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Expert Opinion on Investigational Drugs 2023Schizophrenia is a severe mental illness comprising positive, negative, and cognitive symptoms. Existing pharmacologic options exert their actions on the dopamine... (Review)
Review
INTRODUCTION
Schizophrenia is a severe mental illness comprising positive, negative, and cognitive symptoms. Existing pharmacologic options exert their actions on the dopamine receptor but are largely ineffective at treating negative and cognitive symptoms. Alternative pharmacologic options that do not act directly on the dopamine receptor are being investigated, including potassium channel modulators. It has been hypothesized that dysfunctional fast-spiking parvalbumin-positive GABA interneurons, regulated by Kv3.1 and Kv3.2 potassium channels, contribute to the symptoms of schizophrenia, making potassium channels an area of clinical interest.
AREAS COVERED
This review will highlight potassium channel modulators for the treatment of schizophrenia, with a focus on AUT00206. Background on Kv3.1 and Kv3.2 potassium channels will be explored. Our search strategy included a literature review utilizing PubMed, Clinicaltrials.gov, and sources available on the manufacturer's website.
EXPERT OPINION
Initial data on potassium channel modulators is promising; however, further study is needed, and existing evidence is limited. Early data suggests that dysfunctional GABA interneurons can be ameliorated through modulators of Kv3.1 and Kv3.2 channels. AUT00206 has been shown to improve dopaminergic dysfunction induced by ketamine and PCP, improve resting gamma power in patients with schizophrenia, impact dopamine synthesis capacity in a subgroup of individuals with schizophrenia, and affect reward anticipation-related neural activation.
Topics: Humans; Potassium Channels; Drugs, Investigational; Schizophrenia; gamma-Aminobutyric Acid; Receptors, Dopamine
PubMed: 37247333
DOI: 10.1080/13543784.2023.2219385 -
The Journal of Pharmacology and... Sep 2023Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in...
Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in idiopathic pulmonary fibrosis (IPF). This uncontrolled production of ECM is stimulated by mechanosignaling and transforming growth factor beta 1 (TGF-1) signaling that together promote transcriptional programs including Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). G protein-coupled receptors (GPCRs) that couple to G s have emerged as pharmacological targets to inactivate YAP/TAZ signaling and promote lung fibrosis resolution. Previous studies have shown a loss of expression of "antifibrotic GPCRs"-receptors that couple to G s, in IPF patient-derived fibroblasts compared with non-IPF samples. Of the 14 G s GPCRs we found to be expressed in lung fibroblasts, the dopamine receptor D1 () was one of only two not repressed by TGF-1 signaling, with the 2-adrenergic receptor being the most repressed. We compared the potency and efficacy of multiple D1 and 2 receptor agonists +/- TGF-1 treatment in vitro for their ability to elevate cAMP, inhibit nuclear localization of YAP/TAZ, regulate expression of profibrotic and antifibrotic genes, and inhibit cellular proliferation and collagen deposition. Consistently, the activity of 2 receptor agonists was lost, whereas D1 receptor agonists was maintained, after stimulating cultured lung fibroblasts with TGF-1. These data further support the therapeutic potential of the dopamine receptor D1 and highlight an orchestrated and pervasive loss of antifibrotic GPCRs mediated by TGF-1 signaling. SIGNIFICANCE STATEMENT: Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease with limited therapies. GPCRs have emerged as a primary target for the development of novel antifibrotic drugs; however, a challenge to this approach is the dramatic changes in GPCR expression in response to profibrotic stimuli. Here, we investigate the impact of TGF-1 on the expression of antifibrotic GPCRs and show the D1 dopamine receptor expression is uniquely maintained in response to TGF-1, further implicating it as a compelling target to treat IPF.
Topics: Humans; Fibroblasts; Idiopathic Pulmonary Fibrosis; Lung; Receptors, Dopamine; Receptors, G-Protein-Coupled; Transforming Growth Factor beta; Transforming Growth Factor beta1
PubMed: 37024146
DOI: 10.1124/jpet.122.001442 -
Journal of Neural Transmission (Vienna,... Aug 2018The current standard treatment for Parkinson disease focuses on restoring striatal dopamine levels using L-3,4-dihydroxyphenylalanine (L-DOPA). However, disease... (Review)
Review
The current standard treatment for Parkinson disease focuses on restoring striatal dopamine levels using L-3,4-dihydroxyphenylalanine (L-DOPA). However, disease progression and chronic treatment are associated with motor side effects such as L-DOPA-induced dyskinesia (LID). Dopamine receptor function is strongly associated with the mechanisms underlying LID. In fact, increased D1R signaling is associated with this motor side effect. Compelling evidence demonstrates that dopamine receptors in the striatum can form heteromeric complexes, and heteromerization can lead to changes in the functional and pharmacological properties of receptors compared to their monomeric subtypes. Currently, the most promising strategy for therapeutic intervention in dyskinesia originates from investigations of the D1R-D3R heteromers. Interestingly, there is a correlation between the expression of D1R-D3R heteromers and the development of LID. Moreover, D3R stimulation can potentiate the D1R signaling pathway. The aim of this review is to summarize current knowledge of the distinct roles of heteromeric dopaminergic receptor complexes in LID.
Topics: Animals; Corpus Striatum; Dyskinesia, Drug-Induced; Humans; Receptors, Dopamine D1; Receptors, Dopamine D3
PubMed: 29417335
DOI: 10.1007/s00702-018-1852-x -
International Immunopharmacology Nov 2019Neuroinflammation is a general pathological feature of central nervous system (CNS) diseases, primarily caused by activation of astrocytes and microglia, as well as the... (Review)
Review
Neuroinflammation is a general pathological feature of central nervous system (CNS) diseases, primarily caused by activation of astrocytes and microglia, as well as the infiltration of peripheral immune cells. Inhibition of neuroinflammation is an important strategy in the treatment of brain disorders. Dopamine (DA) receptor, a significant G protein-coupled receptor (GPCR), is classified into two families: D1-like (D1 and D5) and D2-like (D2, D3 and D4) receptor families, according to their downstream signaling pathways. Traditionally, DA receptor forms a wide variety of psychological activities and motor functions, such as voluntary movement, working memory and learning. Recently, the role of DA receptor in neuroinflammation has been investigated widely, mainly focusing on nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, renin-angiotensin system, αB-crystallin, as well as invading peripheral immune cells, including T cells, dendritic cells, macrophages and monocytes. This review briefly outlined the functions and signaling pathways of DA receptor subtypes as well as its role in inflammation-related glial cells, and subsequently summarized the mechanisms of DA receptors affecting neuroinflammation. Meaningfully, this article provided a theoretical basis for drug development targeting DA receptors in inflammation-related brain diseases.
Topics: Animals; Encephalitis; Humans; Neuroglia; Receptors, Dopamine; Signal Transduction
PubMed: 31622861
DOI: 10.1016/j.intimp.2019.105908 -
European Journal of Pharmacology Dec 2021Dopamine (DA) is an important modulator in nociception and analgesia. Spinal DA receptors are involved in descending modulation of the nociceptive transmission. Genetic...
Dopamine (DA) is an important modulator in nociception and analgesia. Spinal DA receptors are involved in descending modulation of the nociceptive transmission. Genetic variations within DA neurotransmission have been associated with altered pain sensitivity and development of chronic pain syndromes. The variant rs6277 in dopamine receptor 2 a (drd2a) has been associated with a decreased D receptor availability and increased nociception. The aim of this study is to further characterize the role of DA neurotransmission in nociception and the anti-nociceptive function of drd2a. The phenotype caused by rs6277 was modelled in zebrafish larvae using morpholino's and the effect on nociception was tested using a validated behavioural assay. The anti-nociceptive role of drd2a was tested using pharmacological intervention of D agonist Quinpirole. The experiments demonstrate that a decrease in drd2a expression results in a pro-nociceptive behavioural phenotype (P = 0.016) after a heat stimulus. Furthermore, agonism of drd2a with agonist Quinpirole (0.2 μM) results in dose-dependent anti-nociception (P = 0.035) after a heat stimulus. From these results it is concluded that the dopamine receptor drd2a is involved in anti-nociceptive behaviour in zebrafish. The model allows further screening and testing of genetic variation and treatment involved in nociception.
Topics: Animals; Behavior, Animal; Dopamine; Hot Temperature; Models, Animal; Morpholinos; Nociception; Quinpirole; Receptors, Dopamine D2; Synaptic Transmission; Zebrafish
PubMed: 34555394
DOI: 10.1016/j.ejphar.2021.174517 -
Expert Opinion on Pharmacotherapy 2023Comorbidity of substance use disorder (SUD) with schizophrenia, referred to as dual disorder (DD), significantly increases morbidity and mortality compared to... (Review)
Review
INTRODUCTION
Comorbidity of substance use disorder (SUD) with schizophrenia, referred to as dual disorder (DD), significantly increases morbidity and mortality compared to schizophrenia alone. A dopaminergic dysregulation seems to be a common pathophysiological basis of the comorbidity.
AREAS COVERED
This article reports the current evidence on the role of dopamine dysregulations in DD, the pharmacological profile of cariprazine, a partial agonist of D3 and D2 dopamine receptors, and first clinical observations that may support its usefulness in the therapy of DD. PubMed/MEDLINE was searched for the keywords 'cariprazine,' 'schizophrenia,' 'dual disorder,' 'dopamine,' and 'dopamine receptor.' Preclinical and clinical studies, and reviews published in English were retrieved.
EXPERT OPINION
Although the management of DD remains challenging, and the evidence for pharmacologic treatments is still unsatisfactory, cariprazine may be a candidate medication in DD due to its unique mechanism of action. Preliminary clinical experiences suggest that cariprazine has both antipsychotic and anticraving properties and should be considered early in patients with DD.
Topics: Humans; Schizophrenia; Dopamine; Receptors, Dopamine D3; Receptors, Dopamine D2; Substance-Related Disorders
PubMed: 37817489
DOI: 10.1080/14656566.2023.2266359 -
Neuroscience and Biobehavioral Reviews Sep 2016The striatum has been involved in complex behaviors such as motor control, learning, decision-making, reward and aversion. The striatum is mainly composed of medium... (Review)
Review
The striatum has been involved in complex behaviors such as motor control, learning, decision-making, reward and aversion. The striatum is mainly composed of medium spiny neurons (MSNs), typically divided into those expressing dopamine receptor D1, forming the so-called direct pathway, and those expressing D2 receptor (indirect pathway). For decades it has been proposed that these two populations exhibit opposing control over motor output, and recently, the same dichotomy has been proposed for valenced behaviors. Whereas D1-MSNs mediate reinforcement and reward, D2-MSNs have been associated with punishment and aversion. In this review we will discuss pharmacological, genetic and optogenetic studies that indicate that there is still controversy to what concerns the role of striatal D1- and D2-MSNs in this type of behaviors, highlighting the need to reconsider the early view that they mediate solely opposing aspects of valenced behaviour.
Topics: Corpus Striatum; Neurons; Receptors, Dopamine D1; Receptors, Dopamine D2; Reward
PubMed: 27235078
DOI: 10.1016/j.neubiorev.2016.05.021 -
Pharmacological Research Nov 2020Dopamine is a member of the catecholamine family and is associated with multiple physiological functions. Together with its five receptor subtypes, dopamine is closely... (Review)
Review
Dopamine is a member of the catecholamine family and is associated with multiple physiological functions. Together with its five receptor subtypes, dopamine is closely linked to neurological disorders such as schizophrenia, Parkinson's disease, depression, attention deficit-hyperactivity, and restless leg syndrome. Unfortunately, several dopamine receptor-based agonists used to treat some of these diseases cause nausea and vomiting as impending side-effects. The high degree of cross interactions of dopamine receptor ligands with many other targets including G-protein coupled receptors, transporters, enzymes, and ion-channels, add to the complexity of discovering new targets for the treatment of nausea and vomiting. Using activation status of signaling cascades as mechanism-based biomarkers to foresee drug sensitivity combined with the development of dopamine receptor-based biased agonists may hold great promise and seems as the next step in drug development for the treatment of such multifactorial diseases. In this review, we update the present knowledge on dopamine and dopamine receptors and their potential roles in nausea and vomiting. The pre- and clinical evidence provided in this review supports the implication of both dopamine and dopamine receptor agonists in the incidence of emesis. Besides the conventional dopaminergic antiemetic drugs, potential novel antiemetic targeting emetic protein signaling cascades may offer superior selectivity profile and potency.
Topics: Animals; Antiemetics; Dopamine; Dopamine Agonists; Dopamine D2 Receptor Antagonists; Humans; Receptors, Dopamine D2; Receptors, Dopamine D3; Signal Transduction; Vomiting
PubMed: 32814171
DOI: 10.1016/j.phrs.2020.105124 -
Neuroscience Letters Aug 2020Dopamine D2-like receptors (D2) mediate various effects of dopamine. Characterizing the structural and functional regions can contribute to understanding the mechanism...
PURPOSE
Dopamine D2-like receptors (D2) mediate various effects of dopamine. Characterizing the structural and functional regions can contribute to understanding the mechanism of biological effects of dopamine.
METHODS
A large scale phylogeny was utilized to construct a comprehensive dataset of D2 receptor, the evolutionary conserved residues were calculated at both super-family and sub-family (included human D2clade) levels, and then 3D structure of human D2 receptor (DRD2) was modeled to evaluate the significance of these conserved residues and motifs linked with structural stability, genetic variants, functional activation, protein interaction and drug binding.
RESULTS
All the drug binding sites and important protein-complex binding motifs showed evolutionary super-family conservation. However, genetic variants linked to different diseases all belonged to sub-family conservation. The extra cellular loop (ECL3) domain consisted of both super-family and sub-family conserved residues.
CONCLUSIONS
Sub-family conserved residues probably play a vital role in the incidence and progression of diseases.
Topics: Amino Acid Sequence; Animals; Biological Evolution; Humans; Phylogeny; Protein Conformation; Receptors, Dopamine D2
PubMed: 32454148
DOI: 10.1016/j.neulet.2020.135081 -
Journal of Clinical Pharmacy and... Feb 2018Hypertension, a major risk factor for adverse cardiovascular events, such as stroke and myocardial infarction, affects 80 million American adults. The aetiology of... (Review)
Review
WHAT IS KNOWN AND OBJECTIVE
Hypertension, a major risk factor for adverse cardiovascular events, such as stroke and myocardial infarction, affects 80 million American adults. The aetiology of hypertension is multifaceted and difficult to identify. Dopamine receptors, especially those in the kidneys, play a role in blood pressure regulation, and alterations in their function can cause hypertension. The objective of this review was to investigate the association between the use of dopamine antagonists with hypertension focusing especially on second-generation antipsychotics, like clozapine that is D4 receptor antagonist.
METHODS
A literature review was conducted using MEDLINE, Ovid, Science Direct, Web of Science and Cochrane Database of Systematic Reviews databases with keywords:hypertension, hypotension, renin-angiotensin-aldosterone system, dopaminergic receptors, blood pressure, antipsychotics. Inclusion criteria were human or animal studies, systematic reviews, meta-analyses, randomized controlled trials, case report/series, published in selected for inclusion.
RESULTS AND DISCUSSION
All 5 dopamine receptor subtypes (ie D1, D2, D3, D4 and D5) regulate sodium excretion and BP. The D1, D3 and D4 receptors interact directly with the renin-angiotensin-aldosterone system, whereas D2 and D5 receptors directly interact with the sympathetic nervous system to regulate BP. Use of dopaminergic agonists or antagonists could therefore disturb the regulation of BP by dopamine receptors.
WHAT IS NEW AND CONCLUSION
Based upon this review, individuals on antipsychotic agents, particularly clozapine, should be routinely monitored for hypertension, and addition of antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is indicated if hypertension occurs.
Topics: Animals; Antihypertensive Agents; Antipsychotic Agents; Blood Pressure; Dopamine Antagonists; Humans; Receptors, Dopamine
PubMed: 29119585
DOI: 10.1111/jcpt.12649