Dopamine D2 Receptor Blockade Research Articles

Lesion network of oculogyric crises maps to brain dopaminergic transcriptomic signature.

Oculogyric crises are acute episodes of sustained, typically upward, conjugate deviation of the eyes. Oculogyric crises usually occur as the result of acute D2-dopamine receptor blockade, but the brain areas causally involved in generating this symptom remain elusive. Here, we used data from 14 previously reported cases of lesion-induced oculogyric crises and employed lesion network mapping to identify their shared connections throughout the brain. This analysis yielded a common network that included basal ganglia, thalamic and brainstem nuclei, as well as the cerebellum. Comparison of this network with gene expression profiles associated with the dopamine system revealed spatial overlap specifically with the gene coding for dopamine receptor type 2 (DRD2), as defined by a large-scale transcriptomic database of the human brain. Furthermore, spatial overlap with DRD2 and DRD3 gene expression was specific to brain lesions associated with oculogyric crises when contrasted to lesions that led to other movement disorders. Our findings identify a common neural network causally involved in the occurrence of oculogyric crises and provide a pathophysiological link between lesion locations causing this syndrome and its most common pharmacological cause, namely DRD2 blockade.

A proposal for reducing maximum target doses of drugs for psychosis: Reviewing dose-response literature.

Presently, there is limited guidance on the maximal dosing of psychosis drugs that is based on effectiveness rather than safety or toxicity. Current maximum dosing recommendations may far exceed the necessary degree of dopamine D2 receptor blockade required to treat psychosis. This may lead to excess harm through cognitive impairment and side effects. This analysis aimed to establish guidance for prescribers by optimally dosing drugs for psychosis based on efficacy and benefit. We used data from two dose-response meta-analyses and reviewed seven of the most prescribed drugs for psychosis in the UK. Where data were not available, we used appropriate comparison techniques based on D2 receptor occupancy to extrapolate our recommendations. We found that the likely threshold dose for achieving remission of psychotic symptoms was often significantly below the currently licensed dose for these drugs. We therefore recommend that clinicians are cautious about exceeding our recommended doses. Individual factors, however, should be accounted for. We outline potentially relevant factors including age, ethnicity, sex, smoking status and pharmacogenetics. Additionally, we recommend therapeutic drug monitoring as a tool to determine individual pharmacokinetic variation. In summary, we propose a new set of maximum target doses for psychosis drugs based on efficacy. Further research through randomised controlled trials should be undertaken to evaluate the effect of reducing doses from current licensing maximums or from doses that are above our recommendations. However, dose reductions should be implemented in a manner that accounts for and reduces the effects of drug withdrawal.

Unraveling the Influence of Age, IQ, Education, and Negative Symptoms on Neurocognitive Performance in Schizophrenia: A Conditional Inference Tree Analysis.

The complex nature of neurocognitive impairment in schizophrenia has been discussed in light of the mixed effects of antipsychotic drugs, psychotic symptoms, dopamine D2 receptor blockade, and intelligence quotient (IQ). These factors have not been thoroughly examined before. This study conducted a comprehensive re-analysis of the CATIE data using machine learning techniques, in particular Conditional Inference Tree (CTREE) analysis, to investigate associations between neurocognitive functions and moderating factors such as estimated trough dopamine D2 receptor blockade with risperidone, olanzapine, or ziprasidone, Positive and Negative Syndrome Scale (PANSS), and baseline IQ in 573 patients with schizophrenia. The study reveals that IQ, age, and education consistently emerge as significant predictors across all neurocognitive domains. Furthermore, higher severity of PANSS-negative symptoms was associated with lower cognitive performance scores in several domains. CTREE analysis, in combination with a genetic algorithm approach, has been identified as particularly insightful for illustrating complex interactions between variables. Lower neurocognitive function was associated with factors such as age>52 years, IQ<94/95,<12/13 education years, and more pronounced negative symptoms (score<26). These findings emphasize the multifaceted nature of neurocognitive functioning in patients with schizophrenia, with the PANSS-negative score being an important predictor. This gives rise to a role in addressing negative symptoms as a therapeutic objective for enhancing cognitive impairments in these patients. Further research must examine nonlinear relationships among various moderating factors identified in this work, especially the role of D2 occupancy.

Enhanced Risky Choice in Male Rats Elicited by the Acute Pharmacological Stressor Yohimbine Involves Prefrontal Dopamine D1 Receptor Activation.

Acute stress alters risk-based decision-making; however, the underlying neural and neurochemical substrates are underexplored. Given their well-documented stress-inducing effects in humans and laboratory animals, glucocorticoids such as cortisol and corticosterone and the α2-adrenoceptor antagonist yohimbine represent potent pharmacological tools to mimic some characteristics of acute stress. Here, we analyzed the effects of the pharmacological stressors corticosterone and yohimbine given systemically on risk-based decision-making in male rats. Moreover, we investigated whether pharmacological stressor effects on risk-based decision-making involve dopamine D1 receptor stimulation in the dorsal prelimbic cortex (PL). We used a risk discounting task that requires choosing between a certain/small reward lever that always delivered 1 pellet and a risky/large reward lever that delivered 4 pellets with a decreasing probability across subsequent trials. Systemic administration of yohimbine increased the preference for the risky/large reward lever. By contrast, systemic single administration of corticosterone did not significantly promote risky choice. Moreover, co-administration of corticosterone did not enhance the effects of yohimbine on risky choice. The data further show that the increased preference for the risky/large reward lever under systemic yohimbine was lowered by a concurrent pharmacological blockade of dopamine D1 receptors in the PL. Our rodent data provide causal evidence that stimulation of PL D1 receptors may represent a neurochemical mechanism by which the acute pharmacological stressor yohimbine, and possibly nonpharmacological stressors as well, promote risky choice.

Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?

Major depressive disorder (MDD) is one of the most disabling psychiatric disorders in the world. First-line treatments such as selective serotonin reuptake inhibitors (SSRIs) still have many limitations, including a resistance to treatment in 30% of patients and a delayed clinical benefit that is observed only after several weeks of treatment. Increasing clinical evidence indicates that the acute administration of psychedelic agonists of the serotonin 5-HT2A receptor (5-HT2AR), such as psilocybin, to patients with MDD induce fast antidepressant effects, which persist up to five weeks after the treatment. However, the involvement of the 5-HT2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT2AR agonists are mandatory to their antidepressant activity is still an open question. Here, we addressed these issues by investigating the effect of two psychedelics of different chemical families, DOI and psilocybin, and a non-hallucinogenic 5-HT2AR agonist, lisuride, in a chronic despair mouse model exhibiting a robust depressive-like phenotype. We show that a single injection of each drug to wild type mice induces anxiolytic- and antidepressant-like effects in the novelty-suppressed feeding, sucrose preference and forced swim tests, which last up to 15 days. DOI and lisuride administration did not produce antidepressant-like effects in 5-HT2A−/− mice, whereas psilocybin was still effective. Moreover, neither 5-HT1AR blockade nor dopamine D1 or D2 receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT2A−/− mice. Collectively, these findings indicate that 5-HT2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.

Nucleus accumbens core dopamine D2 receptors are required for performance of the odor span task in male rats.

The nucleus accumbens (NAc) core gates motivationally relevant behavioral action sequences through afferents from cortical and subcortical brain regions. While the role of the NAc core in reward and effort-based decision making is well established, its role in working memory (WM) processes is incompletely understood. The odor span task (OST) has been proposed as a measure of non-spatial working memory capacity (WMC) as it requires rodents to select a novel odor from an increasing number of familiar odors to obtain a food reward. To assess the role of the NAc core in the OST using (1) reversible chemical inactivation and (2) selective blockade of dopamine D1 and D2 receptors in the area. Well-trained male rats were tested on the OST following intra-NAc core infusions of muscimol/baclofen, the D1 receptorantagonist SCH-23390 (1 μg/hemisphere) and the D2 receptorantagonist eticlopride (1 μg/hemisphere). Behavioral measurements included the average odor span, maximum odor span, choice latency, searching vigor, and patterns of responding during foraging that may relate to impulsivity. Chemical inactivation of the NAc core significantly decreased odor span relative to sham and vehicle conditions. Selective antagonism of D2, but not D1, receptors in the NAc core also produced deficits in odor span. We found that secondary behavioral measures of choice latency, searching vigor, and responding to the first odor stimulus encountered were largely unaffected by treatment. These findings suggest that D2 receptors in the NAc core are required for OST performance.

Schizophrenia: from neurochemistry to circuits, symptoms and treatments.

Schizophrenia is a leading cause of global disability. Current pharmacotherapy for the diseasepredominantly uses one mechanism - dopamine D2 receptor blockade - but often shows limited efficacy and poor tolerability. These limitations highlight the need to better understand the aetiology of the disease to aid the development of alternative therapeutic approaches. Here, we review the latest meta-analyses and other findings on the neurobiology of prodromal, first-episode and chronic schizophrenia, and the link to psychotic symptoms, focusing on imaging evidence from people with the disorder. This evidence demonstrates regionally specific neurotransmitter alterations, including higher glutamate and dopamine measures in the basal ganglia, and lower glutamate, dopamine and γ-aminobutyric acid (GABA) levels in cortical regions, particularly the frontal cortex, relative to healthy individuals. We consider how dysfunction in cortico-thalamo-striatal-midbrain circuits might alter brain information processing to underlie psychotic symptoms. Finally, we discuss the implications of these findings for developing new, mechanistically based treatments and precision medicine for psychotic symptoms, as well as negative and cognitive symptoms.

Regulation of plasma glucose levels by central dopamine D2 receptors is impaired in type 1 but not type 2 diabetic mouse models

Glucose metabolism is reported to be regulated by the central nervous system, but it is unclear whether this regulation is altered in diabetes. We investigated whether regulation of glucose metabolism by central dopamine D2 receptors is altered in type 1 and type 2 diabetic models. Intracerebroventricular injections of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride induced hyperglycemia in control mice, but not in streptozotocin (STZ)-induced diabetic mice, a type 1 diabetic model. Hyperglycemia induced by quinpirole or l-sulpiride was diminished following fasting and these drugs did not affect hyperglycemia in the pyruvate tolerance test. In addition, both quinpirole and l-sulpiride increased hepatic glucose-6-phosphatase (G6Pase) mRNA. In STZ-induced diabetic mice, dopamine and dopamine D2 receptor mRNA in the hypothalamus, which regulates glucose homeostasis, were decreased. Hepatic glycogen and G6Pase mRNA were also decreased in STZ-induced diabetic mice. Neither quinpirole nor l-sulpiride increased hepatic G6Pase mRNA in STZ-induced diabetic mice. In diet-induced obesity mice, a type 2 diabetic model, both quinpirole and l-sulpiride induced hyperglycemia, and hypothalamic dopamine and dopamine D2 receptor mRNA were not altered. These results indicate that (i) stimulation or blockade of dopamine D2 receptors causes hyperglycemia by increasing hepatic glycogenolysis, and (ii) stimulation or blockade of dopamine D2 receptors does not affect glucose levels in type 1 but does so in type 2 diabetic models. Moreover, hypothalamic dopaminergic function and hepatic glycogenolysis are decreased in the type 1 diabetic model, which reduces hyperglycemia induced by stimulation or blockade of dopamine D2 receptors.

Insights into the Mechanism of Action of Antipsychotic Drugs Derived from Animal Models: Standard of Care versus Novel Targets.

Therapeutic intervention for schizophrenia relies on blockade of dopamine D2 receptors in the associative striatum; however, there is little evidence for baseline overdrive of the dopamine system. Instead, the dopamine system is in a hyper-responsive state due to excessive drive by the hippocampus. This causes more dopamine neurons to be in a spontaneously active, hyper-responsive state. Antipsychotic drugs alleviate this by causing depolarization block, or excessive depolarization-induced dopamine neuron inactivation. Indeed, both first- and second-generation antipsychotic drugs cause depolarization block in the ventral tegmentum to relieve positive symptoms, whereas first-generation drugs also cause depolarization in the nigrostriatal dopamine system to lead to extrapyramidal side effects. However, by blocking dopamine receptors, these drugs are activating multiple synapses downstream from the proposed site of pathology: the loss of inhibitory influence over the hippocampus. An overactive hippocampus not only drives the dopamine-dependent positive symptoms, but via its projections to the amygdala and the neocortex can also drive negative and cognitive symptoms, respectively. On this basis, a novel class of drugs that can reverse schizophrenia at the site of pathology, i.e., the hippocampal overdrive, could be effective in alleviating all three classes of symptoms of schizophrenia while also being better tolerated.

Does partial blockade of dopamine D2 receptors with Amisulpride cause anhedonia? An experimental study in healthy volunteers

BackgroundAnhedonia is a frequent cause of functional impairment in psychosis. Although it is plausible that medication-induced D2 receptor blockade could diminish hedonic responding, there is little experimental research testing this hypothesis in humans. MethodsTo inspect possible effects of partial D2 blockade on hedonic experiences, we administered 300 mg of Amisulpride or placebo to 85 participants in a randomized, double-blind, placebo-controlled trial. Participants were then subjected to an emotional evocation task utilizing standardized pictorial pleasant, neutral, and unpleasant stimuli. ResultsWe observed lower positivity ratings in the Amisulpride group compared to placebo across all stimulus categories (p = .026, f = 0.25) and no group differences in negativity or arousal ratings. The Amisulpride group also showed lower electrodermal responses across all stimulus categories compared to placebo (p = .017, f = 0.27). The electrodermal response was especially diminished for pleasant stimuli. ConclusionWe interpret our findings as evidence that D2 blockade via Amisulpride can reduce at-the-moment hedonic responsivity in healthy volunteers. If these results can be confirmed in drug-naïve clinical samples, this would indicate that antipsychotic medication contributes to clinical anhedonia, probably via antagonistic effects at the dopamine D2 receptor.

Blockade of dopamine D3 receptor in ventral tegmental area attenuating contextual fear memory

The abnormal fear memory will lead to the onset of stress disorders, such as post-traumatic stress disorder (PTSD) and so on. Therefore, the intervention in the formation of abnormal fear memory will provide a new strategy for the prevention and treatment of PTSD. In our previous studies, we found that blockade of dopamine D3 receptor (DRD3) with highly selective antagonist YQA14 or knockout of DRD3 was able to attenuate the expression or retrieval of fear memory in PTSD animal models. However, the neurobiological mechanism of regulation of DRD3 in fear is unclear. In the present research, we clarified that DRD3 was expressed in the dopaminergic (DAergic) neurons in the ventral tegmental area (VTA). Then, we identified that microinjection of YQA14 (1 μg/0.2 μl/side) in VTA before the aversive stimuli in the training session or during days subsequent to the shock significantly meliorated the freezing behaviors in the inescapable electric foot-shock model. At last, using fiber photometry system, we found that microinjection of YQA14 in VTA promoted the dopamine neurotransmitter release in the basolateral amygdala (BLA), and pre-training YQA14 infusion in VTA lowered the increase of dopamine (DA) in BLA induced by shock during the training session or by context during the retrieval session. All above the results demonstrated that YQA14 attenuated the fear learning through the blockade of DRD3 in VTA decreasing the excitability of the projection to BLA. This study may provide new mechanisms and potential intervention targets for stress disorders with abnormal fear memory.

SUVN‐I7016031: A Novel M1‐receptor Positive Allosteric Modulator (M1‐PAM) for the treatment of Parkinson's Disease Associated Dementia

AbstractBackgroundParkinson's disease (PD) patients experience progressive cognitive decline over the time and as the disease progresses. Drug‐induced Parkinsonism (DIP) is the second‐most‐common etiology of parkinsonism in the elderly after Parkinson's disease. DIP is indistinguishable from pathological PD as the symptoms are similar for both conditions. Haloperidol is a classical antipsychotic, known for its propensity to cause parkinsonism, which can be accompanied with the cognitive impairment, due to the blockade of striatal dopamine D2 receptors and further the downstream antagonism of M1 receptors in the signaling cascade. Therapeutic potential of SUVN‐I7016031 was evaluated in an animal model reflecting PD associated dementia.MethodHaloperidol was supplied in water feeder bottles at 2 mg/kg, p.o. to induce PD associated dementia. Following one week of haloperidol supplementation, treatment with either SUVN‐I7016031 (0.3, 1, 3 and 10 mg/kg, p.o.) or rivastigmine (0.3 mg/kg, s.c.) was began and the treatments were continued up to 37 days. Social recognition task (SRT) was conducted on day‐13 and day‐37. In SRT, familiarization and recognition trials were conducted with a trial delay of 30 min. Social investigation time by adult rat with either familiar or novel juvenile rat was assessed during recognition trial and compared, along with discriminative index. Statistical analysis is carried out using GraphPad Prism software (Version 7.02).ResultAnimals treated with haloperidol did not discriminate the novel juvenile from the familiar juvenile and showed cognitive impairment on day‐13 and day‐37. Rivastigmine reversed haloperidol‐induced PD dementia on day‐13 and day‐37. SUVN‐I7016031 at 10 mg/kg, p.o., reversed haloperidol‐induced PD dementia on day‐13 of testing. However, on day‐37, SUVN‐I7016031 reversed haloperidol‐induced PD dementia at 1, 3 and 10 mg/kg, p.o. which resulted in dose‐dependent positive efficacy. Further, rivastigmine and SUVN‐I7016031 treatment also resulted in significant improvement of discriminative index relative to haloperidol control on day‐37. Effects observed with SUVN‐I7016031 are more prominent on day‐37 relative to day‐13.ConclusionSUVN‐I7016031 showed positive efficacy in an animal model reflecting PD associated dementia, which could be a future promising therapeutic strategy in improving health related quality of life (hQOL) in PD patients.

Distinct Roles of Dopamine Receptor Subtypes in the Nucleus Accumbens during Itch Signal Processing.

Ventral tegmental area (VTA) dopaminergic neurons, which are well known for their central roles in reward and motivation-related behaviors, have been shown to participate in itch processing via their projection to the nucleus accumbens (NAc). However, the functional roles of different dopamine receptor subtypes in subregions of the NAc during itch processing remain unknown. With pharmacological approaches, we found that the blockade of dopamine D1 receptors (D1R), but not dopamine D2 receptors (D2R), in the lateral shell (LaSh) of the NAc impaired pruritogen-induced scratching behavior in male mice. In contrast, pharmacological activation of D2R in both the LaSh and medial shell (MeSh) of the NAc attenuated the scratching behavior induced by pruritogens. Consistently, we found that dopamine release, as detected by a dopamine sensor, was elevated in the LaSh rather than the MeSh of the NAc at the onset of scratching behavior. Furthermore, the elevation of dopamine release in the LaSh of the NAc persisted even though itch-relieving behavior was blocked, suggesting that the dopamine signal in the NAc LaSh represents a motivational component of itch processing. Our study revealed different dynamics of dopamine release that target neurons expressing two dopamine receptors subtypes within different subregions of the NAc, and emphasized that D1R in the LaSh of the NAc is important in itch signal processing.SIGNIFICANCE STATEMENT Dopamine has been implicated in itch signal processing. However, the mechanism underlying the functional role of dopamine in itch processing remains largely unknown. Here, we examined the role of dopamine D1 receptor (D1R) and D2R in the nucleus accumbens (NAc) shell during pruritogen-induced scratching behavior. We demonstrated that D1R in the NAc lateral shell (LaSh) play an important role in motivating itch-induced scratching behavior, while activation of D2R would terminate scratching behavior. Our study revealed the diverse functional roles of dopamine signals in the NAc shell during itch processing.

Decreased Dorsomedial Striatum Direct Pathway Neuronal Activity Is Required for Learned Motor Coordination.

It has been suggested that the dorsomedial striatum (DMS) is engaged in the early stages of motor learning for goal-directed actions, whereas at later stages, control is transferred to the dorsolateral striatum (DLS), a process that enables learned motor actions to become a skill or habit. It is not known whether these striatal regions are simultaneously active while the expertise is acquired. To address this question, we developed a mouse "Treadmill Training Task" that tracks changes in mouse locomotor coordination during running practice and simultaneously provides a means to measure local neuronal activity using photometry. To measure change in motor coordination over treadmill practice sessions, we used DeepLabCut (DLC) and custom-built code to analyze body position and paw movements. By evaluating improvements in motor coordination during training with simultaneous neuronal calcium activity in the striatum, we found that DMS direct pathway neurons exhibited decreased activity as the mouse gained proficiency at running. In contrast, direct pathway activity in the DLS was similar throughout training. Pharmacological blockade of D1 dopamine receptors in these subregions during task performance demonstrated that dopamine neurotransmission in the direct pathway activity is necessary for efficient motor coordination learning. These results provide new tools to measure changes in fine motor skills with simultaneous recordings of brain activity and reveal fundamental features of the neuronal substrates of motor learning.

The mGlu5 Receptor Protomer-Mediated Dopamine D2 Receptor Trans-Inhibition Is Dependent on the Adenosine A2A Receptor Protomer: Implications for Parkinson’s Disease

The adenosine A2A receptor (A2AR), dopamine D2 receptor (D2R) and metabotropic glutamate receptor type 5 (mGluR5) form A2AR-D2R-mGluR5 heteroreceptor complexes in living cells and in rat striatal neurons. In the current study, we present experimental data supporting the view that the A2AR protomer plays a major role in the inhibitory modulation of the density and the allosteric receptor-receptor interaction within the D2R-mGluR5 heteromeric component of the A2AR-D2R-mGluR5 complex in vitro and in vivo. The A2AR and mGluR5 protomers interact and modulate D2R protomer recognition and signalling upon forming a trimeric complex from these receptors. Expression of A2AR in HEK293T cells co-expressing D2R and mGluR5 resulted in a significant and marked increase in the formation of the D2R-mGluR5 heteromeric component in both bioluminescence resonance energy transfer and proximity ligation assays. A highly significant increase of the the high-affinity component of D2R (D2RKi High) values was found upon cotreatment with the mGluR5 and A2AR agonists in the cells expressing A2AR, D2R and mGluR5 with a significant effect observed also with the mGluR5 agonist alone compared to cells expressing only D2R and mGluR5. In cells co-expressing A2AR, D2R and mGluR5, stimulation of the cells with an mGluR5 agonist like or D2R antagonist fully counteracted the D2R agonist-induced inhibition of the cAMP levels which was not true in cells only expressing mGluR5 and D2R. In agreement, the mGluR5-negative allosteric modulator raseglurant significantly reduced the haloperidol-induced catalepsy in mice, and in A2AR knockout mice, the haloperidol action had almost disappeared, supporting a functional role for mGluR5 and A2AR in enhancing D2R blockade resulting in catalepsy. The results represent a relevant example of integrative activity within higher-order heteroreceptor complexes.

Endogenous dopamine transmission is crucial for motor skill recovery after stroke.

Ischemic stroke frequently causes motor impairments. Despite exercise can improve motor outcomes, many stroke survivors remain life-long disabled. Understanding the mechanisms associated with motor recovery after a stroke is necessary to develop treatments. Here, we show that endogenous DA transmission is required for optimal motor skill recovery following photothrombotic stroke in rats. Blockade of dopamine D1 and D2 receptors impaired the recovery of a forelimb reaching task and decreased the rats’ motivation to complete full training sessions. Our data indicate that dopamine transmission is important to drive motor rehabilitation after stroke through motivational aspects and ultimately suggest that augmented motivation and reward feedback could be an interesting strategy to increase the effectiveness or rehabilitation.

From a Pathophysiological Concept to a New Drug

Although antipsychotics were discovered over fifty years ago, it took another decade until dopamine antagonism was demonstrated as central to their clinical effectiveness. Since accumulated evidence implicates the dopamine system in the pathophysiology of schizophrenia, all licensed first-line treatments operate primarily via antagonism of the dopamine D2 receptor. However, dopamine D2 receptor blockade does not effectively treat negative, cognitive and affective symptoms and, in a significant proportion of patients, it does not improve positive symptoms either. Therefore, additional neurochemical targets were considered. The “revised dopamine hypothesis” proposes that positive symptoms emerge due to hyperactive dopamine transmission in mesolimbic areas, while hypoactive dopamine transmission via the mesocortical pathway in the prefrontal cortex is linked to negative, cognitive, and partly affective symptoms. In this context, the role of D3 receptors were recognised. However, there is also evidence for the involvement of other neurotransmitter systems, suggesting that dopamine signalling relies on a suite of receptors that are thought to either facilitate or inhibit neurotransmitter activity through several interconnected neural circuits. Furthermore, there seem to be clusters of symptoms that cross the boundaries of disorders. Symptoms having similar pathophysiology at neurotransmitter level can be treated with the same drug or class of drugs. Thus, one particular drug might be effective in more than one indication. This lecture aims to illustrate the process of a new drug development by explaining how the underlying pathophysiology on receptor level impacts clinical studies and vice versa.DisclosureEmployee of Gedeon Richter Plc.

The Acute Pharmacological Manipulation of Dopamine Receptors Modulates Judgment Bias in Japanese Quail.

We have studied the effects of dopamine antagonists and agonists on Japanese quail behavior in the spatial judgment task. Twenty-four Japanese quail hens were trained in the spatial discrimination task to approach the feeder placed in the rewarded location (Go response, feeder containing mealworms) and to not approach the punished location (No-Go response, empty feeder plus aversive sound). In a subsequent spatial judgment task, the proportion of Go responses as well as approach latencies to rewarded, punished, and three ambiguous locations (near-positive, middle, near-negative, all neither rewarded nor punished) were assessed in 20 quail hens that successfully mastered the discrimination task. In Experiment 1, each bird received five treatments (0.1 and 1.0 mg/kg of dopamine D1 receptor antagonist SCH 23390, 0.05 and 0.5 mg/kg of dopamine D2 receptor antagonist haloperidol, and saline control) in a different order, according to a Latin square design. All drugs were administered intramuscularly 15 min before the spatial judgment test, with 2 days break between the treatments. Both antagonists caused a significant dose-dependent increase in the approach latencies as well as a decrease in the proportion of Go responses. In Experiment 2, with the design analogous to Experiment 1, the hens received again five treatments (1.0 and 10.0 mg/kg of dopamine D1 receptor agonist SKF 38393, 1.0 and 10.0 mg/kg of dopamine D2 receptor agonist bromocriptine, and saline control), applied intramuscularly 2 h before the test. The agonists did not have any significant effect on approach latencies and the proportion of Go responses in the spatial judgment task, as compared to the saline control, except for 10.0 mg/kg SKF 38393, which caused a decrease in the proportion of Go responses. The approach latency and the proportion of Go responses were affected by the cue location in both experiments. Our data suggest that the dopamine D1 and D2 receptor blockade leads to a decrease in the reward expectation and the negative judgment of stimuli. The effect of dopamine receptor activation is less clear. The results reveal that dopamine receptor manipulation alters the evaluation of the reward and punishment in the spatial judgment task.

Emerging Treatments in Schizophrenia.

Although antipsychotics have been available for almost 70 years and greatly improved outcomes for individuals with schizophrenia, all currently available options derive their efficacy from blockade of dopaminergic receptors. However, this mechanism of action leaves many symptoms unresolved and is associated with a significant side effect burden. The mechanisms underlying schizophrenia, which were initially thought to be related to excessive presynaptic dopamine in specific areas of the brain, are now understood to be much more complex and involve structural and molecular changes throughout brain circuits. Consequently, drug discovery efforts have sought new targets in the search for safer and more effective medications that can improve symptoms of schizophrenia and psychosis, including trace amine-associated receptors (TAARs), muscarinic receptors, and serotonergic receptors. Positive phase 2 trial results indicating efficacy and safety of the TAAR1 agonist ulotaront (SEP-363856) and of the muscarinic M1/M4 agonist KarXT (xanomeline plus trospium) for total, positive, and negative symptoms in patients with acute exacerbation of schizophrenia, and of the serotonin 5-HT2A agonist/antagonist pimavanserin in patients with schizophrenia and predominant negative symptoms for negative symptom control are encouraging. Taken together, these data indicate in the context of ongoing phase 3 trial programs that patients with schizophrenia may soon have access to the first non-D2 blocking medication, which could drastically change the treatment landscape and improve outcomes for many of the individuals with schizophrenia who do not fully respond to or cannot tolerate currently available antipsychotic agents that currently all act via postsynaptic dopamine D2 receptor blockade.

Emerging Treatments in Schizophrenia.

Although antipsychotics have been available for almost 70 years and greatly improved outcomes for individuals with schizophrenia, all currently available options derive their efficacy from blockade of dopaminergic receptors. However, this mechanism of action leaves many symptoms unresolved and is associated with a significant side effect burden. The mechanisms underlying schizophrenia, which were initially thought to be related to excessive presynaptic dopamine in specific areas of the brain, are now understood to be much more complex and involve structural and molecular changes throughout brain circuits. Consequently, drug discovery efforts have sought new targets in the search for safer and more effective medications that can improve symptoms of schizophrenia and psychosis, including trace amine-associated receptors (TAARs), muscarinic receptors, and serotonergic receptors. Positive phase 2 trial results indicating efficacy and safety of the TAAR1 agonist ulotaront (SEP-363856) and of the muscarinic M1/M4 agonist KarXT (xanomeline plus trospium) for total, positive, and negative symptoms in patients with acute exacerbation of schizophrenia, and of the serotonin 5-HT2A agonist/antagonist pimavanserin in patients with schizophrenia and predominant negative symptoms for negative symptom control are encouraging. Taken together, these data indicate in the context of ongoing phase 3 trial programs that patients with schizophrenia may soon have access to the first non-D2 blocking medication, which could drastically change the treatment landscape and improve outcomes for many of the individuals with schizophrenia who do not fully respond to or cannot tolerate currently available antipsychotic agents that currently all act via postsynaptic dopamine D2 receptor blockade.