acts to lessen the amount of Dopamine allowed in the Chemical Trigger Zone (CTZ), which is intended to relieve nausea and vomiting as well as the symptoms of Tourette Syndrome [7]. Consequently this lessening of Dopamine can cause the GPe to over-fire to the Sub-Thalamic Nucleus [3] and consequently excite the Thalamus which is responsible for inhibition of unwanted movement. The over-stimulated Thalamus could then explain the unwanted movement found in symptoms such as Tardive Dyskinesia and Dystonia.
Chlorpromazine also inhibits the Sarcoplasmic Ca2+ Pump. This inhibits contraction, by antagonizing messages already presented by Ca within a relaxed muscle. Ca2+ is allowed into the Sarcoplasm via the Sarcoplasmic Ca2+ Pump. Ca then binds to Troponin and “pull” actin into Tropomyosin binding sites, releasing ADP and stimulating the muscle for contraction. Since Ca is not being pumped into the cell at its natural rate, the action potential is either fully inhibited or delayed entirely. This could explain the delayed reaction response seen in the Parkinson’s Gait (also known as the Thorazine Shuffle).
These effects are also dependent on the vessel size of application and the dosage given. This means that Chlorpromazine’s affects are greater on Type I Motor Units, which are smaller and induce contraction slower than Type II Motor Units. Theoretically this means the effects of Chlorpromazine are most seen in areas with smaller Motor Units stimulating muscle fibers. Chlorpromazine has also been shown to antagonize the androgenic actions of adrenaline within the muscles [2].

Clozapine
Clozapine is known to inhibit GABA innervation. GABA Innervation allows for an influx of Cl- ions into the Dorsal Root Ganglia. GABA innervation is important for stimulation of the Indirect Pathway through the Striatum. Since the Striatum is not being stimulated, there is disconnect in the execution of these voluntary movements, generally presented as a delay in planned, sequenced, or learned movements [3].

Functional Differences between Clozapine and Chlorpromazine
Clozapine and Chlorpromazine are both used to treat the positive side effects of Schizophrenia, but differ in their neuroleptic class and chemical inhibitions.
Clozapine is classified as a “Second Generation Antipsychotic” (SGA). Generally, SGA’s cause less severe extrapyramidal side effects. The side effects they do induce occur less frequently in the sample of individuals who use them. Clozapine is known to increase the risk of diabetes, hypotension, and myocarditis due to its heavy metabolic influence.
Chlorpromazine is a part of the “Traditional Antipsychotic” (TA) family. TA’s are known to cause more severe extrapyramidal effects that last even past drug use termination, and occur more frequently in individuals who use them for a prolonged period of time. This phenomenon is due to brain plasticity and accommodation. Since pathways in the brain are plastic, it is thought that they adapt to the effects of the D2 inhibitions from Chlorpromazine and Clozapine and begin to regulate naturally in a similar way to how the drug regulates them. This causes the delayed onset of Tardive Dyskinesia and the lasting symptoms of Drug-Induced Parkinsonism. The implications of plasticity and long-term observation of Chlorpromazine have weighted consequences for the efficacy of Clozapine and how its side-effects are viewed in terms of their severity. Since Clozapine has not been commonly prescribed for as long as Chlorpromazine, there is less research about its long-term affects due to the lack of time for study [7].

CONCLUSION
Evidently Neuroleptics show that what might be revolutionary for short-term regulation of the Prefrontal Area could have devastating consequences for the long-term functioning of the Motor Cortex and how it enables and regulates voluntary and involuntary muscle contractions. By deadening D2 receptors Neuroleptics are able to lessen the positive symptoms of Schizophrenia, but negatively affect Thalamic and Cortical control and regulation.

GLOSSARY
Akathisia: restlessness usually accompanied by motor hyperactivity
Dystonia: abnormal muscle tone resulting in muscular spasm and abnormal posture
Neuroleptic Malignant Syndrome: a life-threatening neurological disorder including high fever, sweating, unstable blood pressure, stupor, muscular rigidity, and autonomic dysfunction
Drug-Induced Parkinsonism: symptoms of Parkinson’s as developed due to prolonged Neuroleptic drug use
Tardive Dyskinesia: involuntary movements of the face and jaw, usually presented after prolonged neuroleptic use

RELEVANT VIDEOS AND READINGS
Overview of Parkinsons: https://www.youtube.com/watch?v=Hu5KVfFnrh0
Dopamine + Parkinsons Disease: https://www.youtube.com/watch?v=jyBakRkzswU
Schizophrenia: Sacks, Oliver (1995). An Anthropologist on Mars. New York, New York: Vintage Books.

REVIEW QUIZ

1. How does Chlorpromazine affect the biochemistry of motor control pathways?
2. What is a difference between Second Generation Antipsychotics and Traditional Antipsychotics?
3. Chlorpromazine is used to treat:
4. Clozapine effects Receptors.
5. Dopamine is produced by the:
6. Ca2+ is mainly brought into the Sarcoplasm through the:
7. 7. Tardive Dyskinesia and Drug-Induced Parkinsonism discontinue after they are removed from an individual’s system (True/False)
8. Brain Plasticity contributes to the long-lasting side-effects caused by Clozapine and Chlorpromazine (True/False)
9. Dosage has no effect on severity of motor control effects (True/False)
10. Dopamine only contributes to the behavior and decision making of an individual (True/False)

1.


ANSWERS
  1. Dopamine Receptor Inhibition, Antagonism of Adrenaline in the Muscles, and Inhibition of the Sarcoplasmic Ca Pump
  2. Second Generation Antipsychotics have side effects that occur less frequently than side effects associated with Traditional Antipsychotics
  3. Positive Symptoms associated with Schizophrenia, Nasea, and Vomiting
  4. GABA
  5. Substantia Nigra
  6. Ca Sarcoplasmic Pump
  7. False
  8. True
  9. False
  10. False


REFERENCES
[1] College of Psychiatric Neurologic Pharmacists (2016). “Clozapine (Clozaril/FazaClo)”. National Alliance on Mental Illness, 2016. Web. 10 December 2016.
http://www.nami.org/Learn-More/Treatment/Mental-Health-Medications/Clozapine-(Clozaril-FazaClo)
[2] Godraind, T. and Kaba. A. (1969). “Blockade or reversal of the contraction induced by calcium and adrenaline in depolarized arterial smooth muscle”. British Journal of Pharmacology. 36(3), pp. 549-560. Web. 10 December 2016.
http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.1969.tb08010.x/pdf
[3] Keeler, J.F., Pretsell, D.O., and Robbins, T.W. (2014). “Functional impolications of dopamine D1 vs. D2 receptors: A ‘prepare and select’ model of the striatal direct vs. indirect pathways”. Neuroscience 282, pp. 156-175. Web. 10 December 2016.
https://www.parkinsons.org.uk/sites/default/files/publications/download/english/fs38_druginducedparkinsonism.pdf
[4] Medscape. “chlorpromazine (Rx)”. WebMD, 1994-2016. Web. 10 December 2016.
http://reference.medscape.com/drug/chlorpromazine-342970#10
[5] Messamore, Erik. (2004). “Metabolic Side Effects of Antipsychotic Medications: Clinical Laboratory Implications”. Laboratory Medicine 35(10), pp. 625-627. Doi: 10.1309/X63H-9LHU-FFJJ-L6FH. Web. 10 December 2016. https://www.researchgate.net/profile/Erik_Messamore/publication/246756300_Metabolic_Side_Effects_of_Antipsychotic_Medications_Clinical_Laboratory_Implications/links/55d8bec808aed6a199a88b94.pdf
[6] National Center for Biotechnology Information. “Chlorpromazine (By Injection)”. PubMed Health. U.S. National Library of Medicine, 2016. Web. 10 December 2016.
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0009583/?report=details#how_to_use
[7] National Center for Biotechnology Information. “Chlorpromazine”. PubChem, 16 September 2004. Web. 10 December 2016.
https://pubchem.ncbi.nlm.nih.gov/compound/chlorpromazine#section=Top
[8] Olsen, Richard W., and DeLorey, Timothy M. (1999). “GABA Receptor Physiology and Pharmacology”. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6. Web. 10 December 2016.
https://www.ncbi.nlm.nih.gov/books/NBK28090/
[9] Parkinsons Disease Society. “Drug-Induced Parkinsonism: Information Sheet”. Parkinson’s Disease Society of the United Kingdom, 2013. Web. 10 December 2106.
https://www.parkinsons.org.uk/sites/default/files/publications/download/english/fs38_druginducedparkinsonism.pdf



1. What is a difference between Second Generation Antipsychotics and Traditional Antipsychotics?
2. Chlorpromazine is used to treat:
3. Clozapine effects Receptors.
4. Dopamine is produced by the:
5. Ca2+ is mainly brought into the Sarcoplasm through the:
6. Tardive Dyskinesia and Drug-Induced Parkinsonism discontinue after they are removed from an individual’s system (True/False)
7. Brain Plasticity contributes to the long-lasting side-effects caused by Clozapine and Chlorpromazine (True/False)
8. Dosage has no effect on severity of motor control effects (True/False)
9. Dopamine only contributes to the behavior and decision making of an individual (True/False)