The theory is that postsynaptic dopamine receptors can be configured in different states (called high/low for convenience) and that it is the "high" states that lead to supersensitivity.

If you don't mind amateurish answer, then I'd like to say that I believe it's possible.

Post-mortem findings in patient with schizophrenia often reveal thinning brain and widening ventricle. It's a bit hard to make connection between decreasing cell and presynaptic "hyper"function. Of course, there are opinions about excitotoxicity, but it also means that those presynaptic cells should be "excited/triggered by something else".

I believe that there may be some signal by postsynaptic cell to convey that it needs connection from dopaminergic presynaptic neuron, so much that they continue to fire excessively despite general lack of neuron in the brain; even when postsynaptic neuron does not increase it's total receptor.

If we link it to theory of substance abuse, we may need to go beyond "firing or not firing", but more toward "phasic firing and tonic firing." Even if the receptor amount is the same, we can't say the same effect is produced during different phases. Maybe the receptor is later downregulated because of excessive phasic firing?

I believe we can have many more possible scenarios than actual proof, but who knows what future may bring?

Afkar Aulia

Psychiatry resident

May V. Seeman:

Thank you for the reply directly from the author! I know it's about high-affinity dopamine receptors, but very little is written about it!

Afkar Aulia:

A few years ago I thought I understand dopamine theories very well. Now I feel like I understand very little :) Thank you for the answer. It is certainly a very complex issue.

What do you think of this possibility (although it's unproven and very loosely connected to your question)?

Schizophrenia is connected to dopaminergic learning process. In mice, we have understood that dopaminergic manipulation affects it's ability to "learn pulling a lever to get food". However, in human, "pulling a lever" can be associated to various activity, ranging from "making a smile", "getting money", to "developing complicated computer program". Curiously, hallucination and delusion is related to certain social role, instead of simply "heightened perceptive stimulation associated to dopamine".

What if human develops those self-rule and abide to them to get reward as final pathway? It may be related to Freud's oral phase, such that human baby learns a new rule when being fed, and if the rule is completed, the adult human will feel the sensation of reward. The original direct mesolimbic dopaminergic pathway of certain rule is eventually redirected to indirect dopaminergic pathway (probably through prefrontal cortex or other area) toward limbic area.

What if schizophrenia is a "short-circuitting" of this learning process? When human undergoes stress, many of those self-developed rule is unfulfilled, resulting in low reward in limbic system. Limbic system is then seeking for reconnection of previously deactivated direct pathway, probably through back-signalling.

VTA is then reactivates abnormal direct pathway or it will send axon collateral from unrelated direct pathway or limbic area may increase sensitivity of it's postsynaptic receptor.

However, since indirect pathway for that particular rule is already established, it becomes a short-circuit. The presynaptic dopamine receptor serving as "brake" would be increased, while post synaptic total receptor is the same since overall reward is decreased instead.

Probably, before reward is given, the pathway requires the providence of evidence that the rule is done or the rule's problem is caused by outer factor. However, because of the "short-circuit", the reward is already given, and the body will think that "Since the reward is here, then the cause must have happened". The brain is tricked into thinking that the evidence of rule enactment or the evidence that it's someone else's fault is already processed. It will result in hallucination for short term, and result in delusion when the hallucination and thought process is further analyzed.

I'm currently trying to write this with more thorough indirect evidence.