Department of Psychology

Schizophrenia 2:
PSY335/206 Physiological Psychology Lecture Support Material

Table of Contents

Lecture overview
Supplementary material
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Lecture overview

Dopamine receptor subtypes and schizophrenia

According to the DA (dopamine) hypothesis of schizophrenia, schizophrenia is associated with increased activity in dopaminergic neurones. You should revise the events involved in dopamine neurotransmission and the drugs that affect this process. See Carlson. Note that an "agonist' mimics the effects of a neurotransmitter at the receptor site. An "antagonist' blocks the effects of a neurotransmitter at the receptor site.
Dopamine activates receptors in the postsynaptic membrane to release an enzyme (adenyl cyclase) which converts ATP into cyclic AMP (CAMP). CAMP initiates chemical reactions that alter the permeability of the postsynaptic membrane and leads to the production of conduction along the neuron.
In a test tube, when DA is added to membranes containing adenyl cyclase there is increased production of cAMP.

Point to ponder
What would you predict would happen if you added an antipsychotic drug as well as DA to membranes containing adenyl cyclase?
There is a positive correllation between the average clinical dose of an antipsychotic and the ability of the drug to inhibit adenyl cyclase. This suggests that antipsychotic drugs may control schizophrenia by acting at DA receptors to block the conversion of ATP into cAMP. However butyrophenones are very potent drugs clinically but they are not very potent in their ability to inhibit adenyl cyclase.
There are two types of DA receptor (called D1 and D2). The D1 receptor is bound to adenyl cyclase. This enzyme is not bound to the D2 receptor.
The antipsychotic drug haloperidol binds to the D2 receptor. The ability of any antipsychotic drug to bind to the D2 receptor can be measured in terms of its ability to displace radioactive haloperidol from the D2 receptor.
There is a very high correlation between the average clinical dose of an antipsychotic drug and its ability to displace radioactive haloperidol from the D2 receptor.
There is also a very high correlation between the amount of antipsychotic drug needed to block amphetamine-induced stereotyped behaviour and its ability to displace radioactive haloperidol from the D2 receptor.

Point to ponder
What are the disadvantages of relying on D2 receptor binding as a screening test for novel anti-psychotic medication?
The effects of selective D1 and D2 agonists have been studied in rats. According to Braun & Chase (European J. Pharmacology, 131, 301-306, 1986) when D1 and D2 selective agonists are given on their own they do not elicit stereotyped behaviours. However when D1 and D2 agonists are administered together the rat exhibits stereotyped behaviours.
Homovanillic acid is a breakdown product of DA. According to the DA theory, HVA levels should be increased in the brains of schizophrenic patients. According to Crow et al (1978) there is no difference in HVA between normal and schizophrenic brain.
However there do appear to be an increased number of D2 receptors in schizophrenic brain.
Tardive dyskinesia = facial tics and abnormal tongue movements. It seems to occur when there is increased DA activity. For example it occurs when too much L-DOPA is given to patients with Parkinson's disease. It occurs when schizophrenics are taken off their medication. The disorder appears to be due to overstimulation of DA receptors.
Why should antipsychotic drugs (which are supposed to work by blocking DA receptors) cause overstimulation of DA receptors? Perhaps denervation supersensitivity is involved.

Point to ponder
What change in symptoms would you expect to occur under denervation supersensitivity?
There are no differences between D1 and D2 receptors in patients with/without movement disorders like tardive dyskinesia.

Dopamine neurotransmission

Dopamine activates receptors in the postsynaptic membrane to release adenyl cyclase

Dopamine (red) activates the receptor to release (blue) an enzyme (adenyl cyclase) which converts ATP into cyclic AMP (cAMP).
cAMP initiates a series of chemical reactions that alter the membrane's permeability.
Dopamine and adenyl cyclase

Antipsychotics & cAMP

Poor correlation (shown as the red line in the diagram) between inhibition of DA sensitive adenylate cyclase and clinical potency.
Note especially that butyrophenones ( Haloperidol, Pimozide and Spiroperidol ) are very potent drugs clinically but they are not very potent in their ability to inhibit adenylate cyclase. Antipsychotics and cAMP

DA receptor types

Here is a really nice diagram explaining the concept 'receptor' from Hamilton & Timmons online book Drugs, Brains and Behavior
receptor concept

After storage in the presynaptic neuron, dopamine is released into the synaptic cleft, where it may bind to an autoreceptor and thus inhibit the release of more dopamine. However, it may instead bind to a D1 receptor associated with adenylate cyclase, or to a D2 receptor. DA receptor types

Antipsychotics bind to D2 receptors

D2 receptor binding & clinical potency

There is a high correlation (r=0.87) between the affinities of antipsychotic drugs for the D2 receptor site (as measured by interference with the binding of radiolabelled haloperidol) and clinical potency ( as measured by the amount of the drug that needs to be given to schizophrenic patients). From Hamilton & Timmons online book Drugs, Brains and Behavior- well worth a visit.
D2 receptor binding and clinical potency

D2 receptor binding and clinical potency

D1 & D2 receptors in schizophrenia

There are significantly more D2 receptors in the brains of deceased schizophrenics than in nonschizophrenic controls.
There is no significant difference in the number of D1 receptors in schizophrenic and control brains.
D1 and D2 receptors in schizophrenic brain

D1 and D2 receptors in schizophrenic brain

Supplementary material

I strongly recommend the chapter Schizophrenia as a model of dopamine dysfunction in Hamilton & Timmons online book Drugs, Brains and Behavior
For simplicity in my lecture, I only discuss two dopamine receptors. This is intentional. But you should be aware that there are more than two recptor types. This page by James H. Meador-Woodruff, M.D. has images which summarize the distributions of five dopamine receptors found in normal human brain.

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