The Role of Dopamine Receptors in Schizophrenia

by: Rupinder Mann
for: Biochemistry II (CHEM 4420)
5/29/96

Two million people suffer from schizophrenia at some point in their life, making it one of the most common health problems in the United States. Schizophrenia has also been found to be hereditary. This biological disorder of the brain is a result of abnormalities which arise early in life and disrupt the normal development of the brain. These abnormalities involve structural differences between a schizophrenic brain and a healthy brain. Schizophrenic brains tend to have larger lateral ventricles and a smaller volume of tissue in the left temporal lobe in comparison to healthy brains. The chemical nature of a schizophrenic brain is also different in the manner the brain handles dopamine, a neurotransmitter. Neurotransmitters transmit impulses between neurons. (Brown 1994)

The disease schizophrenia can be characterized by disturbances in the areas of the brain that are associated with thought, perception, attention, motor behavior, emotion, and life functioning. The symptoms are divided into negative and positive categories. Negative symptoms consist of behavioral deficits such as blunting of emotions, language deficits, and lack of energy. Positron emission tomography (PET) has been used to show that schizophrenics with negative symptoms have reduced brain activity in the prefrontal cortex of the brain. PET measures the blood flow in the brain by measuring particles (positrons) that are emitted from a radioactive chemical injected into the patient. The rate of positron emission is used to evaluate the metabolic rate of nerve cells in particular regions of the brain. PET allows scientists to determine which areas of the brain are being used as people perform certain tasks.

Positive symptoms are frightening, but they are not as disabling in the long term as negative symptoms. These positive symptoms consist of hallucinations, delusions, and bizarre behavior. Single photon emission tomography (SPET) measures a single photon's rate of emission. It has been used to show that during the delusional hearing of voices, the blood flow is greater than normal to Broca's area. This is the part of the brain that has been linked to articulated language. Some subcategories of schizophrenia include hebephrenic, catatonic, and paranoid schizophrenia. Hebephrenic or disorganized schizophrenia is characterized by profuse hallucinations and delusions that often involve deterioration of the body. Catatonic schizophrenia involves motor disturbances, which alternate between immobility and wild excitement. A paranoid schizophrenic has prominent delusions about persecution. (Davison & Neale 1990) A number of these symptoms are thought to be caused by biochemical factors. One of the most prominent of these factors is the excessive activity of the neurotransmitter dopamine. This excessive activity will be explained by the chemistry of the brain and dopamine receptors.

Thousands of chemical processes take place in a functioning neuron. The transfer of information is mediated by neurotransmitters that interact with certain receptors. (Sedvall & Farde 1995) When drugs block dopamine receptors in the basal ganglia, the symptoms of schizophrenia are reduced. Amphetamines and other drugs that stimulate the receptors produce schizophrenic symptoms in healthy people. (Brown 1994) Five dopamine receptors, D1, D2, D3, D4, and D5, have been discovered. Each of the receptors contain about 400 amino acids, and they have seven regions spanning the neural membrane. Their function is to bind to dopamine secreted by presynaptic nerve cells. This binding triggers changes in the metabolic activity of the postsynaptic nerve cells. A study was conducted in which presynaptic dopamine function (measured by the uptake of fluorodopa) was observed by PET in the brains of seven schizophrenic patients and eight healthy people (controls). The fluorodopa influx constant was higher in the schizophrenic patients. Their receptors took up more fluorodopa. In conclusion, these alterations in presynaptic dopamine function constituted a part of the disrupted neural circuits that predispose people to schizophrenia. (Hietala 1995)

The dopamine receptors involved in these processes can be separated into the D1 and D2 families. The D1 family contains the receptors D1 and D5. The D1 receptors in the brain are linked to episodic memory, emotion, and cognition. These functions are disturbed in schizophrenic patients. In addition, D1 binding of dopamine was found to be lower in schizophrenic patients as compared to healthy subjects of the same age. The binding was lower as a result of fewer D1 receptors. Certain antipsychotic drugs stimulate D1 regulated pathways, which increases the D1 to D2 activity balance in the brain. This balance can also be regained by the release of dopamine. Not much is known about D5 due to the lack of drugs that are selective for it.

The D2 family contains the receptors D2, D3, and D4. D2 is the second most abundant dopamine receptor in the brain. D2 receptor blockade is the main target for antipsychotic drugs, because there is a higher density of D2 in schizophrenic brains. (Sedvall & Farde 1995) A study conducted by Schmauss (1993) found a selective loss of D3 mRNA expression in the parietal and motor cortices of postmortem, schizophrenic brains. This phenomena may be due to either the course of the disease or the therapy given to the patient during the course of the disease. Seeman (1993) found the density of D4 receptors was elevated sixfold in schizophrenic patients.

These dopamine receptors are affected by alterations in the neural cell membranes, which could disrupt communication between cells. Abnormalities in two long-chain fatty acids in the blood cells of people with negative symptoms have been discovered. These substances breakdown into products that are involved in the dopamine system. (Brown 1994) Dopamine is secreted by cells in the midbrain that send their axons to the basal ganglia and frontal lobe. Certain drugs used for schizophrenia bind to the dopamine receptors. This blocks dopamine binding to the receptor. This deactivates the biochemical processes normally initiated by dopamine binding. First dopamine binds to the receptor, and then the receptor autophosphorylates. By phosphorylation, this receptor activates adenylate cyclase, which then makes cAMP. These processes involve the synthesis of cAMP and synaptic action at synapses using dopamine as a transmitter. The dopamine synapses are incapacitated by antipsychotic drugs. Dopamine antagonists are drugs that block dopamine receptors. The brain responds to this receptor blockade by making extra dopamine receptors. This is the postsynaptic cells' attempt to compensate for the weakening of synaptic transmission, which is caused by the drugs. These extra receptors restore the cell's sensitivity to dopamine. The brain also compensates by increasing dopamine synthesis. The increase in dopamine synthesis lasts one to two weeks of medication from the start of therapy, which is the same time required for the medication to become effective. Drugs have been discovered to alleviate the upregulation of receptors and the increased synthesis of dopamine. (Lickey & Gordon 1990)

Anti-schizophrenic drugs are called neuroleptics. A dopamine antagonist is chlorpromazine (Thorazine), and reserpine operates by depleting transmitter stores. Ligand-binding techniques, which use neuroleptic drugs labelled with radioisotopes demonstrate that such drugs bind to dopamine receptors. A correlation exists between this ability to bind dopamine and the dosage required to improve schizophrenic symptoms in patients. This effect could also be directly observed by PET in living subjects . (Sedvall & Farde 1995)

Controlling dopamine and dopamine receptors is essential for the treatment of schizophrenia. Because schizophrenia is hereditary, it is important to see progress for the next generation. (Brown 1994) In the future there will be more sophisticated drugs that do not merely suppress symptoms, but also allow for normal cognitive functioning. Although schizophrenics may never be normal, their lives can still be made more tolerable.

References

Brown, Phyllida (1994). Understanding the inner voices. New Scientist, 143, 26-31.

Davison, Gerald & Neale, John (1990). Abnormal Psychology. John Wiley & Sons: New York.

Hietala, Jarmo (1995). Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. The Lancet, 346, 1130-1131.

Lickey, Marvin & Gordon, Barbara (1990). Medicine and Mental Illness. W. H. Freeman & Company: New York.

Schmauss, Claudia; Haroutunian, Vahram; Davis, Kenneth; & Davidson, Michael (1993). Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia. The Proceedings of the National Academy of Sciences: USA, 90, 8942-8946.

Sedvall, Goran & Farde, Lars (1995). Chemical brain anatomy in schizophrenia. The Lancet, 346, 743-749.

Seeman, Philip; Guan Hong-Chang; & Van Tol, Hubert (1993). Dopamine D4 receptors elevated in schizophrenia. Nature, 365, 441-445.


Copyright 1996 Rupinder Mann and Koni Stone

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