Which effect would be considered to be agonistic

Indeed, aripiprazole dose dependently reduced the firing rate of serotonin-containing dorsal raphe nuclei, an action that was reversed by a 5-HT1AR antagonist [ 57 ]. These data suggest that the inhibition of serotonin neuronal activity by aripiprazole is mediated by its agonist action on somatodendritic 5-HT1AR autoreceptors located onto dorsal raphe serotonergic neurons. The full agonistic activity may be explained by the large 5-HT1AR reserve in these nuclei and may be relevant to the global pharmacological action of aripiprazole.

Dorsal raphe serotonergic neurons provide major afferent projections to the frontal cortex. Agonist action on somatodendritic 5-HT1ARs reduces serotonin release in the cortex, which in turn stimulates dopamine release therein [ 58 ], an action that may be beneficial for negative and cognitive symptoms of schizophrenia. Notably, impairment in recognition memory induced by repeated phencyclidine administration was ameliorated by aripiprazole, whose beneficial effects were in turn abolished by co-administration of a D1R antagonist and a 5-HT1AR antagonist [ 59 ].

Aripiprazole also improved social behavior deficits caused by repeated phencyclidine, an effect that was prevented by pretreatment with a 5-HT1AR antagonist [ 60 , 61 ].

Moreover, aripiprazole appears to inhibit marble-burying behavior, an animal model of obsessive compulsive disorder, via its action on 5-HT1ARs.

This biphasic effect may depend on the prevalence of agonistic 5-HT1AR-mediated effects at low doses, and the prevalence of inhibition of mesocortical dopaminergic neurons activity at high doses [ 65 ].

From a translational perspective, the action of aripiprazole at 5-HT1ARs has been associated with a potential modulation of cognitive effects [ 67 , 68 ]. In C6-glioma cells expressing low levels of endogenous 5-HT1ARs, aripiprazole induced phosphatidyl-inositol PI hydrolysis only at the highest concentrations and significantly less than did serotonin, while in 5-HT1AR-transfected GF62 cells, expressing high levels of the receptors, aripiprazole still behaved as a partial agonist but with a slightly higher intrinsic activity [ 36 ].

The effects on serotonin levels were reversed by high, but not low, concentrations of aripiprazole [ 65 ], a finding in apparent agreement with a partial agonist activity on 5-HT1ARs. However, in rat P11 cells expressing 5-HT1ARs linked to the PI signaling, the effects of serotonin on this pathway were potently blocked by aripiprazole, as well as by other antipsychotics with known antagonist activity at 5-HT1ARs, including risperidone, clozapine, and haloperidol [ 57 ].

In behavioral assays, aripiprazole inhibited the wet-dog shake responses and ameliorated the disruption in pre-pulse inhibition induced by DOI [ 71 ]. These data suggest that aripiprazole may behave as a full 5-HT1AR antagonist in vivo.

The effects at 5-HT2CRs strongly depended on the system under consideration. Agonism at 5-HT2CRs has been considered beneficial to reducing appetite and preventing drug-induced weight gain.

According to these considerations, a statistically significant weight increase was found when aripiprazole was combined with high serotonergic antidepressants [ 72 ], possibly due to the elevation of serotonin tone by these latter compounds.

Intriguingly, the same effect was not observed when aripiprazole was combined with low serotonergic activity antidepressants. Finally, a relevant translational issue dealing with the complexity of the receptor profile of aripiprazole is the co-administration of this agent with other psychotropic compounds, a drug combination frequently used in clinical practice to address multiple dimensions of severe psychiatric diseases such as schizophrenia and bipolar disorders, or to counteract the onset of antipsychotic-resistant schizophrenia.

For instance, the combination of clozapine and aripiprazole may lead to greater D2R antagonism in mesolimbic pathways and, additionally, may combine D2R and D4R antagonism [ 73 ]. Prolonged i. Notably, even at the highest dose and with very high levels of D2R occupancy, a low occurrence of EPS was observed in the subjects.

The relatively low rate of EPS, even with the high aripiprazole-induced D2R occupancy, represents a specific hallmark of the compound, and places aripiprazole in a stand-alone class among antipsychotic compounds. Indeed, low rates or lack of EPS have also been reported with clozapine and quetiapine, a feature that has been attributed to their fast-off kinetics from D2R binding [ 76 ]. However, both compounds are known to reach only low-to-intermediate levels of striatal D2R occupancy [ 74 , 77 ].

Aripiprazole dose and plasma concentration showed a linear correlation with striatal D2R occupancy. Conversely, drug occupancy was lower for 5-HT2ARs and the lowest for 5-HT1ARs in the temporal and frontal cortices, and there was no relationship with aripiprazole dose or plasma concentration.

Notably, previous studies using 18 F-fallypride have shown that clozapine in a certain dose range can have higher D2R binding in the temporal cortex compared with the striatum [ 80 ], leaving the mechanism behind this observation and its clinical meaning to be clarified. One possible explanation of the slight but significantly higher extra-striatal binding in the temporal cortex compared with the striatum may be the higher concentration of dopamine in the striatum and therefore the higher competition with the radioligand binding to D2Rs.

Remarkably, an ex vivo study of synaptic plasticity genes showed a specific pattern of expression of inducible and constitutive postsynaptic density genes in extra-striatal tissues, i.

However, a more recent PET study, using 11 C- S - N - 1-ethylpyrrolidinyl methyl bromo-2,3-dimethoxybenzamide FLB as the radioligand for extra-striatal D2Rs and 11 C-raclopride for striatal D2Rs, failed to support the previous observations on higher extra-striatal D2R occupancy by aripiprazole, and, moreover, showed higher striatal occupancy [ 82 ].

Despite providing intriguing data, these studies did not clarify whether and how aripiprazole may affect the presynaptic dopaminergic function in vivo. No significant changes in the synthesis capacity of dopamine by aripiprazole were found. This observation sharply contrasted with preclinical studies reporting an increase in dopamine synthesis by the compound [ 84 ], a discrepancy most likely depending on the differences in administration, dose and duration of treatment in the different clinical versus preclinical paradigms.

However, most relevantly, the authors found significant negative correlations between baseline dopamine synthesis capacity and the percentage changes in dopamine synthesis capacity after the single aripiprazole administration regimen [ 83 ]. This observation suggests that aripiprazole increases dopamine synthesis in subjects with low baseline dopamine levels and decreases it in subjects with high baseline levels, again providing strong support for a functionally selective action on dopamine receptors and its translational relevance in dopamine dysfunctional pathophysiology.

Aripiprazole-mediated changes of the neuronal transcriptome in relevant biological functions have been studied with gene expression analysis. These studies have also found substantial differences in transcriptome changes between aripiprazole and the other antipsychotics, which corroborate the view that aripiprazole impacts distinctive neurobiological pathways compared with traditional antipsychotics.

Table 2 summarizes the most relevant studies on aripiprazole-mediated gene expression in the central nervous system. Effects of aripiprazole on gene expression in the central nervous system. This table summarizes the most relevant studies on aripiprazole-mediated gene expression in the central nervous system.

Aripiprazole has been observed to differentially modulate the expression of genes implicated in dopaminergic signaling in brain areas belonging to mesolimbic versus nigrostriatal dopamine pathways.

Indeed, week treatment with an oral dose of aripiprazole 2. Conversely, haloperidol has been found to increase the binding density of D2Rs in the nucleus accumbens and caudate putamen, as well as to decrease dopamine transporter DAT binding in these two areas and in the VTA.

Therefore, these results suggest that aripiprazole has more selective effects on the mesolimbic dopaminergic pathway than haloperidol and olanzapine [ 85 ]. Earlier studies also demonstrated that aripiprazole may significantly reduce D2R gene expression in the rat pituitary, whereas haloperidol increases both D2R and prolactin mRNAs [ 86 ], thus providing molecular ground for the clinical observation that aripiprazole may be beneficial in reducing antipsychotic-induced hyperprolactinemia [ 87 ].

Aripiprazole has been also shown to impact gene expression related to neurotransmitter systems other than dopamine. However, these effects do not last after chronic aripiprazole administration [ 88 ]. Moreover, unlike olanzapine, aripiprazole has been demonstrated not to impact H1R mRNA expression in the arcuate hypothalamic nucleus, which is directly correlated with food intake and weight gain associated with antipsychotics [ 89 ]. Increased expression of muscarinic M1 receptors M1R mRNA in the hippocampus and nucleus accumbens has been reported with both sub-chronic and chronic aripiprazole administration in rats, with no impact on nigrostriatal M1R expression, which may be modulated by olanzapine and haloperidol [ 90 ].

With regards to GABAergic neurotransmission, chronic aripiprazole has been demonstrated to reduce mRNA expression of the glutamic acid decarboxylase GAD67 gene, which codes for the predominating enzyme that synthesizes GABA, in the caudate putamen, prefrontal cortex, and somatosensory cortex, whereas GAD67 gene expression may be induced in the hippocampus, hypothalamus, thalamus, and amygdala.

Several other significant changes were found in mRNA expression of the genes coding for the vesicular GABA transporter Slc32a1 , and the transmembrane transporter Slc6a1 and Slc6a11 [ 91 ].

Aripiprazole has been demonstrated to affect the expression of genes coding for glutamate transporters. Specifically, chronic aripiprazole may suppress mRNA expression of the glial excitatory amino acid transporter genes EAAT1 and EAAT2 and of the neuronal transporter EAAT3 in hippocampal sub-regions and of EAAT4 in the frontal cortex, whereas it may enhance the expression of the presynaptic vesicular glutamate transporter vGluT1 in the hippocampus [ 93 ], thus strengthening glutamate neurotransmission in these areas.

Overall, the above-mentioned gene expression studies showed that aripiprazole may exert complex dose- and time-dependent effects on multiple neurotransmitter systems beyond the aripiprazole receptor profile, as they also involve systems, such as the glutamatergic system, that are not directly targeted by the compound. These studies suggest that a wide and yet to be fully characterized range of molecular effects are induced by aripiprazole in the central nervous system, and allow the hypothesis that these effects may be more useful to explain the global therapeutic efficacy and long-term neurobiology of the compound beyond its receptor profile.

Indeed, recent microarray and quantitative real-time polymerase chain reaction qRT-PCR studies have identified multiple genes modulated by aripiprazole [ 94 ], including the up-regulation of early growth response genes 1, 2, 4 Egr1, Egr2, Egr4 , chromobox homolog 7 Cbx7 , cannabinoid receptor Cnr1 , catechol- O -methyltransferase Comt , protein phosphatase 2c, magnesium-dependent Ppm2c , tachykinin receptor 3 Tacr3 , Wiskott—Aldrich syndrome-like gene Wasl , and DNA methyltransferase 3a Dnmt3a [ 94 ].

Gene expression analysis has also demonstrated the impact of aripiprazole on molecules implicated in synaptic plasticity [ 95 ]. Several studies have reported that aripiprazole may modulate the expression of Homer family genes, which are synaptic plasticity-related genes encoded in distinct isoforms, including inducible i. Homer1a and ania-3 and constitutive i. Homer proteins are implicated in downstream glutamatergic signaling and in architectural and functional molecular adaptations within the postsynaptic density microdomain of dendritic spines [ 1 , 98 ].

The inducible early gene Homer1a is significantly induced by antipsychotics according to their antidopaminergic profile [ 99 — ], and its expression is significantly modulated by selective blockade of D2Rs [ ] as well as by compounds acting on the glutamatergic system [ , ].

After acute administration, mRNA expression of Homer1a may be significantly induced in the rat caudate putamen by low doses of aripiprazole, whereas cortical gene expression may be only induced by high doses of aripiprazole [ 81 ].

Chronic treatment with aripiprazole induces Homer1a mRNA expression in both the cortex and the lateral striatum [ 81 ]. These data demonstrate that aripiprazole has a strong impact on plasticity-related genes, in either acute or chronic administration paradigms, and highlight the differential modulation of Homer1a by aripiprazole compared with compounds regulating dopaminergic neurotransmission differently, such as haloperidol, which prevalently stimulates Homer1a striatal expression, or clozapine, which has a predominantly cortical impact on gene expression [ 68 ].

Recent evidence suggests that aripiprazole may also indirectly modulate glutamatergic signaling in key brain areas for antipsychotic therapy, such as the lateral striatum and the anterior cingulate cortex.

Among proteins that have been linked to abnormal synaptic plasticity believed to be involved in schizophrenia is neuregulin 1 NRG1 , a family of epidermal growth factor EGF -like domain-containing trophic factors [ ] interacting with ErbB-4 receptor and strictly linked to the postsynaptic density PSD function.

NRG1 gene has been identified as a schizophrenia susceptibility gene in different populations [ ], and the downregulation of nrg1 in mice expressing high levels of the protein is able to counteract the psychotic-like behavioral abnormalities of these animals [ ].

A link between NRG1 and D2Rs in controlling psychotic-like behavior in rodents has recently been shown [ ]. Distinct temporal and spatial downregulation may be induced by chronic aripiprazole, olanzapine, or haloperidol treatment on different NRG1 isoforms, thus confirming the unique features of functional selectivity among antipsychotic drugs [ ]. Although schizophrenia has often been considered a disrupting disorder with a natural course of illness that is difficult to predict and depends strongly on individual variability [ ], for the most part current evidence shows that antipsychotic medications are still the mainstay treatments for this disease and that continuing therapy may prevent a large percentage of relapses [ ].

Moreover, non-optimal adherence or withdrawal from antipsychotic therapy has been classified as an unequivocal risk of relapse, with a progressively worse outcome [ ]. The beneficial effects of a long treatment duration on the pathophysiology of the disease as well as on dopamine dynamics may be largely improved by continuous treatment with antipsychotics in the LAI formulation. Development of LAI antipsychotics started in the s with the aim of overcoming non-adherence [ ].

However, a large body of evidence highlights the slight differences in effectiveness, as well as the non-significant advantages, between oral and long-acting antipsychotics [ ], although mirror studies in patients eligible for LAI antipsychotics demonstrate a significant superiority of LAI over daily administration of oral antipsychotics.

However, methodological issues should be taken carefully into consideration when discussing the results of studies comparing oral and LAI antipsychotic formulations. A recent meta-analysis of randomized controlled trials RCTs assessing the benefits of LAI over oral antipsychotics failed to find significant differences between the two types of formulations in multiple primary and secondary outcome measures, including prevention of relapse at the longest and at intermediate time-points, all-cause discontinuation, drug inefficacy, and non-adherence [ ].

Nonetheless, the authors of this meta-analysis cast substantial doubts on the reliability of RCTs as the best method to study the issue. It appears that standard RCTs may not be the most correct method to compare these two types of formulations; trial participants may over-represent patients with a good engagement with healthcare providers and who are more likely to be adherent than patients in naturalistic conditions [ ].

On the other hand, naturalistic and mirror studies may represent a more reliable design for affordable comparisons [ , ]. Mirror studies compare a period of LAI treatment and oral antipsychotic treatment in the same patients and therefore might better capture potential differences in the outcomes considered [ ]. However, preclinical studies have repeatedly reported significant, although often conflicting, differences in transient oral or injected antipsychotic administration compared with continuous infusion by means of appropriate devices e.

In both human and animal studies, when defining the action of a particular antipsychotic drug, considerable attention is given to the threshold of occupancy of D2Rs reached by this drug that correlates with clinical and side effects, and may also be useful to differentiate each drug and to understand its molecular actions [ ]. Preclinical animal studies have demonstrated that both first-generation and second-generation antipsychotics when administered in continuous infusion by means of minipumps, despite reaching a lower occupancy of D2Rs than transient injections, induce higher rates of EPS [ , ].

Moreover, Samaha et al. These findings may be attributable to an increase in high-affinity state striatal D2R numbers achieved by continuous treatment compared with transient treatment. Furthermore, it seems also that postsynaptic effects might be different if equivalent doses of drugs are administered with different kinetics. In the same experiments, the authors found that only transient haloperidol may activate striatal c-fos mRNA expression [ ]. Moreover, this lower occupancy does not always correspond to reduced control of symptoms, thereby suggesting that high rates of D2R occupancy are not needed for maintenance therapy.

However, clinical studies comparing oral with LAI antipsychotics have often produced contrasting results, some showing lower efficacy and higher propensity for inducing side effects in the continuous treatments [ ], and some showing pronounced superiority of the LAI drugs compared with oral drugs [ ]. In summary, recent evidence demonstrates that new LAI formulations appear to be equal or superior to their oral equivalent drugs, whereas old depot formulations may have a higher propensity for inducing side effects and lower efficacy compared with the corresponding first-generation antipsychotics [ ].

In a recent double-blind RCT, an aripiprazole LAI formulation demonstrated significantly higher efficacy than placebo and a good tolerance in maintenance therapy for schizophrenic patients [ ]. Moreover, its non-inferiority compared with oral aripiprazole was also demonstrated [ ], as well as its safety and tolerability in patients previously stabilized with other antipsychotics [ ]. Despite the potentially strong interest for clinical applications, only a few studies have been performed to investigate the effects of continuous administration of aripiprazole on dopamine signaling in preclinical paradigms.

In this regard, it can be helpful to first consider the effect of chronic but not continuous i. Different modulation of dopamine neurotransmission between first- and new-generation antipsychotics has been reported. For instance, early studies demonstrated that chronic aripiprazole may exert dopamine antagonist activity at striatal neurons i. Similarly, no effects on prolactin and decreased spiperone binding could be observed in pituitary cells with chronic aripiprazole, whereas haloperidol and sulpiride strongly enhance both parameters [ 86 ].

With regards to dopamine metabolism in the forebrain, microdialysis studies found that acute aripiprazole has no effects on dopamine release in either the medial prefrontal cortex or the striatum, whereas it may strongly increase levels of dopamine extracellular metabolites and inhibit levels of extracellular serotonin metabolites in both regions. These findings differ strongly from those obtained by acute or chronic administration of olanzapine, which both strongly and persistently increases dopamine concentrations and levels of dopamine extracellular metabolites in the medial prefrontal cortex and the striatum [ ].

These effects reveal the intrinsic dopamine-stabilizing characteristics of aripiprazole in chronic paradigms. Moreover, gene expression studies also reported that chronic aripiprazole may activate gene expression programs that differ substantially from other antipsychotics. Recent microarray profiling revealed that 4-week aripiprazole administration at clinically relevant doses may induce differential expression of genes involved in chromatin remodeling and in transcriptional regulation, all of which have been implicated in the pathophysiology of psychosis, such as catechol-O-methyl-transferase COMT or Dnmt3a [ 94 ].

Also, our previous work demonstrated an unusual impact of aripiprazole on synaptic plasticity genes, such as Homer1a.

Indeed, when acutely administered, only relatively low doses of aripiprazole induced striatal expression of Homer1a and its splicing variant ania-3 , similarly to haloperidol, whereas no effects were observed with higher doses [ 81 ]. In contrast, only higher dosages seem to activate Homer1a cortical transcription. Chronic aripiprazole administration, by contrast, persistently upregulated Homer1a expression in the striatum, but concurrently reduced its cortical expression, with similar effects to clozapine [ 81 ].

Interestingly, no effects on D2Rs were reported with chronic aripiprazole in this study. A further study also demonstrated that chronic aripiprazole may attenuate the downregulated expression of brain-derived neurotrophic factor BDNF , glycogen synthase kinase-3 GSK-3beta and beta-catenin, which could be induced by immobilization stress [ ].

Consistently, repeated aripiprazole administration has been reported to modulate the expression of Arc and neuronal PAS domain protein 4 Npsa4 genes, both correlated to neuroplasticity, in an animal model of acute swim stress [ ]. Recently, continuous infusion of aripiprazole via minipumps for 14 days was shown to maintain the levels of D2Rs in rat striatum, and have no impact on locomotor challenge responses to methamphetamine administration, these effects opposing those of haloperidol, which increased both the density of D2Rs and locomotor responses [ ].

These results confirm the lack of impact of chronic aripiprazole, even when administered continuously, on dopamine supersensitivity. Dopamine supersensitivity has been conceptualized as the increase in D2R number or biological action, and may be triggered by persistent reduction of D2R activity, as in the case of chronic treatment with D2R-blocking agents.

However, several other neurobiological mechanisms could be implicated in the phenomenon of dopamine supersensitivity, including gene mutations, brain injury, or drug use [ ]. Notably, it has been observed that a breakthrough psychosis can also occur as the consequence of external stressors in patients treated with low antipsychotic doses [ ]. Whether this condition has to be ascribed to a relapse intrinsic to the natural history of the illness or to a combination of life events and iatrogenic dopamine supersensitivity is an intriguing matter for future studies.

Despite the lack of data, some differences among transient and continuous aripiprazole administration may be inferred from animal behavioral studies. In animal models of cocaine self-administration and subsequent extinction and reinstatement, low doses of aripiprazole administered daily before each self-administration and reinstatement sessions were demonstrated to reduce, yet not prevent, cocaine self-administration, although blocking the reinstatement of cocaine-seeking behavior [ ].

In contrast, when continuously infused, aripiprazole seems to have no significant effects on cocaine self-administration or cocaine choice, whereas acute injection rapidly induces a reduction in seeking behavior, although only at low—intermediate doses [ ].

Therefore, although more studies are needed, these experiments demonstrated the effect of aripiprazole in both acute and chronic paradigms, with different effects at different doses.

Moreover, like other antipsychotics, transient administration produces differential effects than continuous infusion, the kinetics of which are yet to be determined. The role of the duration of treatment with antipsychotics is relevant also for the prediction of antipsychotic response and maintenance of response [ ].

Multiple factors have been suggested as the origin of true treatment resistance to antipsychotics, including, among others, genetic variability in dopamine receptor and other neurotransmitter receptor responsiveness [ — ] and aberrant brain morphology, such as gray matter loss in cortical and sub-cortical regions [ 3 ]. One unmet need in treatment-resistant schizophrenia is the management of progressive loss of effect after successful prolonged treatment.

In other words, after responding to an antipsychotic given at the correct dose for an extended period of time, a patient may experience a relapse with increasing intensity of symptom severity despite good adherence to therapy and without the presence of modifying variables such as drug interactions, or comorbidity with disease that may jeopardize antipsychotic drug treatment [ ].

Even if the mechanism behind this condition is unresolved, one hypothesis that has been strongly backed up by experimental preclinical evidence states that prolonged treatment with antipsychotics that have high affinity for D2Rs may progressively induce increased D2R binding, most probably by increasing the number of high-affinity D2Rs and possibly also D2R maximal specific binding, B max , making the D2Rs more sensitive to dopamine [ ].

Interestingly, it has been postulated that an increased number of high-affinity D2Rs is the common final pathway of multiple and different pharmacological manipulations dopamine antagonists, dopamine indirect agonist, cesarean birth , even those not directly related to the dopamine system, and that the increase in high-affinity D2Rs is a key event in the susceptibility to developing a psychosis-like behavior in animal models of schizophrenia [ ].

If the correlation between an increase in high-affinity D2Rs and progressive reduction in response to antipsychotics is indeed further confirmed, the lack of increase in high-affinity D2Rs after chronic aripiprazole treatment by means of continuous infusion intraperitoneal minipump compared with chronic full antagonist treatment such as haloperidol [ ] may suggest that biased ligands may potentially prevent or delay, in adult animals but not in juvenile rodents [ 84 ], the postulated consequences of the increase in high-affinity D2Rs, such as the onset of resistance to antipsychotic treatment after a period of adequate response.

This observation should be considered together with the finding that repeated administration of aripiprazole produces, as with other D2R-acting antipsychotics, a sensitization effect in the suppression of conditioned avoidance response i. Aripiprazole may act as a complete full agonist or a full antagonist according to the context in which its functions are investigated; these features are unique compared with other classical partial agonists.

Specifically, when tested for D2R intrinsic activity, both DHX and propylDHX demonstrated full D2R agonist activity at postsynaptic D2Rs by inhibiting adenylate cyclase, yet an opposite antagonist action at the presynaptic D2R-mediated inhibition of dopamine release [ , ].

Although also showing interesting antipsychotic features in behavioral studies i. These have demonstrated an increased prefrontal perfusion after a single dose of DHX in schizophrenia patients as well as a good safety and tolerability of a daily mg single dose, although without any improvement in cognitive performances [ , ]. However, a recent study in unmedicated patients with schizotypal personality disorder meeting criteria for cognitive impairment showed that DHX administration significantly ameliorated verbal working memory [ ].

Replication studies, with prolonged DHX administration, are needed to corroborate this view. Concurrently with the development of aripiprazole, other quinolinone derivatives showed different degrees of intrinsic activity.

OPC was the predecessor of aripiprazole on the development pipeline and it showed agonist activity at presynaptic D2Rs and antagonist activity at postsynaptic receptors, with behavioral correlates in preclinical studies [ ]. However, clinical trials demonstrated a worsening in psychotic symptoms [ ].

Several studies have demonstrated that terguride possesses classical partial agonist features, thereby acting as an antagonist in hyperdopaminergic environments and as an agonist in hypodopaminergic environments [ — ]. More recent studies showed that terguride holds higher intrinsic activity in in vitro assays than aripiprazole [ ] and that this could be a detriment to its use as a therapeutic drug. Moreover, both preclinical behavioral [ 54 , ] and molecular studies [ 81 , ] confirmed the substantial differences between terguride and aripiprazole, which may represent possible reasons for the clinical failure of terguride.

However, a recent study identified 2-bromoterguride, a halogen derivative of terguride, as a likely antipsychotic candidate in human studies, because of its lower intrinsic activity at hD2Rs half that of terguride , a high affinity to 5-HT2ARs, and an ability to inhibit amphetamine-induced hyperlocomotor activity in rats without inducing catalepsy [ ].

Several other compounds with potential aripiprazole-like functional effects have been tested for antipsychotic efficacy, with contradictory results. Talipexole is an azepine derivative classified as a D2R agonist agent. However, when clinically tested for the treatment of schizophrenia, only a scarce but significant reduction in negative symptoms score was found, without effects on positive symptoms [ ].

Similar observations were carried out for roxindole, an indole derivative originally developed for the treatment of schizophrenia. Early pharmacological studies revealed that this drug holds a functionally selective agonist activity at presynaptic D2R autoreceptors that was higher than that displayed by talipexole, together with 5-HT1AR agonist and serotonin re-uptake inhibiting activities, all properties confirmed by behavioral studies [ ].

However, clinical trials demonstrated only scarce effects on negative symptoms of schizophrenia and no effects on positive symptoms [ ]. Comparative studies have demonstrated that SDZ — displays higher intrinsic activity than aripiprazole and lower antagonist properties at D2Rs, both features that may potentially account for suboptimal results in treating psychotic symptoms [ ]. In behavioral studies, PD did not produce hyperlocomotor states, yet it inhibited apomorphine-stimulated hyperlocomotion, both functions consistent with partial agonist activity [ ].

To the best of our knowledge, no human studies have yet been performed. In neurophysiological studies, CI showed the ability to reduce dopaminergic nigrostriatal firing, with intrinsic activity lower than apomorphine and talipexole and higher than SDZ — [ ]. Moreover, it may reduce apomorphine-induced hyperlocomotion and inhibit conditioned avoidance responses in behavioral tasks, with a low propensity to EPS [ , ], thus indicating potential antipsychotic efficacy.

Intravenous administration of CI in rats showed a reduction of dopamine release in the nucleus accumbens, with no effects on striatal efflux [ ]. However, although initial human studies revealed good safety and tolerability in schizophrenic patients [ ], no other systematic assessments on efficacy have been carried out to date.

In addition, benzamides such as amisulpride have been thought to hold partial agonist activity or functional selectivity. It is possible that functionally selective signaling at D2Rs may be involved in these peculiar effects of amisulpride compared with other atypical antipsychotics. Recent pharmaceutical development pipelines led to the discovery of other new potentially antipsychotic compounds with dopamine partial agonist characteristics, such as aplindore and cariprazine.

Aplindore shows high affinity for D2 and D3Rs, with low affinity for serotonin receptors and adrenoreceptors. Functional assays showed that aplindore holds potency and intrinsic activity lower than dopamine and higher than aripiprazole [ ]. In behavioral studies, aplindore showed typical partial agonist activity, for example by inducing contralateral movements in unilaterally lesioned rats [ ]. Bifeprunox was originally developed for the treatment of schizophrenia [ ] and showed D2R partial agonism and 5-HT1AR agonism in an in vitro study [ ].

Behavioral studies also demonstrated potential antipsychotic properties, such as inhibition of pre-pulse inhibition deficits [ ]. Comparative studies demonstrated higher intrinsic activity and lower antagonistic properties at D2Rs by bifeprunox compared with aripiprazole [ ].

These pharmacological differences between bifeprunox and aripiprazole have been intensely studied, and recent works demonstrated that the greater intrinsic activity at dopamine receptors with bifeprunox compared with aripiprazole might possibly be responsible for greater beneficial effects, such as weight decrease, but also for the emergence of complicating symptoms, such as anxiety, which may worsen psychosis [ ]. Recent clinical studies showed significantly greater effects of bifeprunox on total primary schizophrenia symptoms compared with placebo, as well as a weight and prolactin reduction, and no induction of EPS [ ].

Other studies revealed a significant lack of impact of bifeprunox on plasma glucose levels compared with other currently used atypical antipsychotics [ ]. Very recent behavioral studies confirm the good antipsychotic efficacy of bifeprunox, thus stimulating further clinical assessments for this drug [ 54 , ].

Cariprazine is a recently developed D3R-preferring partial agonist. At present, it is in late-phase clinical development for the treatment of schizophrenia. Clinical trials have demonstrated superior effects over placebo in reducing all symptoms of schizophrenia, with a low liability for metabolic symptoms and EPS [ ].

However, some recent studies have claimed a relatively high incidence of movement-related disorders with cariprazine compared with other partial agonists [ , ].

Recent clinical trials have shown good results, including the treatment of bipolar mania [ , ]. In the attempt to produce new compounds with dopamine partial agonist activity and functional selectivity, medicinal chemistry researchers focused their attention on the critical molecular characteristics of currently available dopamine partial agonists that seem essential for their intrinsic activity.

Pridopidine and ordopidine display neurochemical and behavioral effects that closely depend on the dopaminergic synaptic state. Recent pharmacological studies further showed the dopamine tone-dependent activity of these drugs. Both pridopidine and ordopidine may dose-dependently increase dopamine release in the striatum as well as dopamine and noradrenaline efflux in the cortex [ ]. Moreover, the two phenylpiperidines display low affinity and low intrinsic activity at D2Rs in vitro, and biochemical experiments suggest a possible allosteric activity [ ].

Although no studies have yet been performed in schizophrenia patients with these compounds, recent works demonstrated that both pridopidine and ordopidine might impact the forebrain expression of genes directly correlated to psychosis pathophysiology. Indeed, Natesan et al. Special mention should be made of brexpiprazole, a very recently developed aripiprazole derivative.

Behavioral studies have confirmed the dopamine-stabilizing features of brexpiprazole. Moreover, brexpiprazole may reduce phencyclidine-induced cognitive impairment in rats by a D2R- 5-HT1AR-mediated mechanism [ , ]. All these effects suggest that brexpiprazole can be considered a partial agonist with a balanced dopamine-serotonin activity.

Recent clinical trials appear to confirm the favorable preclinical results with brexpiprazole. In a 6-week, multicenter, placebo-controlled double-blind phase III study, patients with acute schizophrenia were randomized to brexpiprazole 1, 2, or 4 mg, or placebo once daily.

The tolerability profile of all doses was favorable. Clinical improvements were also seen with lower dosages of brexpiprazole compared with placebo, but they did not reach statistical significance [ ].

Results of these studies have been the object of some poster or oral communications in scientific meetings and appear appealing; however, they have not been published in detail and require replication. Even if considered classically as a D2R partial agonist, multiple lines of evidence suggest that aripiprazole acts at D2Rs impacting the dopaminergic system in different ways, depending on the contingent conditions in which the biological system is examined.

Therefore, aripiprazole has been described as a full antagonist, a moderate antagonist, or a partial agonist at D2Rs in different preclinical paradigms, consistent with biased ligand features of the compound. One main consequence of this feature is that using aripiprazole may prevent the development of long-term dopamine-related neurochemical adaptations that may possibly affect long-term response to antipsychotics. Indeed, chronic treatment with aripiprazole has been observed to prevent the development of dopamine supersensitivity [ ].

While the intermediate intrinsic activity of aripiprazole at D2Rs may per se represent a suitable explanation for the lack of dopamine supersensitivity, it cannot be excluded that this may depend on the pharmacological action of aripiprazole, which ranges from agonism to antagonism and therefore oscillates between stimulation and inactivation of the receptor. In conclusion, the introduction of aripiprazole to the treatment of schizophrenia and other psychiatric diseases has paved the way for a new generation of compounds that not only block dopaminergic transmission via D2Rs but may also be conceptualized as dynamic-acting D2R modulators beyond dopamine antagonism.

This work was partly supported by an unrestricted grant from Otsuka Italia to Andrea de Bartolomeis. The design, implications, and conclusions of the manuscript are solely the responsibility of the authors, and the funding source had no role in the conception, design, or content of the manuscript.

We thank Ray Hill, an independent medical writer, who provided copyediting and journal styling prior to submission, on behalf of Springer Healthcare Communications. This assistance and open access was funded by Otsuka Italia. AdB: research grant from Lundbeck; unrestricted research grant from Otsuka; participation in advisory boards for Janssen, Roche, Otsuka, and Lundbeck; speaker in educational CME activities sponsored by unrestricted grants from Janssen, Roche, Otsuka, and Lundbeck.

FI and CT: no conflicts of interest to declare. National Center for Biotechnology Information , U. CNS Drugs. Published online Sep 7. Author information Copyright and License information Disclaimer. Corresponding author. This article has been cited by other articles in PMC. Abstract Dopamine partial agonism and functional selectivity have been innovative strategies in the pharmacological treatment of schizophrenia and mood disorders and have shifted the concept of dopamine modulation beyond the established approach of dopamine D2 receptor D2R antagonism.

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.

However, the receptor profile of the compound is much more complex, and animal models have shown that aripiprazole affects multiple cellular pathways and several cortical and subcortical neurotransmitter circuitries and has an impact on gene expression distinct from other antipsychotics.

Open in a separate window. Introduction More than 40 years since its first enunciation, the dopamine dysregulation hypothesis of schizophrenia is still considered pivotal for the pathophysiology of the disorder, even if preclinical and clinical research has emphasized the contribution of signaling of other neurotransmitters, primarily the glutamatergic and the serotonergic neurotransmitters [ 1 ].

Simply put, an agonist is like the key that fits in the lock the receptor and turns it to open the door or send a biochemical or electrical signal to exert an effect. The natural agonist is the master key but it is possible to design other keys agonist drugs that do the same job. Specific effects such as pain relief or euphoria happen because opioid receptors are only present in some parts of the brain and body that affect those functions.

The main active ingredient in cannabis, THC, is an agonist of the cannabinoid receptor, and hallucinogenic drug LSD is a synthetic molecule mimicking the agonist actions of the neurotransmitter serotonin at one of its many receptors — the 5HT2A receptor. So the actions of the agonist are blocked by the presence of the antagonist in the receptor molecule.

If someone is experiencing a potentially lethal morphine overdose, the opioid receptor antagonist naloxone can reverse the effects. This is because naloxone marketed as Narcan quickly occupies all the opioid receptors in the body and prevents morphine from binding to and activating them.

Morphine bounces in and out of the receptor in seconds. The effects of Narcan can be dramatic. Even if the overdose victim is unconscious or near death, they can become fully conscious and alert within seconds of injection. Some drugs act to inhibit their action. Selective serotonin reuptake inhibitors SSRIs — such as the antidepressant fluoxetine Prozac — work like this.

Serotonin is a brain neurotransmitter that regulates mood, sleep and other functions such as body temperature. Expectations have graded effects and may affect symptoms to a smaller or larger degree. Although drug effects can be considered stimuli, the investigation of the role of classical conditioning in drug use and drug effects involves special issues that must be carefully considered.

Abstract The research presented here has shown that tolerance to drugs can be accelerated by conditioning processes.