1. Antipsychotics: The Essentials Module 2 Mechanism of Action of Aripiprazole
In this section of module 2 I present the mechanism of action of aripiprazole.
As most conceptions in psychopharmacology, the mechanism I’m going to explain is based on theories on how antipsychotic agents might work.
Flavio Guzmán, MD

2. Aripiprazole is a partial agonist that acts on mesolimbic and mesocortical dopamine pathways.
Let’s begin by a sentence that summarizes this section.
Aripiprazole is a partial agonist that acts on mesolimbic and mesocortical dopamine pathways.

3. What is an partial agonist?
A partial agonist is a drug that binds to and activates a given receptor, but provokes a fraction of the response relative to a full agonist.
Here you can see a dose-response curve, showing in the x axis drug dose and in the y axis the response to activation.
An antagonist binds to the receptor, but doesn’t produce any response, as you can see in the flat line.
In terms of response,a partial agonist is halfway between an antagonist and a full agonist. As you can see in this illustration, the partial agonist stimulates a response that isn’t as high as the response of a full agonist.

4. Aripiprazole as partial agonist
This is a simplified version of the concept I just illustrated, in this figure we can see three different molecules binding the D2 receptor.
The first is a full agonist, dopamine, which is the natural endogenous ligand for D2 receptors. The full agonist elicits an optimal response, this is depicted as a full signal.
The second is aripiprazole, it binds to the D2 receptor with the same affinity but has a lower intrinsic efficacy, so the response it triggers is lower than dopamine, but higher than an antagonist.
The third is a first generation antipsychotic. Most antipsychotics are D2 antagonists, they bind to the receptor but have zero intrinsic activity.

5. Partial agonism in the mesolimbic pathway
In this section we’ll review the theory that postulates that aripiprazole reduces positive symptoms of schizophrenia by lowering an excessive dopaminergic neurotransmission in the dopamine mesolimbic pathway.

6. Dopamine Activity in Healthy Individuals
Dopaminergic neurotransmission
Maximal Activity
Normal Activity
Let’s see in this slide dopamine activity in a person who’s not suffering from schizophrenia.
We have in the left the mesolimbic pathway, showing projections from the ventral tegmental area to the nucleus accumbens. In the right, a figure illustrating dopaminergic neurotransmission at this pathway.
Dopaminergic activity is shown in the y axis, it ranges from basal to maximal. The x axis shows drug concentration in logarithmic scale.
Under normal circumstances, dopamine activity in the mesolimbic pathway is in between basal and maximal activity, as you can see in the green line.
Basal Activity
log [drug]
Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:

7. Schizophrenia: overactivity of the mesolimbic pathway
Dopaminergic neurotransmission
Maximal Activity
Schizophrenia
What happens in the mesolimbic pathway of a person with schizophrenia?
As we saw in the dopamine pathways section, the dopamine theory of schizophrenia postulates that positive symptoms such as hallucinations, delusions and thought disorder might be caused by an excessive activation of the mesolimbic pathway.
The right figure in this case shows in red dopamine activity in schizophrenia. It’s clearly above the normal green neurotransmission, closer to the maximal activity.
Basal Activity
log [drug]
Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:

8. Aripiprazole therapy Dopaminergic neurotransmission
Dotted sigmoidal line: actions of partial agonist in the presence of endogenous concentrations of dopamine.
Maximal Activity
Schizophrenia
How does aripiprazole act on the mesolimbic pathway to reduce psychotic symptoms of schizophrenia?
Take a look at the green sigmoidal line, you can see how it lowers dopamine neurotransmission from high activity to normal activity.
This line represents aripiprazole action in the presence of endogenous dopamine.
You might be wondering, what does the grey line represent? It shows aripiprazole action in the absence of dopamine.
Basal Activity
log [drug]
Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:

9. Partial agonism in the mesocortical pathway
In this section we’ll review the theory that postulates that aripiprazole could reduce symptoms of schizophrenia by increasing dopamine activity in the mesocortical pathway.

10. Dopamine Activity in Normal Circumstances
Dopaminergic neurotransmission
Maximal Activity
Normal Activity
This is the mesocortical pathway in healthy individuals , this pathway runs from the ventral tegmental area to the cortical areas, mainly the prefrontal cortex.
In healthy individuals, dopaminergic neurotransmission is a balance between basal and maximal activity, at a normal range.
Basal Activity
log [drug]
Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:

11. Dopamine System in Schizophrenia
Maximal Activity
Normal Activity
The dopamine theory of negative and cognitive symptoms suggests that there is a hypofunction of dopaminergic neurotransmission in the mesocortical pathway. This is depicted here as a red line showing dopaminergic activity in subnormal levels.
Schizophrenia
Basal Activity
log [drug]
Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:

12. Aripiprazole Therapy Dopaminergic neurotransmission Maximal Activity
Normal Activity
This slide shows a change in dopamine activity after aripiprazole therapy. The sygmoidal green curve shows how aripiprazole can increase dopaminergic activity from a subnormal level to normal activity in the mesocortical pathway.
Schizophrenia
Basal Activity
log [drug]
Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:

13. Aripiprazole effects on other dopamine pathways
Tuberoinfundibular Pathway
Nigrostriatal Pathway
The lack of antagonism on the tuberoinfundibular pathway and the nigrostriatal pathway gives aripiprazole advantages over other antipsychotics in terms of lower risk of hyperprolactinemia and extrapyramidal symptoms.
Less risk of hyperprolactinemia
Less risk of EPS

14. Other pharmacological properties
Other pharmacological properties include 5HT1A partial agonism and 5HT2A antagonism.

15. Key Points Aripiprazole is a partial agonist at D2 receptors.
It may act as an antipsychotic by:
Lowering dopaminergic neurotransmission in the mesolimbic pathway.
Enhancing dopaminergic activity in the mesocortical pathway.
It has a lower risk of EPS and hyperprolactinemia than other antipsychotics.
Aripiprazole is a partial agonist at D2 receptors.
It may act as an antipsychotic by:
Lowering dopaminergic neurotransmission in the mesolimbic pathway.
Enhancing dopaminergic activity in the mesocortical pathway.
It has a lower risk of EPS and hyperprolactinemia than other antipsychotics.

16. References and further reading
Mailman RB, Murthy V. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Current pharmaceutical design 2010;16:
Brunton LB, Lazo JS, Parker KL, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2010.
Stahl, S M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambrigde University Press; 2008