Dopaminergic Hypothesis Research Articles

Brain metabolic profiling of schizophrenia: a path towards a better understanding of the neuropathogenesis of psychosis.

Schizophrenia (SCZ) is a complex psychotic syndrome whose pathogenesis involves countless protagonists, none of which, to date, can fully explain how this disorder develops. In this narrative review, an overview of the biochemical impairment is offered according to several perspectives. Indeed, the metabolic framework behind SCZ dopaminergic hypotheses, glutamate - gamma-amynobutyric acid dysregulation, norepinephrine and serotonin, calcium channel dysfunction is addressed together with the energetic impairment, involving glucose and lipids in SCZ etiopathogenesis, in order to highlight the multilevel pathways affected in this neuropsychiatric disorder. Furthermore, neuroinflammation is analyzed, by virtue of its important role, widely investigated in recent years, in neurodegeneration. Tracing the neurotransmitter activity at the brain level by assessing the metabolic network behind the abovementioned molecules puts into light as unavoidable the need for future studies to adopt an integrate approach to address SCZ pathological and clinical picture. The combination of all these factors, essential in acquiring an overview on the complexity of SCZ pathophysiology represents a crucial step in the development of a more targeted management of SCZ patients.

Neurobiology of Attention Deficit Hyperactivity Disorder (ADHD): A brief review

Attention deficit hyperactivity disorder (ADHD) is a common condition associated with long-lasting psychosocial functioning difficulties and high psychiatric morbidity. ADHD is a heterogeneous syndrome in its clinical presentation and probably in its aetiology. Nevertheless, it can be understood as a spectrum of multifactorial cognitive, emotional, and behavioural dysfunctions under the influence of genetic and environmental factors, mainly perinatal. For several decades, the dopaminergic dysfunction hypothesis has been one of the possible pathways in the origin of ADHD. Still, other neurotransmission systems also appear to play a role, as evidenced by the recent therapeutic development of noradrenergic agonists in this indication.

Dopaminergic and glutamatergic models of psychosis show differential sensitivity to aripiprazole and a novel experimental compound modulating D2/5-HT receptor activity

Dopamine type 2 receptors (D2Rs) constitute the main molecular target in the pharmacotherapy of schizophrenia. However, the second and third generation of antipsychotics comprises multi-target ligands, also binding serotonin type 3 receptors (5-HT3Rs) and other receptor classes as well. Here, we examined two experimental compounds (marked compound K1697 and K1700) from the group of 1,4-di-substituted aromatic piperazines, previously described in the study of Juza et al., 2021, and compared them with the chosen reference antipsychotic, aripiprazole. Their efficacy against schizophrenia-like behavior was tested in two different models of psychosis in the rat, induced by acute administration of either amphetamine (1.5 mg/kg) or dizocilpine (0.1 mg/kg), reflecting the dopaminergic and glutamatergic hypotheses of schizophrenia. The two models exhibited broadly similar behavioral manifestations: hyperlocomotion, disrupted social behavior and impaired prepulse inhibition of the startle response. However, they differed in their treatment responses as hyperlocomotion and prepulse inhibition deficit in the dizocilpine model were resistant to antipsychotic treatment, unlike the amphetamine model. One of the experimental compounds, K1700, ameliorated all the observed schizophrenia-like behaviors in the amphetamine model with an efficacy comparable to or greater than aripiprazole. Whereas social impairments caused by dizocilpine were strongly suppressed by aripiprazole, K1700 was less efficient. Taken together, K1700 showed antipsychotic properties comparable to those of aripiprazole, although the efficacy of the two drugs differed in specific domains of behavior and was also model-dependent. Our present results highlight the differences in these two schizophrenia models and their responsiveness to pharmacotherapy, and confirm compound K1700 as a promising drug candidate.

The Concept of "Hypersexuality" in the Boundary between Physiological and Pathological Sexuality.

The concept of hypersexuality belongs to modern parlance, according to a predominantly clinical meaning, and is understood as a psychological and behavioural alteration as a result of which sexually motivated stimuli are sought in inappropriate ways and often experienced in a way that is not completely satisfactory. Literature up to February 2023 was reviewed, with 25 searches selected. Forty-two articles were included in the review. Hypersexuality is a potentially clinically relevant condition consisting of one or more dysfunctional and pathological behaviours of one's sexual sphere and graded according to the severity of impairment of subjective acting out; for this reason, the Perrotta Hypersexuality Global Spectrum of Gradation (PH-GSS) is suggested, which distinguishes high-functioning forms (pro-active and dynamic hypersexuality) from those of attenuated and corrupted functioning (dysfunctional and pathological hypersexuality of grades I and II). Future research is hoped to address the practical needs of this condition, such as the exact etiopathology, the role of oxytocin in dopaminergic hypotheses (and its ability to attenuate the symptomatology suffered by the patient in terms of manic drive), the best structural and functional personality framing of the subject, and the appropriate therapy to pursue.

Merging and modifying hypotheses on the emotional and cognitive effects of eye movements: The dopaminergic regulation hypothesis

The integration of hypotheses from Eye-Movement Desensitization and Reprocessing (EMDR) and Saccade Induced Retrieval Enhancement (SIRE), both of which have been met with considerable skepticism, may lead to significant gains in both domains. Cognitive accounts of EMDR, the orienting response (OR) and working memory (WM) hypotheses, and of SIRE, the interhemispheric interaction (IHI) and the top-down attentional control (TDAC) hypotheses, are discussed. The accounts show several blind spots and frictions, for instance, on re-imagining during EMs, on hemispheric lateralization, and on emotional influences of eye movements. The failure to consider these factors across and within domains may well explain the many disparate findings. This perspective aims to remove the artificial separation and seeks a theoretical integration of the domains. It combines elements of OR and TDAC into a new dopaminergic regulation hypothesis while replacing affective (i.e., positive vs. negative) by motivational mechanisms (i.e., fostering approach and recoding). EMs are posited to result in a short-latency, targeted release of dopamine, which is the central neuromodulator in approach tendencies. According to this hypothesis, the largest effects are obtained in individuals with collateralized eye dominance and dopamine dominance. Concrete suggestions are made to improve research conditions and therapeutic efficacy.

Next-generation antipsychotics- Trends and perspectives beyond dopaminergic and glutamatergic agents

IntroductionThree generations of antipsychotics, all of which are based on the dopaminergic hypothesis of schizophrenia, are available for clinical use. Still, more than 66% of the patients diagnosed with schizophrenia spectrum disorders (SSD) could not achieve remission. Also, the glutamatergic hypothesis of schizophrenia is supported by translational models of this disease, even if the antipsychotics derived from this conceptual framework are not yet available on the market. However, the need for new pathogenesis models for schizophrenia and new generations of antipsychotics is acute, therefore, an exploration of the antipsychotics in the pipeline could be helpful in understanding the current stage of research in schizophrenia.ObjectivesTo assess the evidence supporting the potential benefits of new antipsychotics in the pipeline.MethodsA literature review was performed through the main electronic databases PubMed, Cochrane, Clarivate/Web Of Science, and EMBASE) and clinical trials repositories (US National Library of Medicine and World Health Organization Clinical Trials Registry Platform) using the search paradigm “antipsychotics” AND “schizophrenia” AND “non-dopaminergic” AND “non-glutamatergic”. All papers published between January 2010 and September 2022 were included.ResultsXanomeline/trospium (xanomeline is a muscarinic M1/M4 receptor agonist at the central nervous system, while trospium limits its peripheral effects) was efficient for schizophrenia in one phase III clinical trial. Pimavanserin (a selective 5HT2A inverse agonist and antagonist) was efficient in improving negative symptoms of schizophrenia in a phase II trial. Roluperidone (a 5HT2A and σ2 receptor antagonist) has been associated with favorable results in phase III clinical trials, mainly on negative symptoms of schizophrenia. SEP-363856 is a TAAR-1 agonist and 5HT1A agonist, currently explored in phase III clinical trials for schizophrenia. MK-8189 is a phosphodiesterase 10A inhibitor, investigated in phase III clinical trials for schizophrenia.ConclusionsBased on the retrieved data in the literature, multiple mechanisms, other than glutamatergic and dopaminergic pathways, are currently being investigated, and many of the antipsychotics based on these mechanisms are in the advanced stage of research. This is important not only for the clinical need to find more efficient and tolerable drugs for patients with schizophrenia but also because they may shed new light on the pathogenesis of this disease.Disclosure of InterestNone Declared

Seventy Years of Antipsychotic Development: A Critical Review.

Since the mid-1950s discovery of the first effective antipsychotic medications (APM), we have only been able to improve the tolerability but not the overall efficacy of currently available APMs, as reflected by effectiveness trials in Europe and the United States. This inability to develop more effective APMs is attributable to multiple factors, including failure to create and use assessment tools to assess core symptom domains in schizophrenia, move beyond the dopaminergic hypothesis and to develop "me too" drugs, imposing ill-defined research domain criteria, and lacking federal funding for clinical trials. The classification of APMs is also confusing, including second-generation, partial agonists, and multimodal APMs in the same class of APMs, despite significant differences in their mechanisms of action. Other factors stagnating drug development include inadequate sample sizes to address heterogeneity, lack of statistical measures correlating with clinical significance, using the atheoretical basis of psychiatric diagnoses, failure to control placebo response, and high cost of newer and perhaps more tolerable APMs. Furthermore, there has been a failure to develop early predictors of antipsychotic response and various tools to optimize an APM response. Finally, some mental health providers are also responsible for the suboptimal use of APMs, by using excessive maintenance doses, often with irrational polypharmacy, further compromising effectiveness and medication adherence. However, some bright spots in antipsychotic development include improved tolerability of APMs and long-acting injectables to address the high prevalence of medication nonadherence. This review critically reviews 70 years of antipsychotic development, the reasons behind the failure to develop more effective APMs, and suggestions for future direction.

Role of Brain Modulators in Neurodevelopment: Focus on Autism Spectrum Disorder and Associated Comorbidities.

Autism spectrum disorder (ASD) and associated neurodevelopmental disorders share similar pathogenesis and clinical features. Pathophysiological changes in these diseases are rooted in early neuronal stem cells in the uterus. Several genetic and environmental factors potentially perturb neurogenesis and synaptogenesis processes causing incomplete or altered maturation of the brain that precedes the symptomology later in life. In this review, the impact of several endogenous neuromodulators and pharmacological agents on the foetus during pregnancy, manifested on numerous aspects of neurodevelopment is discussed. Within this context, some possible insults that may alter these modulators and therefore alter their role in neurodevelopment are high-lighted. Sometimes, a particular insult could influence several neuromodulator systems as is supported by recent research in the field of ASD and associated disorders. Dopaminergic hy-pothesis prevailed on the table for discussion of the pathogenesis of schizophrenia (SCH), atten-tion-deficit hyperactivity disorder (ADHD) and ASD for a long time. However, recent cumulative evidence suggests otherwise. Indeed, the neuromodulators that are dysregulated in ASD and comorbid disorders are as diverse as the causes and symptoms of this disease. Additionally, these neuromodulators have roles in brain development, further complicating their involvement in comorbidity. This review will survey the current understanding of the neuromodulating systems to serve the pharmacological field during pregnancy and to minimize drug-related insults in pa-tients with ASD and associated comorbidity disorders, e.g., SCH or ADHD.

Atrophy in dopaminergic pathways is associated with emergence of delusions in patients with Alzheimer’s disease

AbstractBackgroundPeople with advanced Alzheimer’s disease (AD) may present with delusions that are associated with worse quality of life and prognosis. However, early markers of delusions have not been identified yet. The present study aimed to investigate whether differences in cognitive and grey matter (GM) volume decline can be detected in the year before symptom onset between patients with AD who will and will not develop delusions.MethodTwo samples of patients with AD, 63 who will (AD‐D) and 63 who will not develop delusions (AD‐ND) over a year as recorded by means of the NPI, were identified from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and matched for diagnosis, cognitive status, age, education, sex, handedness and APOE genotype. Sixty‐three additional matched healthy controls (HC) were selected. Group‐by‐time models were used to compare cognitive and clinical data across groups, as well as GM maps by means of VBM. Change in NPI scores was used as covariate. Post hoc analyses were performed to investigate AD‐D vs AD‐ND differences in volume decline in areas found to be more atrophic in the AD‐D group and in brainstem nuclei connected to these areas.ResultNo neurocognitive differences were observed between patient groups either prior to or at symptom onset. When the two patient groups were compared to HC, the AD‐ND showed no greater atrophy over time while greater atrophy in the left caudate was observed in the AD‐D group. Post hoc analyses revealed greater GM loss in the AD‐D group in both caudate bodies and dopaminergic nuclei (i.e. the substantia nigra and the ventral tegmental area), but not in serotoninergic nuclei.ConclusionPatients with AD who will develop delusion showed faster neurodegeneration prior to symptom onset in dopaminergic systems, especially in the nigrostriatal pathway. Therefore, alterations in dopamine neurotransmission due to AD‐related pathology may explain the emergence of delusional thoughts in this population, consistently with the dopaminergic hypothesis of positive symptoms in schizophrenia.

Dopamine and Neuroinflammation in Schizophrenia – Interpreting the Findings from Translocator Protein (18kDa) PET Imaging

Schizophrenia is a complex disease whose pathophysiology is not yet fully understood. In addition to the long prevailing dopaminergic hypothesis, the evidence suggests that neuroinflammation plays a role in the pathophysiology of the disease. Recent studies using positron emission tomography (PET) that target a 18kDa translocator protein (TSPO) in activated microglial cells in an attempt to measure neuroinflammation in patients have shown a decrease or a lack of an increase in TSPO binding. Many biological and methodological considerations have been formulated to explain these findings. Although dopamine has been described as an immunomodulatory molecule, its potential role in neuroinflammation has not been explored in the aforementioned studies. In this review, we discuss the interactions between dopamine and neuroinflammation in psychotic states. Dopamine may inhibit neuroinflammation in activated microglia. Proinflammatory molecules released from microglia may decrease dopaminergic transmission. This could potentially explain why the levels of neuroinflammation in the brain of patients with schizophrenia seem to be unchanged or decreased compared to those in healthy subjects. However, most data are indirect and are derived from animal studies or from studies performed outside the field of schizophrenia. Further studies are needed to combine TSPO and dopamine imaging to study the association between microglial activation and dopamine system function.

Mice with reduced glutamate transporter GLT1 expression exhibit behaviors related to attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder in children. Although animal models and human brain imaging studies indicate a significant role for glutamatergic dysfunction in ADHD, there is no direct evidence that glutamatergic dysfunction is sufficient to induce ADHD-like symptoms. The glial glutamate transporter GLT1 plays a critical role in glutamatergic neurotransmission. We report here the generation of mice expressing only 20% of normal levels of the GLT1. Unlike conventional GLT1 knockout mice, these mice survive to adulthood and exhibit ADHD-like phenotypes, including hyperactivity, impulsivity and impaired memory. These findings indicate that glutamatergic dysfunction due to GLT1 deficiency, a mechanism distinct from the dopaminergic deficit hypothesis of ADHD, underlies ADHD-like symptoms.

Horizontal eye movements foster approach to negative pictures but do not change emotional valence: A dopaminergic regulation hypothesis

A new dopaminergic regulation hypothesis is proposed based on two experiments exploring eye-movement effects. In the Eye Movement Desensitization and Reprocessing (EMDR) and Saccade-Induced Retrieval Enhancement (SIRE) domains, eye-movement mechanisms are mainly studied with explicit measures. Here implicit and explicit measures of emotion and memory for positive and negative pictures were investigated after eye movements or fixation in extreme right-handers. Eye movements enhanced explicit recognition predominantly for negative pictures. The absence of implicit repetition priming in both experiments supported a dissociation between implicit and explicit memory. Motivational eye-movement effects emerged but implicit and explicit affect remained unchanged. Experiment 2 revealed, after initial freezing to negative pictures, an acceleration, particularly of approach responses. Eye movements are postulated to foster approach towards negative memories, and promote, though dopaminergic pathways from the Superior Colliculus, enhanced explicit memory and active emotion regulation, primarily in persons with a collateralization of eye and dopamine dominance.

Quetiapine associated tics in a pediatric patient post overdose on re-initiation: An interesting clinical scenario

The COVID-19 pandemic has led to a multitude of new medical and psychiatric complications and new presentations that were either never seen before or not seen to the extent that they are presenting now. [1,2]. Increased number of suicide attempts and worsening severity of suicide attempts have been noted in the past year since the COVID-19 pandemic has started [1]. Psychotropic medications can often have lesser-known side effects and movement disorders, including tics, can be one of them [3]. Tics are recurrent, simple or complex behaviors that can be motor or phonic in nature [4,5]. Simple motor tics are often observed as rapid movements while complex motor tics are more synchronized and elaborate. Additionally, noises or brief sounds are examples of simple vocal tics, while speaking a string of words or syllables are more characteristic of a complex vocal tic [4]. The underlying pathogenesis of tics and tic disorders has not been well elucidated, dopaminergic hypothesis being the most widely accepted; however, multiple areas of the brain are speculated to be involved [4,6]. Common treatment options for tic disorders include alpha-2 agonists, clonidine and guanfacine, and antipsychotics [4,7]. Previous literature identifies two case reports that documented tics related to quetiapine. One report described a pediatric bipolar patient who developed tics proportional to quetiapine dose [8], and the other report identified an adult patient with schizophrenia who developed tics during quetiapine therapy [9]. In this article, we describe a pediatric patient who presented after overdosing on quetiapine, lamotrigine and sertraline and developed tics after re-initiation of quetiapine at a much lower dose. To the best of our knowledge, this is the first case of its kind where tics, which were previously absent, developed on re-initiation of quetiapine after an overdose.

Theories of the pathogenesis of schizophrenia

Introduction: Schizophrenia is one of the most serious and frightening of all mental illnesses. It affects almost 1% of the population worldwide. The main concept and treatment of schizophrenia are based on the dopaminergic hypothesis. However, accumulating evidence has shown that the core pathophysiology of schizophrenia might involve dysfunction in dopaminergic, glutamatergic, serotonergic, and gamma-aminobutyric acid signaling.The aim of the study: The purpose of this systemic review was to collect and analyse current and new information on the pathogenesis of schizophrenia.Material and method: Standard criteria were used to review the literature data. The search of articles in the PubMed database was carried out using the following keywords: schizophrenia, dopamine hypothesis, serotoninergic hypothesis, hypothesis of schizophrenia .Description of the state of knowledge: There are evidence that pathogenesis of schizophrenia include dysfunction in dopaminergic, serotoninergic, GABAergic, glutamatergic systems. The use of drugs that act on any of these systems reduces the symptoms of the disease. Nicotinic receptors may also be the target for drugs in treatment of schizophrenia. Studies about the role of nicotinic receptors in pathogenesis of schizophrenia show that it normalize many of the sensory processing deficits found in schizophrenia.Summary: Despite the fact that current concept and treatment are still based on the dopaminergic hypothesis of the disease, existing theories and each new theory, open up different ways for treating schizophrenia. Considering that schizophrenia is one of the most serious and frightening of all mental illnesses and has major public health implications, more research about pathogenesis and ways of treatment is needed.

Neuromorphological Aspects of the GABAergic Hypothesis of the Pathogenesis of Schizophrenia

The scientific literature contains several hypotheses for the pathogenesis of schizophrenia. The most widespread hypotheses for schizophrenia are the dopaminergic, serotoninergic, and glutamatergic hypotheses. There is also the suggestion that other neurochemical systems are involved in the pathogenesis of schizophrenia, particularly the GABAergic. This review considers published data on derangements of GABAergic interneurons in schizophrenia, taking account of data on post-mortem, neuroimaging, molecular-genetic, and electrophysiological research. A hypothesis for the pathogenesis of schizophrenia based on impairments to the myelination of GABAergic interneurons is proposed, these impairments leading to decreases in the numbers of intra- and interhemisphere coherent connections and the appearance of symptoms of the disease.

Impairment of motor but not anxiety-like behavior caused by the increase of dopamine during development is sustained in zebrafish larvae at later stages.

Many neuropsychiatric disorders are associated with both dopaminergic (DAergic) and developmental hypotheses. Since DAergic receptors are expressed in the developing brain, it is possible that alterations in dopamine (DA) signaling may impair brain development and consequent behavior. In our previous study, using a zebrafish model, we showed that an increase of DA during the 3 to 5days postfertilization (dpf) developmental window (an important window for GABAergic neuronal differentiation) affects the motor behavior of 5 dpf larvae. In this study, we set out to determine whether these behavioral alterations were sustained in larvae at older stages (7 and 14 dpf). To test this hypothesis, we chronically treated zebrafish larvae from 3 to 5 dpf with DA. After washing the drug, we recorded and analyzed the first 5 and 30min of the motor behavior of 5, 7, and 14 dpf subjects. We analyzed mobile episodes, distance traveled, time mobile, distance traveled per mobile episode, time in movement per mobile episode, and distance traveled per time mobile. We showed, once again, that an increase of DA during the 3 to 5 dpf developmental window reduces the number of movement episodes initiated by 5 dpf larvae. We also detected a decrease of other motor behavior parameters in 5 dpf DA-treated larvae. We observed that these alterations are sustained in the 7 dpf larvae. However, we did not see these general locomotor alterations in the 14 dpf larvae. Moreover, we detected a decrease of distance traveled and an increase of time of locomotion per episode in the first 5min of behavioral analyses in 14 dpf DA-treated larvae. To test if the alterations in the first 5min were due to anxiety-like behavior, we used a light/dark preference paradigm. We recorded 5dpf, 7dpf, and 14dpf larvae for 5min and analyzed time of freezing, preference for light or dark, number of entries to the dark, percentage of time in the light. We observed that 5dpf larvae treated with DA showed more freezing, less passages to the dark, and more time spent in the light as compared to their control counterparts. But 7dpf and 14dpf larvae did not show these alterations. Taken overall, therefore, our results suggest that DA does play a role in the development of zebrafish motor behavior, and, furthermore, that some behaviors are more sensitive than others to the effects of DAergic imbalances during development.

Dopamine perturbation of gene co-expression networks reveals differential response in schizophrenia for translational machinery

The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various oxidative species, and thus has important non-receptor-mediated effects, with empirical evidence of cellular toxicity and neurodegeneration. Here we examine non-receptor-mediated effects of DA on gene co-expression networks and its potential role in SZ pathology. Transcriptomic profiles were measured by RNA-seq in B-cell transformed lymphoblastoid cell lines from 514 SZ cases and 690 controls, both before and after exposure to DA ex vivo (100 μM). Gene co-expression modules were identified using Weighted Gene Co-expression Network Analysis for both baseline and DA-stimulated conditions, with each module characterized for biological function and tested for association with SZ status and SNPs from a genome-wide panel. We identified seven co-expression modules under baseline, of which six were preserved in DA-stimulated data. One module shows significantly increased association with SZ after DA perturbation (baseline: P = 0.023; DA-stimulated: P = 7.8 × 10-5; ΔAIC = −10.5) and is highly enriched for genes related to ribosomal proteins and translation (FDR = 4 × 10−141), mitochondrial oxidative phosphorylation, and neurodegeneration. SNP association testing revealed tentative QTLs underlying module co-expression, notably at FASTKD2 (top P = 2.8 × 10−6), a gene involved in mitochondrial translation. These results substantiate the role of translational machinery in SZ pathogenesis, providing insights into a possible dopaminergic mechanism disrupting mitochondrial function, and demonstrates the utility of disease-relevant functional perturbation in the study of complex genetic etiologies.

Multi-Target Approach for Drug Discovery against Schizophrenia.

Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases with complex pathomechanisms such as schizophrenia. Indeed, second generation or atypical antipsychotics target a number of aminergic G protein-coupled receptors (GPCRs) simultaneously. Novel strategies in drug design and discovery against schizophrenia focus on targets beyond the dopaminergic hypothesis of the disease and even beyond the monoamine GPCRs. In particular these approaches concern proteins involved in glutamatergic and cholinergic neurotransmission, challenging the concept of antipsychotic activity without dopamine D2 receptor involvement. Potentially interesting compounds include ligands interacting with glycine modulatory binding pocket on N-methyl-d-aspartate (NMDA) receptors, positive allosteric modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, positive allosteric modulators of metabotropic glutamatergic receptors, agonists and positive allosteric modulators of α7 nicotinic receptors, as well as muscarinic receptor agonists. In this review we discuss classical and novel drug targets for schizophrenia, cover benefits and limitations of current strategies to design multi-target drugs and show examples of multi-target ligands as antipsychotics, including marketed drugs, substances in clinical trials, and other investigational compounds.

Transcriptomic signatures of schizophrenia revealed by dopamine perturbation in an ex vivo model

The dopaminergic hypothesis of schizophrenia (SZ) postulates that dopaminergic over activity causes psychosis, a central feature of SZ, based on the observation that blocking dopamine (DA) improves psychotic symptoms. DA is known to have both receptor- and non-receptor-mediated effects, including oxidative mechanisms that lead to apoptosis. The role of DA-mediated oxidative processes in SZ has been little studied. Here, we have used a cell perturbation approach and measured transcriptomic profiles by RNAseq to study the effect of DA exposure on transcription in B-cell transformed lymphoblastoid cell lines (LCLs) from 514 SZ cases and 690 controls. We found that DA had widespread effects on both cell growth and gene expression in LCLs. Overall, 1455 genes showed statistically significant differential DA response in SZ cases and controls. This set of differentially expressed genes is enriched for brain expression and for functions related to immune processes and apoptosis, suggesting that DA may play a role in SZ pathogenesis through modulating those systems. Moreover, we observed a non-significant enrichment of genes near genome-wide significant SZ loci and with genes spanned by SZ-associated copy number variants (CNVs), which suggests convergent pathogenic mechanisms detected by both genetic association and gene expression. The study suggests a novel role of DA in the biological processes of immune and apoptosis that may be relevant to SZ pathogenesis. Furthermore, our results show the utility of pathophysiologically relevant perturbation experiments to investigate the biology of complex mental disorders.

Deletion of dopamine D2 receptors from parvalbumin interneurons in mouse causes schizophrenia-like phenotypes

Excessive dopamine neurotransmission underlies psychotic episodes as observed in patients with some types of bipolar disorder and schizophrenia. The dopaminergic hypothesis was postulated after the finding that antipsychotics were effective to halt increased dopamine tone. However, there is little evidence for dysfunction within the dopaminergic system itself. Alternatively, it has been proposed that excessive afferent activity onto ventral tegmental area dopaminergic neurons, particularly from the ventral hippocampus, increase dopamine neurotransmission, leading to psychosis. Here, we show that selective dopamine D2 receptor deletion from parvalbumin interneurons in mouse causes an impaired inhibitory activity in the ventral hippocampus and a dysregulated dopaminergic system. Conditional mutant animals show adult onset of schizophrenia-like behaviors and molecular, cellular, and physiological endophenotypes as previously described from postmortem brain studies of patients with schizophrenia. Our findings show that dopamine D2 receptor expression on parvalbumin interneurons is required to modulate and limit pyramidal neuron activity, which may prevent the dysregulation of the dopaminergic system.