Agonist and Antagonist Effects of Aripiprazole on D2-Like Receptors Controlling Rat Brain Dopamine Synthesis Depend on the Dopaminergic Tone

Abstract

Background:The atypical antipsychotic drug aripiprazole binds with high affinity to a number of G protein coupled receptors, including dopamine D2 receptors, where its degree of efficacy as a partial agonist remains controversial.Methods:We examined the properties of aripiprazole at D2-like autoreceptors by monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo. The effects of the dopaminergic tone on the properties of aripiprazole were assayed by comparing a basal condition (2mM K+, low dopaminergic tone) and a stimulated condition (15mM K+, where dopamine release mimics a relatively higher dopaminergic tone). We also used 2 reference compounds: quinpirole showed a clear agonistic activity and preclamol (S-(-)-PPP) showed partial agonism under both basal and stimulated conditions.Results:Aripiprazole under the basal condition acted as an agonist at D2-like autoreceptors and fully activated them at about 10nM, inhibiting dopamine synthesis similarly to quinpirole. Higher concentrations of aripiprazole had effects not restricted to D2-like autoreceptor activation. Under the stimulated (15mM K+) condition, nanomolar concentrations of aripiprazole failed to decrease dopamine synthesis but could totally block the effect of quinpirole.Conclusions:Under high dopaminergic tone, aripiprazole acts as a D2-like autoreceptor antagonist rather than as an agonist. These data show that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D2-like autoreceptors. Such unusual effects were not seen with the typical partial agonist preclamol and are consistent with the hypothesis that aripiprazole is a functionally selective D2R ligand.

Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity

“…There is evidence that aripiprazole functions as both a presynaptic D2 agonist and post synaptic D2 antagonist [ 7 , 99 , 100 ]. Presynaptic D2 autoreceptors may play a vital role in the ability of aripiprazole to act as a DA system stabilizer, but at higher doses (such as the ones used to treat schizophrenia), aripiprazole also has a significant binding affinity at post synaptic D2 receptors [ 145 ].…”

“…Presynaptic D2 autoreceptors may play a vital role in the ability of aripiprazole to act as a DA system stabilizer, but at higher doses (such as the ones used to treat schizophrenia), aripiprazole also has a significant binding affinity at post synaptic D2 receptors [ 145 ]. A study by Ma and colleagues (2015) investigated the agonist and antagonist effects of aripiprazole on D2 like receptors by measuring DA synthesis [ 7 ]. Under basal conditions, aripiprazole acted as a D2 autoreceptor agonist at 10nM as evidenced by the ability to inhibit DA synthesis in a similar manner to quinpirole [ 7 ].…”

“…A study by Ma and colleagues (2015) investigated the agonist and antagonist effects of aripiprazole on D2 like receptors by measuring DA synthesis [ 7 ]. Under basal conditions, aripiprazole acted as a D2 autoreceptor agonist at 10nM as evidenced by the ability to inhibit DA synthesis in a similar manner to quinpirole [ 7 ]. Aripiprazole has also been successful at reducing reserpine induced increases in DOPA accumulation in the rodent forebrain, and at the same dose was able to inhibit apomorphine induced hyperlocomotion [ 11 ].…”

“…Presynaptic agonist activity was evidenced by a decrease in tyrosine hydroxylase activity following aripiprazole administration and the drug displayed post synaptic D2 antagonism by inhibiting apomorphine induced hyperlocomotion [ 11 ]. These results suggest aripiprazole may act as a presynaptic D2 agonist and a postsynaptic D2 antagonist, which could account for the high treatment efficacy in the absence of significant EPS [ 7 , 11 , 12 ].…”

“…The drug is generally considered to be a partial agonist at 5-HT1A and DA D2 receptors, and an antagonist at the 5-HT2A [ 10 ]. However, there is evidence that aripiprazole has a unique pharmacological profile at D2 receptors that expands beyond partial agonism to include functionally selective effects on intracellular signaling pathways [ 7 , 8 , 11 , 12 ], suggesting that the pharmacological profile of aripiprazole is more complicated than originally thought. Other reviewers have reached similar conclusions regarding the functionally selective actions of aripiprazole [ 13 ].…”