Figure 1. Red dots represent phosphorylation events. Dopamine exerts its effects via the stimulation of five different G-protein coupled dopamine receptors Figure 1. These receptors are divided in two groups based on their coupling and gene structures D1-class receptors mediate post-synaptic responses to dopamine.
In contrast D2-class receptors can both mediate post-synaptic responses and act as presynaptic auto-receptors to limit dopamine synthesis and release Of note, the DRD2 gene encodes two splice variants of the receptor. The long isoform D2L is mostly expressed on post-synaptic neurons while the short isoform D2S is preferentially expressed by pre-synaptic dopamine neurons Activation of D2-class receptor results in a reduction of cAMP by inhibiting this same mechanism PKA are holoenzymes comprised of a catalytic subunit and different regulatory subunits.
Regulation of PKA activity by dopamine receptors is involved in several cellular processes including, among others, the regulation of gene expression by transcription factors and the regulation of ionotropic receptors for various neurotransmitters. Among several targets of interest, the activity of cAMP response elements binding proteins family of leucine zipper transcription factors i.
The signaling of dopamine receptors is not restricted to the regulation of cAMP production. Furthermore, DRD2 modulates neuronal function by acting on G-protein independent mechanisms. Following their activation, dopamine receptors are phosphorylated by G-protein receptor kinases e.
This leads to the recruitment of beta-arrestins ARBB1 and ARBB2 , which inactivate G-protein coupling, stimulate receptor internalization and mediate additional cell signaling functions 33 , However, beta-catenin does not appear to be a major determinant of antipsychotic drug action downstream of DRD2 in mice The RNA binding protein fragile-X-mental-retardation-autosomal-homolog-1 FXR1 is a recently identified GSK3B substrate 39 that has been shown to modulate ionotropic glutamate receptor functions in vivo 40 , In particular, genetics studies on schizophrenia endo-phenotypes, i.
Candidate gene investigations have identified allelic variation in SNPs of functional relevance to D2, D3, and D4 receptors to be associated with response to antipsychotic medication Table 2.
Table 2. Genetic studies on the role of DRD2 genetic variation in the pathophysiology and risk for schizophrenia and response to antipsychotics have been motivated by the evidence that DRD2 antagonism is a key mechanism of action of antipsychotic agents to the extent that occupancy of this receptor subtype is correlated with antipsychotic potency Table 1.
For example, rs also known as Taq1A is a missense variant determining a Glu-to-Lys substitution at position of DRD2 gene and associated with the gene mRNA stability and expression 68 , striatal dopamine receptor density 69 , and modification in DRD2 binding in human striatum Interestingly, rs has been associated with performance in Working Memory, a prototypical endophenotypes of schizophrenia, mainly subtended by pre-frontal cortex activity Similarly, rs, a SNP occurring in DRD2 gene and determining a Ser-to-Cys substitution at position of DRD2 gene SerCys has been shown to alter the physiology and function of DRD2 receptor 72 and has consistently been associated with risk for schizophrenia in a number of studies since 73 —for a meta-analysis see: Rs has been associated with risk for schizophrenia 76 , behavior and brain activity during cognitive and emotion processing in healthy controls and patients with schizophrenia 77 , with efficiency of pre-fronto-striatal activity during Working Memory 78 and levels of striatal dopamine For example, rs, a cis -eQTL of AKT1 gene that interacts with rs in affecting pre-frontal AKT1 mRNA expression levels along with level of phosphorylation of the AKT1 kinase target GSK3beta, interacts with rs also on cingulate cortex activity during attentional control, another cognitive function typically impaired by schizophrenia Similarly, rs 80 and rs 81 , two eQTLs of GSK3beta and PPP2R2B gene, respectively, have been associated with cognitive performance and related brain activity critically implicated in the disorder.
Functional variation of DRD2 gene has also been studied as predictor of antipsychotic response, for a review see: In general, dopamine receptors variants associated with reduced expression of the receptor protein or altered functioning were also associated with poorer response to antipsychotic drugs, confirming that these receptors mediate antipsychotic activity.
Rs has been associated with response to nemonapride 43 , haloperidol 44 , risperidone 45 , and clozapine Similarly, rs has been associated with response to risperidone 47 , while interaction between rs and rs has been implicated in response to olanzapine as measured by variation in Positive and Negative Symptoms Scale total scores after 56 days of stable dosage treatment Other SNPs in DRD2 have been associated with antipsychotics response, including rs, also known as Taq1B, whose B1 allele has been associated with reduced DRD2 protein density in the striatum, and B2 allele has been implicated in response to clozapine Further mutations have been associated with clinical response to chlorpromazine 49 and aripiprazole DRD3 has systematically been studied by pharmacogenetics since many antipsychotic drugs show high affinity for the D3 dopamine receptor A missense polymorphism in exon 1 of DRD3 leading to a serine to glycine substitution at amino acid position 9 rs has been associated with altered DRD3 dopamine affinity and density in some brain areas 84 along with response to first-generation antipsychotics and lack of response to clozapine Some studies 52 found rs to be associated with greater acute positive symptom remission after olanzapine treatment.
The same effects were observed for different SNPs in linkage disequilibrium with rs Further studies have also implicated rs in response to the second-generation antipsychotic aripiprazole Evidence has also established a correlation between response to antipsychotics and functional genetic variation of the DRD4 gene.
In particular, since DRD4 is targeted by clozapine, the most effective antipsychotic drug currently available 85 , studies have particularly focused on the effect of genetic variability of corresponding gene on response to such a drug.
Importantly, the longer repeat version of the protein has been associated with reduced clozapine binding, thus suggesting the 48 bp VNTR to be an interesting candidate polymorphism to study as predictor of clinical response to this antipsychotic. However, while some studies have reported an effect of rs on responsiveness to various antipsychotics including clozapine 54 — 57 several other studies also reported no associations, as reviewed in Zhang and Malhotra Along with genes coding for dopamine receptors, other genes belonging to the dopaminergic system have also been implicated in pathophysiology and risk for schizophrenia, hence becoming candidate genes for as regulators of response to antipsychotics Table 2.
A large number of studies have investigated the genetic association between rs and the diagnosis of schizophrenia with mixed results—for a meta-analysis see: In line with the role of COMT in dopamine turnover, pharmacogenetic investigations have reported an association between rs allelic variations and the clinical response to antipsychotics acting on dopamine receptors.
A number of additional studies, then, confirmed the impact of the COMT ValMet polymorphism on the efficacy of first-generation 61 , 62 and second-generation antipsychotics 63 , 64 , Studies have also implicated SLC6A3 , coding for the dopamine transporter, in schizophrenia phenotypes and response to medication.
Alleles of this polymorphism range from 3 to 11 repeats, with the 9- and repeat alleles by far the most common 88 , As compared with the 9-repeat allele, the repeat allele has been associated with increased SLC6A3 gene expression both in vitro 90 , 91 and in human striatum Furthermore, studies have reported that the repeat allele is associated with more focused cortical activity during memory and attention, two critical endophenotypes of schizophrenia 93 — Evidence has also documented an interaction between DRD2 rs and SLC6A3 3'-VNTR on further imaging phenotypes associated with the disorder, such as pre-fronto-striatal activity and volume in humans Although not directly targeted by antipsychotic medications, the dopamine transporter, may influence dopamine-signaling intensity by virtue of its function of dopamine clearance at the synaptic level and contribute to treatment outcome.
Consistently, a number of studies have reported association between polymorphisms in the gene coding for this transporter, including 3'-VNTR and level of response to first and second-generation antipsychotics 65 , GWAS have allowed for detection of genetic variants associated with a specific disease without any a priori hypothesis on its pathophysiology hypothesis-free or data-driven studies.
Such an approach has confirmed the polygenic nature of risk for schizophrenia since it has identified more than one hundred genetic variants associated with the disorder at genome wide statistical level of significance i. Furthermore, studies attempting at collapsing GWAS multigenic risk in so called Polygenic Risk Scores PRSs have probed these scores to predict behavioral and neuroimaging phenotypes of schizophrenia Nevertheless, since GWAS and PRSs do not provide any specific insights into the biological role of genetic variation associated with a disease, different approaches have been developed in order to dissect risk into biologically meaningful pathways and probe the impact of pathway-specific risk variants and PRSs onto pathophysiology of schizophrenia and related phenotypes Several genes, including DRD2 , have been associated with schizophrenia by GWAS, even though, most findings have implicated different variants from those detected by candidate gene approaches 1.
Nonetheless, as for candidate genes investigation, risk variants identified by GWAS have been implicated in response to antipsychotic medication, confirming the hypothesis that schizophrenia pathophysiology and response to treatment share genetic bases that are partially involving dopamine signaling.
Zhang and collaborators 50 examined whether genotype at this SNP could predict response to 12 weeks of risperidone or aripiprazole treatment in a cohort of patients with first episode of psychosis and found that homozygotes for the risk C allele at this SNP had significantly greater reduction in positive symptoms after treatment with either risperidone or aripiprazole as compared to the T allele carriers.
From a pharmacogenomics perspective, a pivotal role in the study of antipsychotics response has been played by the Clinical Antipsychotics Trials of Intervention Effectiveness CATIE , a multicenter research project promoted by the USA National Institute of Health and investigating the effectiveness of first and second-generation antipsychotics. The first GWAS 66 found a SNP rs located on Chromosome 4 in an intergenic position, to be associated with response of schizophrenia positive symptoms to the second-generation antipsychotic ziprasidone, while another SNP in the same intergenic region approached, but did not reach, genome wide significance.
Both rs and this second SNP functions remain unknown, but involvement in dopamine signaling cannot be excluded. Interestingly, in a different study, the same group looked at neurocognition as an outcome of antipsychotics response and found a weak association with SNPs in DRD2 gene.
GWAS were also used to explore the clinical response to new antipsychotics partially exerting their pharmacological action by blocking dopamine transmission. For example, two of these studies , investigated genome wide association with response to Iloperidone, an antagonist of D2 and D3 dopamine receptors also blocking noradrenergic and serotonergic neuronal signaling.
None of the SNPs reaching genome wide significance were directly involved in dopaminergic system, even though one of the genes associated, GRIA4 , codes for AMPA 4 glutamate receptor, that may impact on dopamine neurotransmission by mediation of glutamate signaling.
In fact, evidence suggests that aberrant glutamatergic function may alter dopamine system function in psychotic disorders , and dopamine exert several of its biological actions by modulating ionotropic AMPA and NMDA glutamate receptor functions 7 , Interestingly, a study looking at drugs targeting proteins encoded by genes GWAS associated with schizophrenia, found that antipsychotics are the only medication surviving enrichment procedures and that, two of the four genes associated with antipsychotic response were either directly implicated in glutamatergic signaling namely, GRIN2A or indirectly related to dopaminergic system i.
GWAS-based pharmacogenomics studies on antipsychotic response have also used PRS strategies in order to explore the cumulative role of genetic risk on pharmacological effects. For example, one study showed a PRS based on schizophrenia-associated SNPs reported by the Psychiatric Genomics Consortium 1 to predict clozapine response, in that clozapine responders had higher PRS as compared to non-responders. Furthermore, a study using a multistage GWAS-PRS-Pathway Analysis approach 6 to detect genetic variation associated with response to the second-generation antipsychotic lurasidone, suggested associated variants to belong to functional categories of relevance to neuronal transmission and being, at least partially, involved in dopamine signaling by impacting on glutamate an serotonin systems modulation.
At first glance, most schizophrenia risk SNPs identified by GWAS are not associated to genes encoding products generally related to dopamine transmission or cellular responses to antipsychotic drugs 1. However, some of these loci may still encode proteins regulated by therapeutic agents. Investigating such genes in the context of known mechanisms of antipsychotic actions may thus be a fruitful avenue for future studies.
All three proteins play a role in regulating the development of several tissues including the brain. Furthermore, these proteins are also implicated in the regulation of neuronal functions — The Fragile X mental retardation syndrome is a primary monogenic cause of autistic spectrum disorders ASDs and is caused by mutations in FMR1 gene, which is highly expressed in neurons and plays a crucial role in regulating synaptic plasticity — Proteins from this family comprise homologous amino-terminal regions containing a tandem Tudor domain which can mediate binding to methylated lysine on histones The amino-terminal region of these proteins also includes a nuclear localization and export signals NLS and NES that mediate shuttling between nucleus and cytoplasm Finally, the three proteins sequences are most divergent at the carboxyl-terminal domain, which seem to functionally distinguish members of the family All three fragile X family proteins participate to the regulation of mRNA translation, degradation, and are associated with ribosomes , , FMR1 is by far the most studied of these three proteins.
Interestingly, an exome study of rare genetic variants in schizophrenia identified an enrichment for gene encoding mRNA that are associated to FMR1 Furthermore, a postmortem study has shown altered protein levels of FMR1 targets in the frontal cortex of subjects with schizophrenia or bipolar disorder In contrast to FMR1, FXR1 came out of the shadow after its identification as one of the top 30 potential genetic risk factor for schizophrenia 1.
For a long time FXR1 was considered either a protein functionally redundant to FMR1 or as its muscle specific homolog Both FXR1 and FMR1 have been shown to interact together but can also have mutually exclusive functions and cellular localization It would thus be premature to conclude that changes in FMR1 targets identified in schizophrenia results from altered FXR1 functions since these two proteins are not biologically equivalent.
The FXR1 gene encodes seven major alternatively spliced mRNA variants Figure 2 , mouse gene used as an example , three of which are expressed specifically in muscles and testis , Altered splicing in the locus of exon 15 is associated and functionally changed in presence of the rs schizophrenia risk allele The expression of exon 15 containing isoforms of FXR1 has only been demonstrated in muscle and testicular tissues by means of western blot.
However, the presence of exon 15 RNAs has been detected by sequencing in other tissues, thus suggesting that minor amounts of the protein carrying this exon could be expressed outside of the muscle and testis Figure 2. Fxr1 gene mouse gene depicted as an example alternatively spliced mRNAs and common domain structure on example of the longest isoform—e.
The presence of exon 15 provides an additional nucleolar targeting signal. Exon 15 provides an additional nucleolar-targeting signal NoS2 , which is necessary for efficient shuttling between cytoplasm and nucleoli. Interestingly, unlike other family members that exhibit a similar cytoplasmic localization between fetal and adult tissues, FXR1 has been reported to have nuclear localization only during brain and muscle development , Thus, it is possible that alteration in the nuclear or nucleolar localization of FXR1, regulated by the NoS2 of exon 15, may contribute to increase the risk to develop schizophrenia.
In healthy humans, this interaction has been shown to affect amygdala response to emotional faces, as measured by functional Magnetic Resonance Imaging fMRI. The same interaction was observed on measures of trait Emotional Stability as conceived within the Big Five Model of Personality Finally, interaction between these functional SNPs has been replicated and showed to affect symptoms severity and, putatively, treatment responsiveness in bipolar patients Evidence for a contribution of FXR1 to dopamine signaling and responsiveness to psychiatric disorders remains preliminary.
However, the existing observations would support that FXR1 is one example of a gene for which further investigation of contribution to schizophrenia, DRD2 signaling, and antipsychotics drug responsiveness is warranted. Further examination of other GWAS identified loci may allow finding additional candidate genes of interest with more distal relations to dopamine neurotransmission.
Genetic investigations of risk factors for schizophrenia and determinants of drug responsiveness revealed a very multi-genic landscape for both indications. This suggests that schizophrenia arises from a combination of multiple genetic and socio-environmental hits occurring during development. This is also in line with the variable profile of drug responsiveness observed at the clinical level. This picture can be discouraging as several risk factors may only participate to disease at a pre-onset stage or, contribute to ubiquitous functions across different organs, thus preventing their practical or ethical use as therapeutic targets.
Nonetheless, the overlap of schizophrenia risk and genes affecting responsiveness to existing drugs also points toward a nexus of biological mechanisms engaged by medication and those contributing to disease etiology. This supports the idea that disease remediation can intersect with disease causation and help compensate for developmental insults, even during adulthood. The prevalence of genes involved in dopamine transmission among those associated with treatment responsiveness is flagrant.
Furthermore, the integrated investigation of new and old variants associated both to genetic risk and treatment responsiveness can provides the bases for the development of personalized treatment protocols for schizophrenia.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Biological insights from schizophrenia-associated genetic loci. Nature —7. Genome-scale neurogenetics: methodology and meaning.
Nat Neurosci. While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada the dosages at which this happens are below those needed to alleviate psychosis. Relevance: The "fast-off-D2" theory, on the other hand, predicts which antipsychotic compounds will or will not produce EPS and hyperprolactinemia and which compounds present a relatively low risk for tardive dyskinesia.
This theory also explains why L-dopa psychosis responds to low atypical antipsychotic dosages, and it suggests various individualized treatment strategies. Abstract Background: Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms EPS. Publication types Research Support, Non-U. Gov't Research Support, U.
Gov't, P. This pattern is similar to that observed in some electrophysiological studies, where clozapine displays a state-dependent action, reducing neuronal hyperactivity e. Thus, clozapine would activate the mesocortical DA system from basal conditions but would dampen cortical hyperactivity. The inability of clozapine to counteract DOI's effect in these rats suggests the involvement of other receptors, different from 5-HT 2A Rs, to reverse the action of DOI in control rats.
Alternatively, it is conceivable that other receptor—receptor interactions might explain this marked discrepancy between in-vitro and in-vivo actions of APDs at 5-HT 1A Rs. Our conclusions are restricted to the role of 5-HT receptors required to enhance mesocortical DA, an effect potentially important for the actions of APDs on negative symptoms and cognitive deficits of schizophrenia patients.
Given the lack of adequate treatment of these problems, further detailed studies are required to examine the ability of APDs — and in particular, of clozapine — to stimulate cortical 5-HT 1A R-mediated neurotransmission despite their low or negligible in-vitro affinity.
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