Why do antipsychotics bind to D2-like instead of D1-like receptors?

Question

My understanding is that:

1. The dopamine hypothesis of schizophrenia states that the positive symptoms are a result of excessive neurotransmission of dopamine in the mesolimbic pathway.
2. D1-like receptors have an excitatory effect on the postsynaptic neuron, while D2-like receptors have an inhibitory effect.
3. The goal of first-generation antipsychotics is to block D2-like receptors so that dopamine cannot bind to them, which prevents the typical postsynaptic response.

Given the above, I would expect that preventing dopamine from binding to D2-like receptors would lead to an increase in the probability that the postsynaptic neuron will fire, which would increase dopamine neurotransmission along the pathway. On the other hand, it would make sense to me if antipsychotics blocked D1-like receptors, since those have an excitatory effect. What am I missing here? Am I oversimplifying the effects of D2-like receptor activation?

Answer 1

There is a difference between the excessive transmission of dopamine and excessive neuron firing. The first can mean that a lot of dopamine will inhibit or excite neurons and cause them to fire more or less (depending on the neuron), but the second one means that the neuron is firing too much, which may be where your confusion lies!

Usually, the words misregulated or misfiring neurons are used to reduce confusion - we try to show that whatever the element of the brain is doing, it is not what it is supposed to be: too much or too little. Schizophrenia often involves a misregulated dopamine system, among other changes.

Here's a paper to describe the mechanisms of D2 receptors: Ford CP. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience. 2014 Dec 12;282:13-22. doi: 10.1016/j.neuroscience.2014.01.025. Epub 2014 Jan 23. PMID: 24463000; PMCID: PMC4108583.

And this one for the specific role of antipsychotics on d2 receptors: Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002 Feb;47(1):27-38. PMID: 11873706.