How the Dopamine Works With Partial Agonism

How the Dopamine Works With Partial Agonism Schizophrenia Print How Antipyschotic Dopamine Works With Partial Agonism By Adrian Preda, MD Medically reviewed by Medically reviewed by Steven Gans, MD on August 05, 2016 Steven Gans, MD is board-certified in psychiatry and is an active supervisor, teacher, and mentor at Massachusetts General Hospital. Learn about our Medical Review Board Steven Gans, MD Updated on January 31, 2020 More in Disorders Schizophrenia Addiction ADHD Eating Disorders Social Anxiety Disorder Bipolar Disorder BPD Depression OCD GAD Panic Disorder PTSD View All In this article, you will learn about dopamine partial agonism. This effect is best illustrated by aripiprazole (brand name: Abilify), a second-generation antipsychotic/atypical neuroleptic that stands apart from all the other atypical antipsychotics due do a different mechanism of action. How Aripiprazole Is Different From Other Atypicals Most atypical antipsychotics have a clear effect of the brain serotonin receptors but a rather weak and limited effect on the brain dopamine receptors. Aripiprazole is different than most of the other atypicals with regards to its mechanism of action. In essence, aripiprazole works via dopamine. Thus, from the point of view of it works, aripiprazole is closer to typical or first-generation neuroleptics, which share the blocking of dopamine in the brain (so-called dopamine antagonism) as a common mechanism of action. If Aripiprazole Works on Dopamine Why is it 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 which 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. Partial Dopamine Agonists A partial dopamine 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 partial dopamine 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 partial dopamine agonist) by taking the dopamine space on the receptors and activating them only partially will actually take down the effect of the too much 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 partial dopamine 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).