How Dopamine Receptor Partial Agonism Works as an Antipsychotic

In this article, you will learn about dopamine partial agonism. This effect is best illustrated by Abilify (aripiprazole) and and Rexulti (brexipiprazole). These second-generation antipsychotic/atypical neuroleptics stand apart from all the other atypical antipsychotics due to a different mechanism of action.

How Is Aripiprazole Different?

The majority of second-generation (atypical) antipsychotics block the D-2 (dopamine-2) receptors but also usually equally as much block the 5HT-2a (serotonin-2a) receptors). The second-generation antipsychotics such as risperidone, ziprasidone, and paliperidone are all potent antagonists of dopamine D2 receptors while clozapine and quetiapine are weak D2 antagonists. 

Depending on endogenous dopamine levels and signaling status, aripiprazole may act as a full antagonist, a moderate antagonist, or a partial agonist at dopamine D2 receptors (D2Rs), consistent with purported biased ligand pharmacology.

The efficacy of aripiprazole can be mainly attributed to this combination of partial agonism/antagonism at D2Rs and serotonin 5-HT1A receptors, together with antagonism at serotonin 5-HT2A receptors.

Why Is Aripiprazole Classified as an Atypical?

The reason is aripiprazole’s clinical action: its risk for certain neurological adverse effects such as episodes of acute muscular rigidity (dystonia) or involuntary abnormal movement disorders (dyskinesia) is low, which earns it accolades as an atypical; as opposed to antipsychotics with a high risk for this type of adverse effects, which are classified as typicals.

Aripiprazole is a dopamine partial agonist as opposed to a dopamine antagonist or blocker like most first-generation antipsychotics.

Dopamine Antagonism

Dopamine is one of the neurotransmitters found at the level of the synaptic space, space in-between neurons. Dopamine is released in the synaptic space from vesicles housed in the pre-synaptic neuron, then binds to dopamine receptors at the level of the postsynaptic neuron. Think of this as a key and lock type of effect where dopamine receptors are locks that open when the dopamine “key” enters the lock.

One of the hypotheses of schizophrenia is that in certain parts of the brain there is too much dopamine in the synapse. The positive symptoms of schizophrenia are thought to be a result of all these “extra” dopamine molecules binding to dopamine receptors.

Dopamine antagonists bind to the dopamine receptors, thus block dopamine binding. And without the proper key, i.e. dopamine, the lock does not open; in other words, as the dopamine excess problem is corrected at the level of the synapse there are no ill effects (positive symptoms) resulting from it.

The problem though is that the dopamine blockade occurs all over the brain while the dopamine excess in schizophrenia is limited to specific parts of the brain. Further, in schizophrenia, while some parts of the brain are subject to dopamine excess, other parts are in fact experiencing a dopamine deficit.

Dopamine antagonists do not only block receptors in places where there is too much of it but also in places where there is not enough dopamine.

This is why these medications, while effective for positive symptoms due to blocking of receptors in brain regions having too much dopamine, tend to also increase negative symptoms, cognitive issues, as well as the risk for parkinsonism in patients taking them, due to blocking of dopamine in brain regions where there is too little dopamine. A potential solution to this problem is using partial agonists.

Dopamine Partial Agonists

A dopamine partial agonist is a molecule that binds to the receptor and partially activates it. Think about it as a key that sorts of fit in the lock so that the door can be wriggled about but not completely open.

The effect of a dopamine partial agonist is less than the full effect of dopamine but more than a complete lack of effect, which is what happens when a receptor is completely blocked. In other words, a partial effect.

This partial effect means that when there is too much dopamine around aripiprazole (a dopamine partial agonist) by taking the dopamine space on the receptors and activating them only partially will actually take down the effect of the excess dopamine.

It also means that in situations when there is too little dopamine around to activate all the available receptors aripiprazole will actually bind to unoccupied receptors and its effect, even if only partial, is now added to the dopamine effect in the synapse for a net increase of the dopaminergic effect of a dopamine-deprived synapse.

To summarize, aripiprazole, as a dopamine partial agonist, acts as a modulator of dopamine effects. When present, it diminishes the effects of both dopamine excess (by decreasing dopamine action when there is too much of it) and deficit (by increasing dopamine action when there is too little of it).

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