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Brain and Language Dec 2021Reading impairments are prominent trait-like features of cognitive deficits in schizophrenia, predictive of overall cognitive functioning and presumably linked to...
Reading impairments are prominent trait-like features of cognitive deficits in schizophrenia, predictive of overall cognitive functioning and presumably linked to dopaminergic abnormalities. To evaluate this, we used F-fallypride PET in 19 healthy and 21 antipsychotic-naïve schizophrenia subjects and correlated dopamine receptor binding potentials in relevant AFNI-derived regions and voxelwise with group performance on WRAT4 single-word reading subtest. Healthy subjects' scores were positively and linearly associated with D/D receptor availability in the rectus, orbital and superior frontal gyri, fusiform and middle temporal gyri, as well as middle occipital gyrus and precuneus, all predominantly in the left hemisphere and previously implicated in reading, hence suggesting that higher dopamine receptor density is cognitively advantageous. This relationship was weakened in schizophrenia subjects and in contrast to healthy participants followed an inverted U-shaped curve both in the cortex and dorsal striatum, indicating restricted optimal range of dopamine D/D receptor availability for cognitive performance in schizophrenia.
Topics: Cognition; Dopamine; Humans; Positron-Emission Tomography; Reading; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia
PubMed: 34763166
DOI: 10.1016/j.bandl.2021.105046 -
Progress in Neuro-psychopharmacology &... Aug 2020Addictions involve a spectrum of behaviors that encompass features of impulsivity and compulsivity, herein referred to as impulsive-compulsive spectrum disorders... (Review)
Review
Addictions involve a spectrum of behaviors that encompass features of impulsivity and compulsivity, herein referred to as impulsive-compulsive spectrum disorders (ICSDs). The etiology of ICSDs likely involves a complex interplay among neurobiological, psychological and social risk factors. Neurobiological risk factors include the status of the neuroanatomical circuits that govern ICSDs. These circuits can be altered by disease, as well as exogenous influences such as centrally-acting pharmacologics. The 'poster child' for this scenario is Parkinson's disease (PD) medically managed by pharmacological treatments. PD is a progressive neurodegenerative disease that involves a gradual loss of dopaminergic neurons largely within nigrostriatal projections. Replacement therapy includes dopamine receptor agonists that directly activate postsynaptic dopamine receptors (bypassing the requirement for functioning presynaptic terminals). Some clinically useful dopamine agonists, e.g., pramipexole and ropinirole, exhibit high affinity for the D2/D3 receptor subtypes. These agonists provide excellent relief from PD motor symptoms, but some patients exhibit debilitating ICSD. Teasing out the neuropsychiatric contribution of PD-associated pathology from the drugs used to treat PD motor symptoms is challenging. In this review, we posit that modern clinical and preclinical research converge on the conclusion that dopamine replacement therapy can mediate addictions in PD and other neurological disorders. We provide five categories of evidences that align with this position: (i) ICSD prevalence is greater with D2/D3 receptor agonist therapy vs PD alone. (ii) Capacity of dopamine replacement therapy to produce addiction-like behaviors is independent of disease for which the therapy is being provided. (iii) ICSD-like behaviors are recapitulated in laboratory rats with and without PD-like pathology. (iv) Behavioral pathology co-varies with drug exposure. (v) ICSD Features of ICSDs are consistent with agonist pharmacology and neuroanatomical substrates of addictions. Considering the underpinnings of ICSDs in PD should not only help therapeutic decision-making in neurological disorders, but also apprise ICSDs in general.
Topics: Animals; Behavior, Addictive; Dopamine; Dopamine Agonists; Humans; Parkinson Disease; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 32272129
DOI: 10.1016/j.pnpbp.2020.109942 -
Biomolecules Jan 2021Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong... (Review)
Review
Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson's disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.
Topics: Animals; Biomedical Research; Brain; Central Nervous System Diseases; Humans; Neurons; Receptors, Dopamine D3; Translational Research, Biomedical
PubMed: 33466844
DOI: 10.3390/biom11010104 -
Medical Hypotheses Oct 2020Prepulse inhibition (PPI) of acoustic startle reflex is a measure of sensorimotor gating that may reflect the biological processes underlying gaiting impairments in...
Prepulse inhibition (PPI) of acoustic startle reflex is a measure of sensorimotor gating that may reflect the biological processes underlying gaiting impairments in schizophrenia. Although PPI is clinically useful, why PPI is inhibited in schizophrenia is largely unknown. Prepulse inhibition is mediated by M2-like muscarinic acetylcholine receptor on neurons in the caudal pontine reticular nucleus (PnC), activation of this receptor induces Gαi dissociation, and inhibits adenylyl cyclase, resulting in the inhibition of the neurons. On the other hand, the symptoms of schizophrenia are mainly linked to hyperactive dopaminergic activity, mediated by dopamine D2-like receptor. Interestingly, D2-like receptor also uses Gαi. This means that both M2-like acetylcholine receptor and D2-like dopamine receptor use same Gαi-protein, competitively. Thus, chronic over-activation of D2-like receptor observed in schizophrenia may disrupt normal M2-like acetylcholine receptor functions due to their shared coupling to Gαi-proteins, i.e. by reducing the amount of Gαi-protein available for M2-like acetylcholine receptors, resulting in the impairment of PPI.
Topics: Acoustic Stimulation; Humans; Prepulse Inhibition; Receptors, Dopamine; Reflex, Startle; Schizophrenia
PubMed: 32502900
DOI: 10.1016/j.mehy.2020.109901 -
Brain Research May 2023Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their...
Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are logical candidates for investigation. We analyzed data from two recently published studies that characterized availability of dopamine D2-like receptors (D2R) with [C]raclopride PET imaging and dopamine D receptor (DR) sensitivity with quinpirole-induced yawning in cocaine-naïve rhesus monkeys who subsequently acquired cocaine self-administration and completed a cocaine self-administration dose-effect curve. The present analysis compared D2R availability in several brain areas and characteristics of quinpirole-induced yawning, both acquired when monkeys were drug-naïve, with measures of initial sensitivity to cocaine. D2R availability in the caudate nucleus was negatively correlated with the ED of the cocaine self-administration curve, although the significance of this relationship was driven by an outlier and was not present after the outlier was removed. No other significant associations were observed between D2R availability in any examined brain region and measures of sensitivity to cocaine reinforcement. However, there was a significant negative correlation between DR sensitivity, represented by the ED of the quinpirole-induced yawning curve, and the dose at which monkeys acquired cocaine self-administration. We also report no change from baseline D2R availability when a second PET scan was conducted after completion of the dose-effect curves. These data suggest the utility of DR sensitivity, but not D2R availability, as a biomarker for vulnerability and resilience to cocaine. The well-established relationships between dopamine receptors and cocaine reinforcement in cocaine-experienced humans and animals may require extensive cocaine exposure.
Topics: Humans; Animals; Male; Cocaine; Dopamine; Quinpirole; Macaca mulatta; Receptors, Dopamine D3; Dopamine Agonists; Receptors, Dopamine D2; Self Administration; Dose-Response Relationship, Drug
PubMed: 36914041
DOI: 10.1016/j.brainres.2023.148323 -
Technology in Cancer Research &... 2021The dopamine receptors (DRs) family includes 5 members with differences in signal transduction and ligand affinity. Abnormal DRs expression has been correlated multiple... (Review)
Review
The dopamine receptors (DRs) family includes 5 members with differences in signal transduction and ligand affinity. Abnormal DRs expression has been correlated multiple tumors with their clinical outcome. Thus, it has been proposed that DRs-targeting drugs-developed for other diseases as schizophrenia or Parkinson's disease-could be helpful in managing neoplastic diseases. In this review, we discuss the role of DRs and the effects of DRs-targeting in tumor progression and cancer cell biology using multiple high-prevalence neoplasms as examples. The evidence shows that DRs are valid therapeutic targets for certain receptor/disease combinations, but the data are inconclusive or contradictory for others. In either case, further studies are required to define the precise role of DRs in tumor progression and propose better therapeutic strategies for their targeting.
Topics: Animals; Dopamine Agonists; Dopamine Antagonists; Humans; Molecular Targeted Therapy; Neoplasms; Receptors, Dopamine; Signal Transduction
PubMed: 34212819
DOI: 10.1177/15330338211027913 -
ACS Chemical Neuroscience Mar 2020Kinetic analysis of dopamine receptor activation and inactivation and the study of dopamine-dependent signaling requires precise simulation of the presynaptic release of...
Kinetic analysis of dopamine receptor activation and inactivation and the study of dopamine-dependent signaling requires precise simulation of the presynaptic release of the neurotransmitter dopamine and tight temporal control over the release of dopamine receptor antagonists. The 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group was conjugated to dopamine and the dopamine receptor antagonist sulpiride to generate "caged" versions of these neuromodulators (CyHQ--DA and CyHQ-sulpiride, respectively) that could release their payloads with 365 or 405 nm light or through 2-photon excitation (2PE) at 740 nm. These compounds are stable under physiological conditions in the dark, yet photolyze rapidly and cleanly to yield dopamine or sulpiride and the caging remnant CyHQ-OH. CyHQ--DA mediated the light activation of dopamine-1 (D1) receptors on the breast cancer cell line MDA-MB-231 in culture. In mouse brain slice from the substantia nigra pars compacta, localized flash photolysis of CyHQ--DA accurately mimicked the natural presynaptic release of dopamine and activation of dopamine-2 (D2) receptors, causing a robust, concentration-dependent, and repeatable G protein-coupled inwardly rectifying potassium channel-mediated outward current in whole-cell voltage clamp recordings that was amplified by cocaine and blocked by sulpiride. Photolysis of CyHQ-sulpiride rapidly blocked synaptic activity, enabling measurement of the unbinding rates of dopamine and quinpirole, a D2 receptor agonist. These tools will enable more detailed study of dopamine receptors, their interactions with other GPCRs, and the physiology of dopamine signaling in the brain.
Topics: Animals; Dopamine; Dopamine Agonists; Dopaminergic Neurons; Kinetics; Mice; Quinpirole; Receptors, Dopamine D1; Sulpiride
PubMed: 32077679
DOI: 10.1021/acschemneuro.9b00675 -
Medicinal Research Reviews Jan 2023Dopamine is a biologically active amine synthesized in the central and peripheral nervous system. This biogenic monoamine acts by activating five types of dopamine... (Review)
Review
Dopamine is a biologically active amine synthesized in the central and peripheral nervous system. This biogenic monoamine acts by activating five types of dopamine receptors (D Rs), which belong to the G protein-coupled receptor family. Antagonists and partial agonists of D Rs are used to treat schizophrenia, Parkinson's disease, depression, and anxiety. The typical pharmacophore with high D R affinity comprises four main areas, namely aromatic moiety, cyclic amine, central linker and aromatic/heteroaromatic lipophilic fragment. From the literature reviewed herein, we can conclude that 4-(2,3-dichlorophenyl), 4-(2-methoxyphenyl)-, 4-(benzo[b]thiophen-4-yl)-1-substituted piperazine, and 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine moieties are critical for high D R affinity. Four to six atoms chains are optimal for D R affinity with 4-butoxyl as the most pronounced one. The bicyclic aromatic/heteroaromatic systems are most frequently occurring as lipophilic appendages to retain high D R affinity. In this review, we provide a thorough overview of the therapeutic potential of D R modulators in the treatment of the aforementioned disorders. In addition, this review summarizes current knowledge about these diseases, with a focus on the dopaminergic pathway underlying these pathologies. Major attention is paid to the structure, function, and pharmacology of novel D R ligands, which have been developed in the last decade (2010-2021), and belong to the 1,4-disubstituted aromatic cyclic amine group. Due to the abundance of data, allosteric D R ligands and D R modulators from patents are not discussed in this review.
Topics: Humans; Dopamine; Receptors, Dopamine D2; Ligands; Receptors, G-Protein-Coupled
PubMed: 36111795
DOI: 10.1002/med.21923 -
Drugs Oct 2019Bipolar disorder is a chronic, disabling, and costly illness with frequent relapses and recurrences, high rates of co-morbid conditions, and poor adherence to treatment.... (Review)
Review
Bipolar disorder is a chronic, disabling, and costly illness with frequent relapses and recurrences, high rates of co-morbid conditions, and poor adherence to treatment. Mood stabilizers and antipsychotics are the cornerstones of treatment. Dopamine receptor partial agonists are a novel class of antipsychotic agents with original pharmacodynamic properties. Among them, two have been approved by the US Food and Drug Administration for the treatment of bipolar disorder. Aripiprazole (oral formulation) has been approved as monotherapy for the treatment of manic/mixed episodes in adult and pediatric populations and for maintenance treatment in adults, and as adjunctive treatment to mood stabilizers, for the acute treatment of manic/mixed episodes and for maintenance in adults. An intramuscular formulation of aripiprazole has been approved for the treatment of agitation in mania and a long-acting injectable formulation has been approved as maintenance treatment. In the USA, cariprazine has been approved as monotherapy for the acute treatment of manic/mixed as well as bipolar depressive episodes. Brexpiprazole is not yet approved to treat bipolar disorder. The evidence supporting these indications is reviewed via an analysis of clinical registration trials as well as additional studies, on the basis of a systematic literature search. Further studies dealing with other aspects of bipolar illness are also presented. Aripiprazole and cariprazine are efficacious and generally well tolerated agents that have shown cost effectiveness, and may therefore enrich our therapeutic armamentarium for bipolar illness. Brexpiprazole, which displays an overall promising tolerability profile, deserves further efficacy studies.
Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Dopamine Agonists; Humans; Piperazines; Receptors, Dopamine; United States; United States Food and Drug Administration
PubMed: 31468317
DOI: 10.1007/s40265-019-01189-8 -
Bioorganic & Medicinal Chemistry Letters Mar 2022Dopamine is one of the crucial neurotransmitters in the human brain. Its out-of-range concentration can lead to various neurological diseases with special interest for...
Dopamine is one of the crucial neurotransmitters in the human brain. Its out-of-range concentration can lead to various neurological diseases with special interest for dopamine D and D receptor subtypes. Although BODIPY is a highly versatile structural moiety for fluorescence labeling, we have looked out for structurally related pyridine-based moieties. We used BOPPY labelling of well-described DR/DR pharmacophores to obtain ligands with moderate to low nanomolar binding affinities as well as low to excellent quantum yields for bright fluorescence ligands. To best of our knowledge, this is the first report on the application of BOPPY fluorophores to GPCR ligands. This approach offers a general applicable way for fluorescence labelling via primary aliphatic amine elements.
Topics: Amines; Fluorescent Dyes; Humans; Ligands; Molecular Structure; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 35063632
DOI: 10.1016/j.bmcl.2022.128573