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Dopamine, Cognitive Impairments and Second-Generation Antipsychotics: From Mechanistic Advances to More Personalized Treatments

Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Genetics of Cognition laboratory, Neuroscience area, Istituto Italiano di Tecnologia, 16163 Genova, Italy
Author to whom correspondence should be addressed.
Pharmaceuticals 2020, 13(11), 365;
Submission received: 11 October 2020 / Revised: 31 October 2020 / Accepted: 3 November 2020 / Published: 5 November 2020
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)


The pharmacological treatment of cognitive impairments associated with schizophrenia is still a major unmet clinical need. Indeed, treatments with available antipsychotics generate highly variable cognitive responses among patients with schizophrenia. This has led to the general assumption that antipsychotics are ineffective on cognitive impairment, although personalized medicine and drug repurposing approaches might scale down this clinical issue. In this scenario, evidence suggests that cognitive improvement exerted by old and new atypical antipsychotics depends on dopaminergic mechanisms. Moreover, the newer antipsychotics brexpiprazole and cariprazine, which might have superior clinical efficacy on cognitive deficits over older antipsychotics, mainly target dopamine receptors. It is thus reasonable to assume that despite more than 50 years of elusive efforts to develop novel non-dopaminergic antipsychotics, dopamine receptors remain the most attractive and promising pharmacological targets in this field. In the present review, we discuss preclinical and clinical findings showing dopaminergic mechanisms as key players in the cognitive improvement induced by both atypical antipsychotics and potential antipsychotics. We also emphasize the concept that these mechanistic advances, which help to understand the heterogeneity of cognitive responses to antipsychotics, may properly guide treatment decisions and address the unmet medical need for the management of cognitive impairment associated with schizophrenia.

1. Introduction

Schizophrenia is a chronic multifactorial neuropsychiatric disorder with an incidence of 0.7–1% [1]. Patients with schizophrenia experience severe symptoms that are historically allocated in three main symptom clusters: (i) positive symptoms (e.g., delusions, hallucinations); (ii) negative symptoms (e.g., lack of motivation and social withdrawal); (iii) cognitive impairments (impairment across several cognitive domains including memory, attention, and executive functioning) [2].
At a pharmacological level, antipsychotics represent first-line pharmacotherapy for the treatment of schizophrenia [3,4]. In line with the clinical heterogeneity of this disorder, the pharmacological responses to antipsychotics are highly variable [5]. In particular, whereas antipsychotics substantially reduce or eliminate positive symptoms, their effects on negative symptoms and cognitive impairment are highly variable and far from optimal [4,6]. Regarding cognitive impairments associated with schizophrenia (CIAS), no pharmacological treatments have been approved so far by any regulatory agencies worldwide [7,8]. This has produced considerable interest mostly because CIAS have been reported as the main cause of functional disability and poor quality of life [9]. Classically, antipsychotics fall into two categories: Typical antipsychotic drugs or first-generation antipsychotic (FGAs) drugs, and atypical antipsychotic drugs or second-generation-antipsychotic (SGAs) drugs. There is still a debate if SGAs are superior to FGAs in treating CIAS. Meta-analyses have reported SGAs as being modestly more effective than FGAs in ameliorating CIAS [10,11]. Nevertheless, FGAs may have opposite effects on CIAS. FGAs may indeed worsen CIAS [12]; They may improve CIAS similarly to SGAs at low doses [13]; Sometimes they may also result in being more effective compared to SGAs in ameliorating CIAS [14]. Overall, both FGAs and SGAs, when administered at appropriate doses, may produce an improvement in CIAS, but neither category results in being clinically superior to the other. At a mechanistic level, SGAs generally differ from FGAs for their lower affinity for dopamine D2 receptors and high affinity for serotonin 5-HT2A receptors. However, multiple lines of evidence suggest that the cognitive improvement exerted by old and new SGAs still depends on dopaminergic mechanisms, and it is unclear whether the efficacy of SGAs is linked to serotoninergic mechanisms [15]. In this respect, not only the dopamine D2 receptor (D2R) but also D1, D3, and D4 receptors (D1R, D3R, D4R) have been investigated for their possible contribution in the SGAs-induced cognitive improvement. Among these previously overlooked dopamine receptors, the D3R appears to be highly involved in the cognitive improvement produced by some SGAs and currently represents one the most attractive target for future drug development or repositioning in the context of CIAS pharmacotherapy.

2. The Dopamine Hypothesis of Schizophrenia

Dopamine (DA) influences multiple physiological functions, including reward, cognition and emotional processes through two classes of DA receptors—the D1-like receptors (D1R and D5R) and the D2-like receptors (D2R, D3R, and D4R)—which are G-protein-coupled receptors coupled to Gs and Gi protein, respectively [16,17,18,19]. Dopaminergic neurons, which are mainly located in the midbrain, create four major dopaminergic pathways [20]. Dopaminergic neurons of the ventral tegmental area (VTA) give rise to the mesocortical pathway by innervating the prefrontal cortex (PFC). They also give rise to the mesolimbic pathway, sending dopaminergic projections to the ventral striatum. The nigrostriatal pathway consists of dopaminergic projections from the substantia nigra to the dorsal striatum. Lastly, dopaminergic neurons located in the arcuate nucleus of the hypothalamus, which send projections to the median eminence, create the tuberoinfundibular pathway.
The DA hypothesis of schizophrenia, which postulates a dysregulation of dopaminergic pathways in the etiology of the disorder, has been reconceptualised over the last five decades. The first version of DA hypothesis of schizophrenia postulated an overall hyperdopaminergia and then an excess transmission at DA receptors [21,22]. In 1991, Davis and colleagues [23] proposed an updated version (second version) that postulated a frontal hypodopaminergia and a striatal hyperdopaminergia. They specifically hypothesized that the frontal hypodopaminergia caused negative symptoms, whereas the striatal hyperdopaminergia was responsible for the onset of the positive symptoms. In the more recent version (third version), Howes and Kapur [24] hypothesized that interactions between multiple environmental and genetic risk factors lead to a final common pathway of increased presynaptic striatal dopaminergic function. In contrast to the classic mesolimbic dogma of schizophrenia, recent in vivo neuroimaging data suggest that this presynaptic dopaminergic dysfunction is more prominent in the dorsal striatum rather than in the ventral striatum [15,25,26]. Interestingly, this increased dorsal striatal dopaminergic signalling play, a prominent role not only in the development of positive symptoms, but also in the development of the CIAS, mainly by disturbing dopamine-dependent cortical processes [27].

3. Dopamine, Cognition and CIAS

DA modulation of bidirectionally interconnected cortico-striatal circuitries is fundamental for the expression of cognitive functions. In accordance with multiple lines of evidence, this modulation appears rather complex. For instance, the relationship between DA and cognition, mainly in the PFC, follows an inverted U-shaped curve, where either high or low DA levels impair performance in cognitive tasks [28,29]. This is further complicated by findings showing variable effects of dopaminergic drugs on the cognition of human subjects, differing for their baseline levels of cognitive performance [30,31]. According to preclinical studies, the effects of dopaminergic drugs may depend on baseline levels of DA in the PFC [32,33], which hosts a large number of DA receptors [34]. Although there is consensus that the stimulation of D1Rs leads to pro-cognitive effects, this is not always the case. Indeed, the administration of a D1R agonist in rodents may improve or impair cognitive performance during difficult and easy tasks, respectively [35,36]. Moreover, an inverted-U shaped response to D1 receptor stimulation has been reported in monkeys, where low doses of the D1R agonist SKF81297 improved spatial working memory and a high dose of the same agonist impaired spatial working memory [37]. With regard to D2R, the administration of either antipsychotics with high affinity for D2R or more selective D2R antagonists have been basically associated with cognitive impairment [12,38,39]. Clinical and preclinical studies have reported that this detrimental effect is related to a disruption of the D2R-mediated signalling in the PFC. In fact, the administration of sulpride impaired the working memory of human volunteers tested in PFC-dependent tasks [40,41]. These results were substantiated by a rodent study, showing an impairment of novel object recognition memory after a selective blockade of D2R in PFC [42]. In this context, much attention has been paid to another member of the D2-like family, the D3R, which appears to have a prominent role in the modulation of PFC-related cognitive functions [43,44]. Indeed, if in the past it was believed that D3R was located only in subcortical regions of the brain. Nowadays, new technological advancements (bacterial artificial chromosome transgenic GFP reporter mice, [45]) have allowed us to discover a cortical localization of D3R and thus a role of this receptor in the homeostasis of PFC. In particular, Clarkson and colleagues demonstrated that the D3Rs are localized in a novel subclass of pyramidal neurons in the layer V of the medial PFC (mPFC), which project their axons toward different cortical and subcortical areas, and are both electrophysiologically and anatomically distinct from adjacent neurons expressing D1Rs or D2Rs [46]. In line with this evidence, D3R modulates PFC-dependent cognitive function, as demonstrated by the fact that either pharmacological or genetic manipulation, able to affect prefrontal D3R, alter cognition [42,47,48,49]. Opposite to D2R, it is well-established that antagonism/partial agonism on D3R produces pro-cognitive effects across species [50].
Although PFC is the brain region most studied in this field, increasing evidence suggests that DA modulates cognition by acting directly within other brain areas, such as the striatum and the hippocampus [51,52,53,54]. Thus, it is not surprising that dysfunctions of dopaminergic signalling are associated with CIAS. Generally, CIAS are thought to originate from a hypofunctionality of the mesocortical dopaminergic pathway [55]. This concept has been widely supported by several lines of research involving either patients or animals. For instance, it has been observed that reduced levels of DA metabolites in the cerebrospinal fluid of schizophrenic patients, correlated with working memory deficits [56]. In line with these findings, a more recent preclinical study reports a significant reduction in DA and DOPAC in the PFC of mice that exhibited schizophrenia like-behaviors, including memory impairment [57]. Noteworthy, only in 2015, after the accumulation of multiple findings indicating a cortical hypodopaminergia in schizophrenia, Slifstein and colleagues provided, for the first time, in vivo evidence for a diminished amphetamine-induced DA release in the dorsolateral PFC of schizophrenic patients, which correlated with working memory-induced activation of the same area [58]. This prefrontal hypodopaminergia leads to an insufficient D1R stimulation, which in turn triggers CIAS [59]. In this regard, a higher dorsolateral PFC D1R availability in drug naïve schizophrenic patients has been observed, which negatively correlated with working memory abilities [60,61]. These findings may be explained as possible compensatory mechanisms in response to blunted D1R-mediated signaling in PFC. It has also been suggested that CIAS may originate from an imbalance between D1R/D2R activation in the PFC [62]. With respect to the D2R, a genetic-driven disruption of D2R-mediated signaling in PFC has been associated with CIAS [63]. Moreover, we recently found that an interaction between D3R and dysbindin, which is a protein that has been specifically linked to CIAS, generates a D2R/D3R imbalance in the PFC [43].
Besides the cortical brain areas, the striatum plays a key role in the modulation of cognitive functions and thus in the pathophysiological mechanisms underlying CIAS [27]. Related to that, the striatal hyperdopaminergic state characterizing schizophrenic patients, which has been historically linked to positive symptoms, is also responsible for the appearance of CIAS [27]. This may be strictly linked to the functional and anatomical connection between the striatum and the cortex. It has indeed reported that an increased postsynaptic D2R-mediated dopaminergic signaling in the striatum may induce a cortical hypodopaminergia, by interfering with the firing pattern of VTA dopaminergic neurons [27,58,64,65]. This concept is supported by several preclinical findings. In particular, the selective increase in D2R availability in the striatum of genetically modified mice, which showed long-lasting cognitive deficits during prefrontal-dependent cognitive tasks relevant to schizophrenia, generated a reduced DA turnover in the PFC [66,67]. As mentioned above, the striatal hyperdopaminergic state in schizophrenia is more restricted to the dorsal part (associative striatum) than to the ventral part of the striatum [15]. With regard to CIAS, this hyperdopaminergic state within the associative striatum has been linked to disrupted decision-making processes observed in schizophrenia [68]. Thus, it is still reasonable to state that therapeutic interventions aimed at reversing these dopaminergic dysfunctions may be fundamental for treating CIAS.

4. Potential Antipsychotics or SGAs Targeting Specific Dopamine Receptors May Become the Cornerstone of CIAS Pharmacotherapy

4.1. Potential Antipsychotics

In an attempt to overcome the clinical issue related to the problematic pharmacological management of CIAS, several efforts have been made to develop effective drugs targeting DA receptors. Among them, the D1R represents a promising pharmacological target in the context of CIAS [69]. In particular, full D1R agonists may be effective against CIAS, according to what has already been discussed above. Several clinical studies have in fact reported the full D1R agonist dihydrexidine (DAR-0100A) effective in improving CIAS (especially working memory deficits) both in individuals with schizophrenia and in individuals with schizotypal personality disorder [70,71]. However, DAR-0100A, which has a limited pharmacokinetic profile, also failed to improve CIAS in a randomized controlled trial involving patients with schizophrenia, likely because of its lack of D1R occupancy at low doses [72]. This has prompted researchers to develop better D1R agonists able to achieve sufficient D1R occupancy. Related to that, Meltzer and colleagues demonstrated that the allosteric DA D1R potentiator DETQ, was able to counteract the object recognition memory deficits in mice tested in the phencyclidine (PCP) model for the study of schizophrenia [73]. More recently, it has been characterized a novel non-catecholamine DA receptor D1 agonist, PF-6142, which belongs to a new series of D1R-selective non-catechol agonists endowed with optimal pharmacokinetic properties. Intriguingly, PF-6142 improved cognitive deficits in different rodent models for the study of schizophrenia, based on NMDA receptor hypofunction [74].
As discussed before, multiple lines of evidence have underlined the great potential of drugs targeting the D3R for the treatment of CIAS. In this regard, Sun and colleagues proposed a potent D3R antagonist, Y-QA31, as a potential antipsychotic by proving its preclinical efficacy in well-validated models for the study of schizophrenia. Y-QA31, besides its ability to ameliorate MK-801-induced hyperlocomotion, and methamphetamine-induced prepulse inhibition disruption, was shown to be effective on the MK-801-induced impairment of novel object recognition memory [75]. Another potential antipsychotic, F17464, which interestingly, has reached the clinical phases, is characterized by a potent D3R antagonist activity [76]. In rodents, F17464 was more effective in counteracting scopolamine-induced cognitive deficits than other SGAs [44]. More importantly, in a randomized, double-blind, placebo-controlled study, Bitter and colleagues demonstrated the pharmacological efficacy of F17646 in patients with schizophrenia. At a dose of 40 mg, F17464 showed therapeutic efficacy in ameliorating positive and negative symptoms and, especially, CIAS without the occurrence of weight gain or extrapyramidal side effects [77]. The success of this clinical trial might be ascribed to the relationship between the dose and the D3R occupancy. It was indeed reported that, 6–9 h after the administration of 30 mg of F17464, D3R occupancy in the brain is very high (94% on average), and sufficient to induce pro-cognitive effects [78]. Interestingly, a clinical study reported that buspirone, which is an azapirone anxiolytic drug having 5-HT1A partial agonist activity, as well as D3R/D4R antagonist activity [79], co-administered with SGAs, better ameliorated CIAS than SGAs alone in patients with schizophrenia. In this respect, we previously showed that buspirone counteracted MK-801-induced schizophrenia-like phenotypes, including the deficit of temporal order recognition memory, selectively through its D3R antagonism [80]. However, the beneficial effect of buspirone on CIAS needs to be further investigated because it may be more complex through a possible involvement of other neurotransmitter systems [81].
The role of D4R in cognition and in the development of CIAS is unclear and needs to be further investigated. However, there is evidence that D4R stimulation may be a valuable strategy to improve CIAS [82,83]. RP5063 is a potential SGA under development, having peculiar pharmacological proprieties, including partial agonism at D2R, D3R and also D4R. Notably, Rajagopal and colleagues showed that the beneficial effect of acute administration of RP5063 on sub-chronic PCP-induced impairment in novel object recognition memory can be blocked by a pre-treatment with a selective D4R antagonist [84].

4.2. Second-Generation Antipsychotic Drugs (SGAs)

As mentioned before, there is still one question to be answered: Are commercially available SGAs effective against CIAS? Here, we review evidence suggesting that some SGAs, through dopaminergic mechanisms, are able to ameliorate CIAS.

4.2.1. Clozapine

Clozapine, the first SGA developed, is basically one of the most effective, although its use is limited because of the possible occurrence of severe adverse effects. The precise clozapine mechanism of action and mainly the mechanisms whereby clozapine exerts beneficial effects, particularly on CIAS [11,12,85,86], are still unclear despite more than 50 years of research [87]. Nevertheless, it is well-known that clozapine is endowed with nanomolar affinity for serotonin receptors (5-HT2A, 5-HT2C, 5-HT6, 5-HT7) and uniquely for D4R [88]. Evidence supports the idea that the pro-cognitive effects induced by clozapine rely on dopaminergic mechanisms. For instance, the clinical benefits of clozapine on emotional memory deficits observed in schizophrenic patients have been associated to the capacity of clozapine to stabilize DA levels in the amygdala in a dopaminergic state-dependent manner [89]. In line with this, the pro-cognitive effect of clozapine has been further linked to the evidence that this drug restored DA turnover in the dorsolateral PFC, prelimbic cortex, and cingulate cortex of monkeys chronically treated with PCP [90]. In addition, the pro-cognitive effect of clozapine in mice that exhibited PCP-induced cognitive impairment relevant for schizophrenia, depended on the activation of D1R in the PFC [91].
As mentioned above, there is considerable variability in the clinical responses to antipsychotics. This phenomenon may be explained, taking into account genetic variation, namely differences in DNA among patients. Related to that, it is noteworthy to mention a clinical research paper in which Woodward and colleagues discovered an association between a single nucleotide polymorphism (SNP), the val108/158met, within the gene encoding for catechol-O-methyltransferase (COMT), which is an enzyme involved in the control of PFC DA neurotransmission, and the cognitive improvement induced by clozapine. In particular, 6 months of treatment with clozapine induced a cognitive improvement exclusively in met homozygous and val/met heterozygous patients with schizophrenia [92].

4.2.2. Risperidone

Risperidone is an SGA that has high affinity for the 5-HT2A and D2R as well as moderate to low affinity for, D1R, D3R, and D4R receptors [93]. Evidence from translational studies indicates that risperidone improves CIAS, especially in schizophrenic patients with genetic-induced alterations of the cortical dopaminergic signaling. Scheggia and colleagues reported, indeed, a pharmacogenetic interaction between genetic variants associated with reduced dysbindin expression and the cognitive improvement exerted by antipsychotics including risperidone [6]. They discovered that the viral-mediated silencing of D2Rs in the mPFC of dysbindin heterozygous mice abolished the beneficial effect of risperidone on cognitive dysfunctions relevant for schizophrenia. Furthermore, they discovered that this pharmacogenetic interaction triggers an enhancement of presynaptic cortical D2R-mediated signaling through an increased D2S/D2L ratio, which are the functional isoforms of D2R. Along with these findings, we have recently reported that an epistatic interaction, dysbindin/D3R, drives different cognitive improvement after treatment with risperidone. In particular, we demonstrated that chronic treatment with risperidone produced a greater improvement of executive and working memory functions specifically in both schizophrenic patients and genetically modified mice bearing concomitant reduction in D3R and Dys functionality [43].

4.2.3. Aripiprazole

Aripiprazole differs from earlier SGAs in having partial agonist activity at D2R/D3R, 5HT1A and 5HT2C [94]. In this respect, findings from preclinical models utilized for studying CIAS reported that the aripiprazole’s potential for the treatment of CIAS may depend on dopaminergic mechanisms and its partial agonist activity. Fejgin and colleagues indeed suggested that the superior preclinical efficacy of aripiprazole compared to clozapine and olanzapine in counteracting the PCP-induced the impairment of prepulse inhibition [95], which might model the attentional deficits present in treatment-resistant patients with schizophrenia [96], may indeed rely on its partial agonism-induced DA stabilizing effects. Despite the low affinity of aripiprazole for D1R [97], the pro-cognitive effect of this SGA on PCP-induced cognitive impairment in mice, was found to depend on the activation of D1R [98]. At a clinical level, the relationship between D2R/D3R receptor occupancy by aripiprazole and cognition/CIAS has been interestingly investigated. Whereas higher striatal D2R/D3R receptor occupancy by aripiprazole was associated with decreased working memory in healthy volunteers [99], the same higher striatal D2R/D3R receptor occupancy by aripiprazole was instead reported to be positively correlated with cognitive improvement in patients with schizophrenia [100].

4.2.4. Asenapine

Asenapine is also a multitarget SGA with peculiar pharmacological properties. In particular, asenapine has high affinity for serotonin receptors (5HT1A, 5HT1B, 5HT2A, 5HT2C, 5HT6 and 5HT7) and among DA receptors, it has higher affinity for D3R than D2R [101]. In line with the aforementioned data linking D1R activation by SGAs (clozapine and aripiprazole) and the induction of pro-cognitive effects, also in the case of asenapine, its ameliorative effect on PCP-induced memory impairment can be blocked through the administration of a selective a D1R antagonist [102]. This effect might be indeed due to the ability of asenapine to increase dopaminergic neurotransmission and facilitate NMDA-mediated neurotransmission in the mPFC selectively through D1R activation [103]. However, further studies need to be carried out in order to better understand the mechanisms by which asenapine exerts its pro-cognitive effect, also in relation to its preferential binding to D3R, which it is currently a well-established and interesting pharmacological target for CIAS treatment [16,50].

4.2.5. Blonanserin

Blonanserin differs from the earlier SGAs for its equal antagonist activity at D2R and 5HT2A as well as for its potent antagonist activity at D3R [104,105]. Hida and colleagues provided evidence for an involvement of both D1R and D3R in the ameliorating effect of blonanserin on the PCP-induced cognitive impairment of mice. Indeed, this beneficial effect of blonanserin could be blocked by a pretreatment with either a D3R agonist or a D1R antagonist [106]. These findings were further supported by a different study reporting that the blonanserin-induced cortical-striatal acetylcholine, DA, noradrenaline and striatal DA efflux rely selectively on its antagonism on D3, as well as the concomitant ameliorating effect of blonanserin on PCP-induced cognitive impairment [107]. Interestingly, this effect appears to be reproducible across species because it was also reported that blonanserin rescued the executive function deficits induced in marmosets through the administration of a D3R agonist [108].

4.2.6. Cariprazine

Cariprazine is a recently FDA-approved D3R/D2R partial agonist, which preferentially binds to D3R. Among SGAs that behave like partial agonists, cariprazine has the highest affinity for D3R, followed by aripiprazone and bexpiprazole [109,110]. This feature may be responsible for the pro-cognitive effect of cariprazine observed in preclinical studies. It has been indeed observed that cariprazine counteracted PCP-induced impairments of working memory, attention set-shifting, and recognition memory in wild-type mice, but not in D3R knock-out mice [111]. These findings were further strengthened by other preclinical studies showing an ameliorating effect of cariprazine on cognitive dysfunctions relevant for schizophrenia, which were modelled by using different animal models for the study of CIAS [112,113]. At a mechanistic level, this pro-cognitive effect of cariprazine may be linked to its D3R partial agonist activity, which may normalize DA-induced cortical-striatal abnormalities characterizing schizophrenia.

4.2.7. Brexpiprazole

Brexpiprazole is a novel SGA endowed with partial agonist activity at D2R/D3R and 5-HT1A together with antagonist activity at 5-HT2A. There is evidence that the preclinical beneficial effect of brexpiprazole on cognitive impairment relevant for schizophrenia [114], may depend on dopaminergic mechanisms. In fact, brexpiprazole, through the stimulation of D1R, is able to potentiate NMDAR-induced currents and electrically evoked EPSPs in the mPFC, which is a mechanism linked to pro-cognitive effects [115].

5. Concluding Remarks and Future Directions

The pharmacological treatment of CIAS is challenging because of the highly variable cognitive responses observed in patients with schizophrenia chronically treated with antipsychotics. According to evidence discussed in this review, these heterogeneous pharmacological responses might be ascribable to genetic variability, which affects dopaminergic signaling, might interfere with individual capacity to recover from CIAS depending on antipsychotic treatment. In this context, several findings discussed in this review demonstrate that selectively targeting the dopaminergic system might be a good strategy for the treatment of CIAS. In this context, we want also to underline that cognitive-enhancing drugs targeting other neurotransmitter systems involved in the pathophysiology of schizophrenia, such as the glutamatergic system, may be useful. These drugs can be used in combination with SGAs, if possible, at low doses, to obtain a better clinical efficacy on CIAS and to lower the occurrence of side effects associated with D2R blockade. Moreover, focusing on the genetics of individual patients and identify novel mechanisms affecting cognitive responses—mainly dopaminergic based—may allow for a better patient stratification and may help to guide the choice of the more appropriate drug. In an age when the low clinical success rate for de novo drug discovery has led several pharmaceutical industries to downscale or close their clinical neuroscience research programs, improving the use of commercially available SGAs or the repositioning of drugs for which a dopaminergic-based pro-cognitive effect has been demonstrated, might be useful to improve the pharmacological management of CIAS in genetically selected patients with schizophrenia.

Author Contributions

S.A.T. and G.M.L. have substantially contributed to the conception and design of the article. S.L., G.C., A.D.L., F.M. and F.G. revised and interpreted the relevant literature. F.P., S.S. and F.D. revised the article critically and can otherwise be considered experts on the topic. S.A.T. and G.M.L. wrote the manuscript. All authors have read and agreed to the published version of the manuscript.


This work was supported by University of Catania intramural funds (Starting Grant 2020 to GML); Italian Ministry of University and Research (PRIN 2017-Prot. 201779W93T to GML and PRIN 2017- Prot. 2017K2NEF4 to FD).

Conflicts of Interest

The authors declare no conflict of interest.


  1. Landek-Salgado, M.A.; Faust, T.E.; Sawa, A. Molecular substrates of schizophrenia: Homeostatic signaling to connectivity. Mol. Psychiatry 2016, 21, 10–28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Van Os, J.; Kapur, S. Schizophrenia. Lancet 2009, 374, 635–645. [Google Scholar] [CrossRef]
  3. Miyamoto, S.; Duncan, G.E.; Marx, C.E.; Lieberman, J.A. Treatments for schizophrenia: A critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol. Psychiatry 2005, 10, 79–104. [Google Scholar] [CrossRef] [PubMed]
  4. Miyamoto, S.; Miyake, N.; Jarskog, L.F.; Fleischhacker, W.W.; Lieberman, J.A. Pharmacological treatment of schizophrenia: A critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol. Psychiatry 2012, 17, 1206–1227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Case, M.; Stauffer, V.L.; Ascher-Svanum, H.; Conley, R.; Kapur, S.; Kane, J.M.; Kollack-Walker, S.; Jacob, J.; Kinon, B.J. The heterogeneity of antipsychotic response in the treatment of schizophrenia. Psychol. Med. 2011, 41, 1291–1300. [Google Scholar] [CrossRef] [PubMed]
  6. Scheggia, D.; Mastrogiacomo, R.; Mereu, M.; Sannino, S.; Straub, R.E.; Armando, M.; Manago, F.; Guadagna, S.; Piras, F.; Zhang, F.; et al. Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment. Nat. Commun. 2018, 9, 2265. [Google Scholar] [CrossRef] [Green Version]
  7. Cotter, J.; Barnett, J.H.; Granger, K. The Use of Cognitive Screening in Pharmacotherapy Trials for Cognitive Impairment Associated with Schizophrenia. Front. Psychiatry 2019, 10, 648. [Google Scholar] [CrossRef]
  8. Keefe, R.S.; Haig, G.M.; Marder, S.R.; Harvey, P.D.; Dunayevich, E.; Medalia, A.; Davidson, M.; Lombardo, I.; Bowie, C.R.; Buchanan, R.W.; et al. Report on ISCTM Consensus Meeting on Clinical Assessment of Response to Treatment of Cognitive Impairment in Schizophrenia. Schizophr. Bull. 2016, 42, 19–33. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Bowie, C.R.; Harvey, P.D. Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatr. Dis. Treat. 2006, 2, 531–536. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Thornton, A.E.; Van Snellenberg, J.X.; Sepehry, A.A.; Honer, W. The impact of atypical antipsychotic medications on long-term memory dysfunction in schizophrenia spectrum disorder: A quantitative review. J. Psychopharmacol. 2006, 20, 335–346. [Google Scholar] [CrossRef]
  11. Woodward, N.D.; Purdon, S.E.; Meltzer, H.Y.; Zald, D.H. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int. J. Neuropsychopharmacol. 2005, 8, 457–472. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Purdon, S.E.; Woodward, N.; Lindborg, S.R.; Stip, E. Procedural learning in schizophrenia after 6 months of double-blind treatment with olanzapine, risperidone, and haloperidol. Psychopharmacology 2003, 169, 390–397. [Google Scholar] [CrossRef] [PubMed]
  13. Keefe, R.S.; Seidman, L.J.; Christensen, B.K.; Hamer, R.M.; Sharma, T.; Sitskoorn, M.M.; Rock, S.L.; Woolson, S.; Tohen, M.; Tollefson, G.D.; et al. Long-term neurocognitive effects of olanzapine or low-dose haloperidol in first-episode psychosis. Biol. Psychiatry 2006, 59, 97–105. [Google Scholar] [CrossRef]
  14. Keefe, R.S.; Bilder, R.M.; Davis, S.M.; Harvey, P.D.; Palmer, B.W.; Gold, J.M.; Meltzer, H.Y.; Green, M.F.; Capuano, G.; Stroup, T.S.; et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch. Gen. Psychiatry 2007, 64, 633–647. [Google Scholar] [CrossRef]
  15. McCutcheon, R.A.; Abi-Dargham, A.; Howes, O.D. Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms. Trends Neurosci. 2019, 42, 205–220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Leggio, G.M.; Bucolo, C.; Platania, C.B.; Salomone, S.; Drago, F. Current drug treatments targeting dopamine D3 receptor. Pharmacol. Ther. 2016, 165, 164–177. [Google Scholar] [CrossRef] [PubMed]
  17. Leggio, G.M.; Micale, V.; Le Foll, B.; Mazzola, C.; Nobrega, J.N.; Drago, F. Dopamine D3 receptor knock-out mice exhibit increased behavioral sensitivity to the anxiolytic drug diazepam. Eur. Neuropsychopharmacol. 2011, 21, 325–332. [Google Scholar] [CrossRef]
  18. Leggio, G.M.; Torrisi, S.A.; Castorina, A.; Platania, C.B.; Impellizzeri, A.A.; Fidilio, A.; Caraci, F.; Bucolo, C.; Drago, F.; Salomone, S. Dopamine D3 receptor-dependent changes in alpha6 GABAA subunit expression in striatum modulate anxiety-like behaviour: Responsiveness and tolerance to diazepam. Eur. Neuropsychopharmacol. 2015, 25, 1427–1436. [Google Scholar] [CrossRef]
  19. Torrisi, S.A.; Leggio, G.M.; Drago, F.; Salomone, S. Therapeutic Challenges of Post-traumatic Stress Disorder: Focus on the Dopaminergic System. Front. Pharmacol. 2019, 10, 404. [Google Scholar] [CrossRef] [PubMed]
  20. Hillarp, N.A.; Fuxe, K.; Dahlstrom, A. Demonstration and mapping of central neurons containing dopamine, noradrenaline, and 5-hydroxytryptamine and their reactions to psychopharmaca. Pharmacol. Rev. 1966, 18, 727–741. [Google Scholar]
  21. Carlsson, A.; Lindqvist, M. Effect of Chlorpromazine or Haloperidol on Formation of 3methoxytyramine and Normetanephrine in Mouse Brain. Acta Pharmacol. Toxicol. 1963, 20, 140–144. [Google Scholar] [CrossRef] [PubMed]
  22. Carlsson, A.; Lindqvist, M.; Magnusson, T. 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 1957, 180, 1200. [Google Scholar] [CrossRef]
  23. Davis, K.L.; Kahn, R.S.; Ko, G.; Davidson, M. Dopamine in schizophrenia: A review and reconceptualization. Am. J. Psychiatry 1991, 148, 1474–1486. [Google Scholar] [CrossRef] [PubMed]
  24. Howes, O.D.; Kapur, S. The dopamine hypothesis of schizophrenia: Version III—The final common pathway. Schizophr. Bull. 2009, 35, 549–562. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Howes, O.; Bose, S.; Turkheimer, F.; Valli, I.; Egerton, A.; Stahl, D.; Valmaggia, L.; Allen, P.; Murray, R.; McGuire, P. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: A PET study. Mol. Psychiatry 2011, 16, 885–886. [Google Scholar] [CrossRef] [Green Version]
  26. Howes, O.D.; Montgomery, A.J.; Asselin, M.C.; Murray, R.M.; Valli, I.; Tabraham, P.; Bramon-Bosch, E.; Valmaggia, L.; Johns, L.; Broome, M.; et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch. Gen. Psychiatry 2009, 66, 13–20. [Google Scholar] [CrossRef] [Green Version]
  27. Simpson, E.H.; Kellendonk, C.; Kandel, E. A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron 2010, 65, 585–596. [Google Scholar] [CrossRef] [Green Version]
  28. Cools, R.; D’Esposito, M. Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol. Psychiatry 2011, 69, e113–e125. [Google Scholar] [CrossRef] [Green Version]
  29. Kroener, S.; Chandler, L.J.; Phillips, P.E.; Seamans, J.K. Dopamine modulates persistent synaptic activity and enhances the signal-to-noise ratio in the prefrontal cortex. PLoS ONE 2009, 4, e6507. [Google Scholar] [CrossRef] [Green Version]
  30. Gibbs, S.E.; D’Esposito, M. Individual capacity differences predict working memory performance and prefrontal activity following dopamine receptor stimulation. Cogn. Affect. Behav. Neurosci. 2005, 5, 212–221. [Google Scholar] [CrossRef] [Green Version]
  31. Kimberg, D.Y.; D’Esposito, M.; Farah, M.J. Effects of bromocriptine on human subjects depend on working memory capacity. Neuroreport 1997, 8, 3581–3585. [Google Scholar] [CrossRef] [PubMed]
  32. Lidow, M.S.; Koh, P.O.; Arnsten, A.F. D1 dopamine receptors in the mouse prefrontal cortex: Immunocytochemical and cognitive neuropharmacological analyses. Synapse 2003, 47, 101–108. [Google Scholar] [CrossRef]
  33. Zahrt, J.; Taylor, J.R.; Mathew, R.G.; Arnsten, A.F. Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance. J. Neurosci. 1997, 17, 8528–8535. [Google Scholar] [CrossRef] [Green Version]
  34. De Almeida, J.; Palacios, J.M.; Mengod, G. Distribution of 5-HT and DA receptors in primate prefrontal cortex: Implications for pathophysiology and treatment. Prog. Brain Res. 2008, 172, 101–115. [Google Scholar] [CrossRef] [Green Version]
  35. Chudasama, Y.; Robbins, T.W. Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex. Neuropsychopharmacology 2004, 29, 1628–1636. [Google Scholar] [CrossRef] [Green Version]
  36. Floresco, S.B.; Phillips, A.G. Delay-dependent modulation of memory retrieval by infusion of a dopamine D1 agonist into the rat medial prefrontal cortex. Behav. Neurosci. 2001, 115, 934–939. [Google Scholar] [CrossRef] [PubMed]
  37. Vijayraghavan, S.; Wang, M.; Birnbaum, S.G.; Williams, G.V.; Arnsten, A.F. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat. Neurosci. 2007, 10, 376–384. [Google Scholar] [CrossRef]
  38. Arnsten, A.F.; Cai, J.X.; Steere, J.C.; Goldman-Rakic, P.S. Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: The effects of quinpirole on memory and motor performance in monkeys. J. Neurosci. 1995, 15, 3429–3439. [Google Scholar] [CrossRef]
  39. Ramaekers, J.G.; Louwerens, J.W.; Muntjewerff, N.D.; Milius, H.; de Bie, A.; Rosenzweig, P.; Patat, A.; O’Hanlon, J.F. Psychomotor, Cognitive, extrapyramidal, and affective functions of healthy volunteers during treatment with an atypical (amisulpride) and a classic (haloperidol) antipsychotic. J. Clin. Psychopharmacol. 1999, 19, 209–221. [Google Scholar] [CrossRef]
  40. Mehta, M.A.; Montgomery, A.J.; Kitamura, Y.; Grasby, P.M. Dopamine D2 receptor occupancy levels of acute sulpiride challenges that produce working memory and learning impairments in healthy volunteers. Psychopharmacology 2008, 196, 157–165. [Google Scholar] [CrossRef]
  41. Mehta, M.A.; Sahakian, B.J.; McKenna, P.J.; Robbins, T.W. Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson’s disease. Psychopharmacology 1999, 146, 162–174. [Google Scholar] [CrossRef]
  42. Watson, D.J.; Loiseau, F.; Ingallinesi, M.; Millan, M.J.; Marsden, C.A.; Fone, K.C. Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: A key role for the prefrontal cortex. Neuropsychopharmacology 2012, 37, 770–786. [Google Scholar] [CrossRef]
  43. Leggio, G.M.; Torrisi, S.A.; Mastrogiacomo, R.; Mauro, D.; Chisari, M.; Devroye, C.; Scheggia, D.; Nigro, M.; Geraci, F.; Pintori, N.; et al. The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans. Mol. Psychiatry 2019, 1–14. [Google Scholar] [CrossRef]
  44. Sokoloff, P.; Le Foll, B. The dopamine D3 receptor, a quarter century later. Eur. J. Neurosci. 2017, 45, 2–19. [Google Scholar] [CrossRef]
  45. Heintz, N. Gene expression nervous system atlas (GENSAT). Nat. Neurosci. 2004, 7, 483. [Google Scholar] [CrossRef]
  46. Clarkson, R.L.; Liptak, A.T.; Gee, S.M.; Sohal, V.S.; Bender, K.J. D3 Receptors Regulate Excitability in a Unique Class of Prefrontal Pyramidal Cells. J. Neurosci. 2017, 37, 5846–5860. [Google Scholar] [CrossRef] [Green Version]
  47. Black, K.J.; Hershey, T.; Koller, J.M.; Videen, T.O.; Mintun, M.A.; Price, J.L.; Perlmutter, J.S. A possible substrate for dopamine-related changes in mood and behavior: Prefrontal and limbic effects of a D3-preferring dopamine agonist. Proc. Natl. Acad. Sci. USA 2002, 99, 17113–17118. [Google Scholar] [CrossRef] [Green Version]
  48. Glickstein, S.B.; Desteno, D.A.; Hof, P.R.; Schmauss, C. Mice lacking dopamine D2 and D3 receptors exhibit differential activation of prefrontal cortical neurons during tasks requiring attention. Cereb. Cortex 2005, 15, 1016–1024. [Google Scholar] [CrossRef]
  49. Glickstein, S.B.; Hof, P.R.; Schmauss, C. Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits. J. Neurosci. 2002, 22, 5619–5629. [Google Scholar] [CrossRef] [Green Version]
  50. Nakajima, S.; Gerretsen, P.; Takeuchi, H.; Caravaggio, F.; Chow, T.; Le Foll, B.; Mulsant, B.; Pollock, B.; Graff-Guerrero, A. The potential role of dopamine D(3) receptor neurotransmission in cognition. Eur. Neuropsychopharmacol. 2013, 23, 799–813. [Google Scholar] [CrossRef] [Green Version]
  51. Cools, R. Dopaminergic control of the striatum for high-level cognition. Curr. Opin. Neurobiol. 2011, 21, 402–407. [Google Scholar] [CrossRef]
  52. Darvas, M.; Palmiter, R.D. Restriction of dopamine signaling to the dorsolateral striatum is sufficient for many cognitive behaviors. Proc. Natl. Acad. Sci. USA 2009, 106, 14664–14669. [Google Scholar] [CrossRef] [Green Version]
  53. Lodge, D.J.; Grace, A.A. Amphetamine activation of hippocampal drive of mesolimbic dopamine neurons: A mechanism of behavioral sensitization. J. Neurosci. 2008, 28, 7876–7882. [Google Scholar] [CrossRef] [Green Version]
  54. Lodge, D.J.; Grace, A.A. Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends Pharmacol. Sci. 2011, 32, 507–513. [Google Scholar] [CrossRef] [Green Version]
  55. Weinberger, D.R. Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 1987, 44, 660–669. [Google Scholar] [CrossRef]
  56. Kahn, R.S.; Harvey, P.D.; Davidson, M.; Keefe, R.S.; Apter, S.; Neale, J.M.; Mohs, R.C.; Davis, K.L. Neuropsychological correlates of central monoamine function in chronic schizophrenia: Relationship between CSF metabolites and cognitive function. Schizophr. Res. 1994, 11, 217–224. [Google Scholar] [CrossRef]
  57. Tomasella, E.; Bechelli, L.; Ogando, M.B.; Mininni, C.; Di Guilmi, M.N.; De Fino, F.; Zanutto, S.; Elgoyhen, A.B.; Marin-Burgin, A.; Gelman, D.M. Deletion of dopamine D2 receptors from parvalbumin interneurons in mouse causes schizophrenia-like phenotypes. Proc. Natl. Acad. Sci. USA 2018, 115, 3476–3481. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Slifstein, M.; van de Giessen, E.; Van Snellenberg, J.; Thompson, J.L.; Narendran, R.; Gil, R.; Hackett, E.; Girgis, R.; Ojeil, N.; Moore, H.; et al. Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: A positron emission tomographic functional magnetic resonance imaging study. JAMA Psychiatry 2015, 72, 316–324. [Google Scholar] [CrossRef]
  59. Thompson, J.L.; Rosell, D.R.; Slifstein, M.; Girgis, R.R.; Xu, X.; Ehrlich, Y.; Kegeles, L.S.; Hazlett, E.A.; Abi-Dargham, A.; Siever, L.J. Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: A PET study with [(1)(1)C]NNC112. Psychopharmacology 2014, 231, 4231–4240. [Google Scholar] [CrossRef] [Green Version]
  60. Abi-Dargham, A.; Mawlawi, O.; Lombardo, I.; Gil, R.; Martinez, D.; Huang, Y.; Hwang, D.R.; Keilp, J.; Kochan, L.; Van Heertum, R.; et al. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J. Neurosci. 2002, 22, 3708–3719. [Google Scholar] [CrossRef] [Green Version]
  61. Abi-Dargham, A.; Xu, X.; Thompson, J.L.; Gil, R.; Kegeles, L.S.; Urban, N.; Narendran, R.; Hwang, D.R.; Laruelle, M.; Slifstein, M. Increased prefrontal cortical D(1) receptors in drug naive patients with schizophrenia: A PET study with [(1)(1)C]NNC112. J. Psychopharmacol. 2012, 26, 794–805. [Google Scholar] [CrossRef] [PubMed]
  62. Durstewitz, D.; Seamans, J.K. The dual-state theory of prefrontal cortex dopamine function with relevance to catechol-o-methyltransferase genotypes and schizophrenia. Biol. Psychiatry 2008, 64, 739–749. [Google Scholar] [CrossRef]
  63. Papaleo, F.; Yang, F.; Garcia, S.; Chen, J.; Lu, B.; Crawley, J.N.; Weinberger, D.R. Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol. Psychiatry 2012, 17, 85–98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Fusar-Poli, P.; Howes, O.D.; Allen, P.; Broome, M.; Valli, I.; Asselin, M.C.; Grasby, P.M.; McGuire, P.K. Abnormal frontostriatal interactions in people with prodromal signs of psychosis: A multimodal imaging study. Arch. Gen. Psychiatry 2010, 67, 683–691. [Google Scholar] [CrossRef] [Green Version]
  65. Krabbe, S.; Duda, J.; Schiemann, J.; Poetschke, C.; Schneider, G.; Kandel, E.R.; Liss, B.; Roeper, J.; Simpson, E.H. Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area. Proc. Natl. Acad. Sci. USA 2015, 112, E1498–E1506. [Google Scholar] [CrossRef] [Green Version]
  66. Bach, M.E.; Simpson, E.H.; Kahn, L.; Marshall, J.J.; Kandel, E.R.; Kellendonk, C. Transient and selective overexpression of D2 receptors in the striatum causes persistent deficits in conditional associative learning. Proc. Natl. Acad. Sci. USA 2008, 105, 16027–16032. [Google Scholar] [CrossRef] [Green Version]
  67. Kellendonk, C.; Simpson, E.H.; Polan, H.J.; Malleret, G.; Vronskaya, S.; Winiger, V.; Moore, H.; Kandel, E.R. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 2006, 49, 603–615. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Conn, K.A.; Burne, T.H.J.; Kesby, J.P. Subcortical Dopamine and Cognition in Schizophrenia: Looking Beyond Psychosis in Preclinical Models. Front. Neurosci. 2020, 14, 542. [Google Scholar] [CrossRef]
  69. Arnsten, A.F.; Girgis, R.R.; Gray, D.L.; Mailman, R.B. Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. Biol. Psychiatry 2017, 81, 67–77. [Google Scholar] [CrossRef] [Green Version]
  70. Mu, Q.; Johnson, K.; Morgan, P.S.; Grenesko, E.L.; Molnar, C.E.; Anderson, B.; Nahas, Z.; Kozel, F.A.; Kose, S.; Knable, M.; et al. A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia. Schizophr. Res. 2007, 94, 332–341. [Google Scholar] [CrossRef]
  71. Rosell, D.R.; Zaluda, L.C.; McClure, M.M.; Perez-Rodriguez, M.M.; Strike, K.S.; Barch, D.M.; Harvey, P.D.; Girgis, R.R.; Hazlett, E.A.; Mailman, R.B.; et al. Effects of the D1 dopamine receptor agonist dihydrexidine (DAR-0100A) on working memory in schizotypal personality disorder. Neuropsychopharmacology 2015, 40, 446–453. [Google Scholar] [CrossRef]
  72. Girgis, R.R.; Van Snellenberg, J.X.; Glass, A.; Kegeles, L.S.; Thompson, J.L.; Wall, M.; Cho, R.Y.; Carter, C.S.; Slifstein, M.; Abi-Dargham, A.; et al. A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia. J. Psychopharmacol. 2016, 30, 428–435. [Google Scholar] [CrossRef]
  73. Meltzer, H.Y.; Rajagopal, L.; Matrisciano, F.; Hao, J.; Svensson, K.A.; Huang, M. The allosteric dopamine D1 receptor potentiator, DETQ, ameliorates subchronic phencyclidine-induced object recognition memory deficits and enhances cortical acetylcholine efflux in male humanized D1 receptor knock-in mice. Behav. Brain Res. 2019, 361, 139–150. [Google Scholar] [CrossRef]
  74. Kozak, R.; Kiss, T.; Dlugolenski, K.; Johnson, D.E.; Gorczyca, R.R.; Kuszpit, K.; Harvey, B.D.; Stolyar, P.; Sukoff Rizzo, S.J.; Hoffmann, W.E.; et al. Characterization of PF-6142, a Novel, Non-Catecholamine Dopamine Receptor D1 Agonist, in Murine and Nonhuman Primate Models of Dopaminergic Activation. Front. Pharmacol. 2020, 11, 1005. [Google Scholar] [CrossRef]
  75. Sun, X.; Gou, H.Y.; Li, F.; Lu, G.Y.; Song, R.; Yang, R.F.; Wu, N.; Su, R.B.; Cong, B.; Li, J. Y-QA31, a novel dopamine D3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia. Acta Pharmacol. Sin. 2016, 37, 322–333. [Google Scholar] [CrossRef] [Green Version]
  76. Krogmann, A.; Peters, L.; von Hardenberg, L.; Bodeker, K.; Nohles, V.B.; Correll, C.U. Keeping up with the therapeutic advances in schizophrenia: A review of novel and emerging pharmacological entities. CNS Spectr. 2019, 24, 38–69. [Google Scholar] [CrossRef]
  77. Bitter, I.; Lieberman, J.A.; Gaudoux, F.; Sokoloff, P.; Groc, M.; Chavda, R.; Delsol, C.; Barthe, L.; Brunner, V.; Fabre, C.; et al. Randomized, double-blind, placebo-controlled study of F17464, a preferential D3 antagonist, in the treatment of acute exacerbation of schizophrenia. Neuropsychopharmacology 2019, 44, 1917–1924. [Google Scholar] [CrossRef] [PubMed]
  78. Slifstein, M.; Abi-Dargham, A.; Girgis, R.R.; Suckow, R.F.; Cooper, T.B.; Divgi, C.R.; Sokoloff, P.; Leriche, L.; Carberry, P.; Oya, S.; et al. Binding of the D3-preferring antipsychotic candidate F17464 to dopamine D3 and D2 receptors: A PET study in healthy subjects with [(11)C]-(+)-PHNO. Psychopharmacology 2020, 237, 519–527. [Google Scholar] [CrossRef]
  79. Leggio, G.M.; Camillieri, G.; Platania, C.B.; Castorina, A.; Marrazzo, G.; Torrisi, S.A.; Nona, C.N.; D’Agata, V.; Nobrega, J.; Stark, H.; et al. Dopamine D3 receptor is necessary for ethanol consumption: An approach with buspirone. Neuropsychopharmacology 2014, 39, 2017–2028. [Google Scholar] [CrossRef]
  80. Torrisi, S.A.; Salomone, S.; Geraci, F.; Caraci, F.; Bucolo, C.; Drago, F.; Leggio, G.M. Buspirone Counteracts MK-801-Induced Schizophrenia-Like Phenotypes through Dopamine D3 Receptor Blockade. Front. Pharmacol. 2017, 8, 710. [Google Scholar] [CrossRef]
  81. Kardos, J.; Dobolyi, A.; Szabo, Z.; Simon, A.; Lourmet, G.; Palkovits, M.; Heja, L. Molecular Plasticity of the Nucleus Accumbens Revisited-Astrocytic Waves Shall Rise. Mol. Neurobiol. 2019, 56, 7950–7965. [Google Scholar] [CrossRef] [Green Version]
  82. Huang, M.; Kwon, S.; He, W.; Meltzer, H.Y. Neurochemical arguments for the use of dopamine D4 receptor stimulation to improve cognitive impairment associated with schizophrenia. Pharmacol. Biochem. Behav. 2017, 157, 16–23. [Google Scholar] [CrossRef]
  83. Miyauchi, M.; Neugebauer, N.M.; Meltzer, H.Y. Dopamine D4 receptor stimulation contributes to novel object recognition: Relevance to cognitive impairment in schizophrenia. J. Psychopharmacol. 2017, 31, 442–452. [Google Scholar] [CrossRef]
  84. Rajagopal, L.; Kwon, S.; Huang, M.; Michael, E.; Bhat, L.; Cantillon, M.; Meltzer, H.Y. RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia. Behav. Brain Res. 2017, 332, 180–199. [Google Scholar] [CrossRef]
  85. Lee, M.A.; Thompson, P.A.; Meltzer, H.Y. Effects of clozapine on cognitive function in schizophrenia. J. Clin. Psychiatry 1994, 55 (Suppl. B), 82–87. [Google Scholar]
  86. Purdon, S.E.; Woodward, N.D.; Mintz, A.; LaBelle, A. Procedural learning improvements after six weeks of clozapine treatment. Schizophr. Res. 2002, 53, 165–166. [Google Scholar] [CrossRef]
  87. Regen, F.; Cosma, N.C.; Otto, L.R.; Clemens, V.; Saksone, L.; Gellrich, J.; Uesekes, B.; Ta, T.M.T.; Hahn, E.; Dettling, M.; et al. Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia. Mol. Psychiatry 2020. [Google Scholar] [CrossRef]
  88. Meltzer, H.Y. An overview of the mechanism of action of clozapine. J. Clin. Psychiatry 1994, 55 (Suppl. B), 47–52. [Google Scholar]
  89. Kawano, M.; Oshibuchi, H.; Kawano, T.; Muraoka, H.; Tsutsumi, T.; Yamada, M.; Inada, K.; Ishigooka, J. Dopamine dynamics during emotional cognitive processing: Implications of the specific actions of clozapine compared with haloperidol. Eur. J. Pharmacol. 2016, 781, 148–156. [Google Scholar] [CrossRef]
  90. Elsworth, J.D.; Jentsch, J.D.; Morrow, B.A.; Redmond, D.E., Jr.; Roth, R.H. Clozapine normalizes prefrontal cortex dopamine transmission in monkeys subchronically exposed to phencyclidine. Neuropsychopharmacology 2008, 33, 491–496. [Google Scholar] [CrossRef] [Green Version]
  91. Aoyama, Y.; Mouri, A.; Toriumi, K.; Koseki, T.; Narusawa, S.; Ikawa, N.; Mamiya, T.; Nagai, T.; Yamada, K.; Nabeshima, T. Clozapine ameliorates epigenetic and behavioral abnormalities induced by phencyclidine through activation of dopamine D1 receptor. Int. J. Neuropsychopharmacol. 2014, 17, 723–737. [Google Scholar] [CrossRef] [Green Version]
  92. Woodward, N.D.; Jayathilake, K.; Meltzer, H.Y. COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophr. Res. 2007, 90, 86–96. [Google Scholar] [CrossRef]
  93. Leysen, J.E.; Janssen, P.M.; Megens, A.A.; Schotte, A. Risperidone: A novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. J. Clin. Psychiatry 1994, 55 (Suppl. 5–12). [Google Scholar]
  94. Casey, A.B.; Canal, C.E. Classics in Chemical Neuroscience: Aripiprazole. ACS Chem. Neurosci. 2017, 8, 1135–1146. [Google Scholar] [CrossRef]
  95. Fejgin, K.; Safonov, S.; Palsson, E.; Wass, C.; Engel, J.A.; Svensson, L.; Klamer, D. The atypical antipsychotic, aripiprazole, blocks phencyclidine-induced disruption of prepulse inhibition in mice. Psychopharmacology 2007, 191, 377–385. [Google Scholar] [CrossRef] [PubMed]
  96. Braff, D.L. Information processing and attention dysfunctions in schizophrenia. Schizophr. Bull. 1993, 19, 233–259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Tuplin, E.W.; Holahan, M.R. Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity. Curr. Neuropharmacol. 2017, 15, 1192–1207. [Google Scholar] [CrossRef] [Green Version]
  98. Nagai, T.; Murai, R.; Matsui, K.; Kamei, H.; Noda, Y.; Furukawa, H.; Nabeshima, T. Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors. Psychopharmacology 2009, 202, 315–328. [Google Scholar] [CrossRef]
  99. Kim, E.; Howes, O.D.; Turkheimer, F.E.; Kim, B.H.; Jeong, J.M.; Kim, J.W.; Lee, J.S.; Jang, I.J.; Shin, S.G.; Kapur, S.; et al. The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory: A dual [(11)C]raclopride and [(18) F]FDG imaging study with aripiprazole. Psychopharmacology 2013, 227, 221–229. [Google Scholar] [CrossRef] [PubMed]
  100. Shin, S.; Kim, S.; Seo, S.; Lee, J.S.; Howes, O.D.; Kim, E.; Kwon, J.S. The relationship between dopamine receptor blockade and cognitive performance in schizophrenia: A [(11)C]-raclopride PET study with aripiprazole. Transl. Psychiatry 2018, 8, 87. [Google Scholar] [CrossRef]
  101. Shahid, M.; Walker, G.B.; Zorn, S.H.; Wong, E.H. Asenapine: A novel psychopharmacologic agent with a unique human receptor signature. J. Psychopharmacol. 2009, 23, 65–73. [Google Scholar] [CrossRef]
  102. Snigdha, S.; Idris, N.; Grayson, B.; Shahid, M.; Neill, J.C. Asenapine improves phencyclidine-induced object recognition deficits in the rat: Evidence for engagement of a dopamine D1 receptor mechanism. Psychopharmacology 2011, 214, 843–853. [Google Scholar] [CrossRef]
  103. Jardemark, K.; Marcus, M.M.; Shahid, M.; Svensson, T.H. Effects of asenapine on prefrontal N-methyl-D-aspartate receptor-mediated transmission: Involvement of dopamine D1 receptors. Synapse 2010, 64, 870–874. [Google Scholar] [CrossRef] [PubMed]
  104. Ohoyama, K.; Yamamura, S.; Hamaguchi, T.; Nakagawa, M.; Motomura, E.; Shiroyama, T.; Tanii, H.; Okada, M. Effect of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex. Eur. J. Pharmacol. 2011, 653, 47–57. [Google Scholar] [CrossRef]
  105. Tadori, Y.; Forbes, R.A.; McQuade, R.D.; Kikuchi, T. Functional potencies of dopamine agonists and antagonists at human dopamine D(2) and D(3) receptors. Eur. J. Pharmacol. 2011, 666, 43–52. [Google Scholar] [CrossRef] [PubMed]
  106. Hida, H.; Mouri, A.; Mori, K.; Matsumoto, Y.; Seki, T.; Taniguchi, M.; Yamada, K.; Iwamoto, K.; Ozaki, N.; Nabeshima, T.; et al. Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: The complex mechanism of blonanserin action involving D(3)-5-HT(2)A and D(1)-NMDA receptors in the mPFC. Neuropsychopharmacology 2015, 40, 601–613. [Google Scholar] [CrossRef]
  107. Huang, M.; Kwon, S.; Oyamada, Y.; Rajagopal, L.; Miyauchi, M.; Meltzer, H.Y. Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement. Pharmacol. Biochem. Behav. 2015, 138, 49–57. [Google Scholar] [CrossRef]
  108. Kotani, M.; Enomoto, T.; Murai, T.; Nakako, T.; Iwamura, Y.; Kiyoshi, A.; Matsumoto, K.; Matsumoto, A.; Ikejiri, M.; Nakayama, T.; et al. The atypical antipsychotic blonanserin reverses (+)-PD-128907- and ketamine-induced deficit in executive function in common marmosets. Behav. Brain Res. 2016, 305, 212–217. [Google Scholar] [CrossRef] [PubMed]
  109. Calabrese, F.; Tarazi, F.I.; Racagni, G.; Riva, M.A. The role of dopamine D3 receptors in the mechanism of action of cariprazine. CNS Spectr. 2020, 25, 345–351. [Google Scholar] [CrossRef]
  110. Pich, E.M.; Collo, G. Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective drugs. Eur. Neuropsychopharmacol. 2015, 25, 1437–1447. [Google Scholar] [CrossRef]
  111. Zimnisky, R.; Chang, G.; Gyertyan, I.; Kiss, B.; Adham, N.; Schmauss, C. Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. Psychopharmacology 2013, 226, 91–100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Neill, J.C.; Grayson, B.; Kiss, B.; Gyertyan, I.; Ferguson, P.; Adham, N. Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology. Eur. Neuropsychopharmacol. 2016, 26, 3–14. [Google Scholar] [CrossRef]
  113. Watson, D.J.G.; King, M.V.; Gyertyan, I.; Kiss, B.; Adham, N.; Fone, K.C.F. The dopamine D(3)-preferring D(2)/D(3) dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia. Eur. Neuropsychopharmacol. 2016, 26, 208–224. [Google Scholar] [CrossRef]
  114. Maeda, K.; Lerdrup, L.; Sugino, H.; Akazawa, H.; Amada, N.; McQuade, R.D.; Stensbol, T.B.; Bundgaard, C.; Arnt, J.; Kikuchi, T. Brexpiprazole II: Antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator. J. Pharmacol. Exp. Ther. 2014, 350, 605–614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Bjorkholm, C.; Marcus, M.M.; Konradsson-Geuken, A.; Jardemark, K.; Svensson, T.H. The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism. Eur. Neuropsychopharmacol. 2017, 27, 411–417. [Google Scholar] [CrossRef]
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MDPI and ACS Style

Torrisi, S.A.; Laudani, S.; Contarini, G.; De Luca, A.; Geraci, F.; Managò, F.; Papaleo, F.; Salomone, S.; Drago, F.; Leggio, G.M. Dopamine, Cognitive Impairments and Second-Generation Antipsychotics: From Mechanistic Advances to More Personalized Treatments. Pharmaceuticals 2020, 13, 365.

AMA Style

Torrisi SA, Laudani S, Contarini G, De Luca A, Geraci F, Managò F, Papaleo F, Salomone S, Drago F, Leggio GM. Dopamine, Cognitive Impairments and Second-Generation Antipsychotics: From Mechanistic Advances to More Personalized Treatments. Pharmaceuticals. 2020; 13(11):365.

Chicago/Turabian Style

Torrisi, Sebastiano Alfio, Samuele Laudani, Gabriella Contarini, Angelina De Luca, Federica Geraci, Francesca Managò, Francesco Papaleo, Salvatore Salomone, Filippo Drago, and Gian Marco Leggio. 2020. "Dopamine, Cognitive Impairments and Second-Generation Antipsychotics: From Mechanistic Advances to More Personalized Treatments" Pharmaceuticals 13, no. 11: 365.

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