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CNS Spectrums Dec 2016The broad use of atypical antipsychotics was expected to dramatically reduce the prevalence and incidence of tardive dyskinesia (TD), but data show that TD remains an... (Review)
Review
The broad use of atypical antipsychotics was expected to dramatically reduce the prevalence and incidence of tardive dyskinesia (TD), but data show that TD remains an important challenge due the persistent nature of its symptoms and resistance to numerous treatment modalities, including antipsychotic discontinuation. Recent insights on genetic risk factors and new concepts surrounding pathophysiology have spurred interest in the possibility of targeted treatment for TD. As will be reviewed in this article, the number of evidence-based strategies for TD treatment is small: only clonazepam, amantadine, ginkgo biloba extract, and the vesicular monoamine transporter 2 (VMAT2) inhibitor tetrabenazine have compelling data. Using new insights into the metabolism of tetrabenazine and the properties of its active metabolites, 2 modifications of tetrabenazine have been synthesized to improve the kinetic profile, and are currently involved in double-blind placebo controlled studies aimed at U.S. Food and Drug Administration (FDA) regulatory approval. The possible availability of these new agents, deuterated tetrabenazine and valbenazine, significantly widens the range of treatment choices for patients with TD. For clinicians with patients at risk for TD due to dopamine antagonist exposure, experience has shown that the problem of TD will be an ongoing issue in modern psychiatry, and that an appreciation of new developments in the pathophysiology of, risk factors for, and treatment of TD is crucial to managing this condition.
Topics: Adrenergic Uptake Inhibitors; Amantadine; Antipsychotic Agents; Clonazepam; Dopamine Agents; Dopamine Antagonists; GABA Modulators; Ginkgo biloba; Humans; Plant Extracts; Risk Factors; Tardive Dyskinesia; Tetrabenazine; Valine
PubMed: 28044943
DOI: 10.1017/S1092852916000730 -
Brain Research Bulletin Apr 2022Beta band (12-30 Hz) hypersynchrony within the basal ganglia-thalamocortical network has been suggested as a hallmark of Parkinson's disease (PD) pathophysiology....
Beta band (12-30 Hz) hypersynchrony within the basal ganglia-thalamocortical network has been suggested as a hallmark of Parkinson's disease (PD) pathophysiology. Abnormal beta band oscillations are found in the pedunculopontine nucleus (PPN) and primary motor cortex (M1) and are correlated with dopamine depletion. Dopamine acts locomotion and motor performance mainly through dopamine receptors (D1 and D2). However, the precise mechanism by which dopamine receptors regulate beta band electrophysiological activities between the PPN and M1 is still unknown. Here, we recorded the neuronal activity of the PPN and M1 simultaneously by the administration of the drug (SCH23390 and raclopride), selectively blocking the dopamine D1 receptor and D2 receptor. We discovered that the increased coherent activity of the beta band (12-30 Hz) between M1 and PPN in the lesioned group could be reduced and restored by injecting raclopride in the resting and wheel running states. Our studies revealed the unique role of D2 dopamine receptor signaling in regulating β band oscillatory activity in M1 and PPN and their relationship after the loss of dopamine, which contributes to elucidating the underlying mechanism of the pathophysiology of PD.
Topics: Animals; Benzazepines; Beta Rhythm; Disease Models, Animal; Dopamine Antagonists; Motor Cortex; Parkinson Disease; Pedunculopontine Tegmental Nucleus; Raclopride; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 35077843
DOI: 10.1016/j.brainresbull.2022.01.012 -
General and Comparative Endocrinology Dec 2017Gonadotropin-releasing hormone (GnRH) stimulates luteinizing hormone release to control ovulation and spermiation in vertebrates. Dopamine (DA) has a clear inhibitory...
Gonadotropin-releasing hormone (GnRH) stimulates luteinizing hormone release to control ovulation and spermiation in vertebrates. Dopamine (DA) has a clear inhibitory role in the control of reproduction in numerous teleosts, and emerging evidence suggests that similar mechanisms may exist in amphibians. The interactions between GnRH and DA on spawning success and pituitary gene expression in the Northern leopard frog (Lithobates pipiens) were therefore investigated. Frogs were injected during the natural breeding season with a GnRH agonist [GnRH-A; (Des-Gly, D-Ala, Pro-NHEt)-LHRH; 0.1μg/g and 0.4μg/g] alone and in combination with the dopamine receptor D2 antagonist metoclopramide (MET; 5μg/g and 10μg/g). Injected animals were allowed to breed in outdoor mesocosms. Time to amplexus and oviposition were assessed, and egg mass release, incidences of amplexus, egg mass weight, total egg numbers and fertilization rates were measured. To examine gene expression, female pituitaries were sampled at 12, 24 and 36h following injection of GnRH-A (0.4μg/g) alone and in combination with MET (10μg/g). The mRNA levels of the genes lhb, fshb, gpha, drd2 and gnrhr1 were measured using quantitative real-time PCR. Data were analyzed by a two-way ANOVA. Both GnRH-A doses increased amplexus, oviposition and fertilization alone. Co-injection of MET with GnRH-A did not further enhance spawning success. Injection of GnRH-A alone time-dependently increased expression of lhb, fshb, gpha and gnrhr1. The major effect of MET alone was to decrease expression of drd2. Importantly, the stimulatory effects of GnRH-A on lhb, gpha and gnrhr1 were potentiated by the co-injection of MET at 36h. At this time, expression of fshb was increased only in animals injected with both GnRH-A and MET. Spawning success was primarily driven by the actions of GnRH-A. The hypothesized inhibitory action of DA was supported by pituitary gene expression analysis. The results from this study provide a fundamental framework for future time- and dose-response investigations to improve current spawning methods in amphibians.
Topics: Animals; Dopamine Antagonists; Female; Gene Expression Regulation; Gonadotropin-Releasing Hormone; Injections, Intraperitoneal; Male; Metoclopramide; Ovum; Rana pipiens; Reproduction; Seasons; Time Factors
PubMed: 28964731
DOI: 10.1016/j.ygcen.2017.09.023 -
Investigative Ophthalmology & Visual... Oct 2020Animal models have demonstrated a link between decreases in retinal dopamine levels and the development of form-deprivation myopia (FDM). However, the consistency of...
PURPOSE
Animal models have demonstrated a link between decreases in retinal dopamine levels and the development of form-deprivation myopia (FDM). However, the consistency of dopamine's role in the other major form of experimental myopia, that of lens-induced myopia (LIM), is less clear, raising the question as to what extent dopamine plays a role in human myopia. Therefore, to better define the role of dopamine in both forms of experimental myopia, we examined how consistent the protection afforded by dopamine and the dopamine agonist 6-amino-5,6,7,8-tetrahydronaphthalene-2,3-diol hydrobromide (ADTN) is between FDM and LIM.
METHODS
Intravitreal injections of dopamine (0.002, 0.015, 0.150, 1.500 µmol) or ADTN (0.001, 0.010, 0.100, 1.000 µmol) were administered daily to chicks developing FDM or LIM. Axial length and refraction were measured following 4 days of treatment. To determine the receptor subtype by which dopamine and ADTN inhibit FDM and LIM, both compounds were coadministered with either the dopamine D2-like antagonist spiperone (0.005 µmol) or the D1-like antagonist SCH-23390 (0.005 µmol).
RESULTS
Intravitreal administration of dopamine or ADTN inhibited the development of FDM (ED50 = 0.003 µmol and ED50 = 0.011 µmol, respectively) and LIM (ED50 = 0.002 µmol and ED50 = 0.010 µmol, respectively) in a dose-dependent manner, with a similar degree of protection observed in both paradigms (P = 0.471 and P = 0.969, respectively). Coadministration with spiperone, but not SCH-23390, inhibited the protective effects of dopamine and ADTN against the development of both FDM (P = 0.214 and P = 0.138, respectively) and LIM (P = 0.116 and P = 0.100, respectively).
CONCLUSIONS
pharmacological targeting of the retinal dopamine system inhibits FDM and LIM in a similar dose-dependent manner through a D2-like mechanism.
Topics: Animals; Axial Length, Eye; Chickens; Contact Lenses; Disease Models, Animal; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Form Perception; Intravitreal Injections; Male; Myopia; Refraction, Ocular; Retina; Sensory Deprivation
PubMed: 33016984
DOI: 10.1167/iovs.61.12.4 -
Continuum (Minneapolis, Minn.) Aug 2015This article discusses the treatment of status migrainosus in the emergency department and the treatment of intractable migraine in an inpatient setting. (Review)
Review
PURPOSE OF REVIEW
This article discusses the treatment of status migrainosus in the emergency department and the treatment of intractable migraine in an inpatient setting.
RECENT FINDINGS
Multiple agents of various drug classes have been tried for the treatment of acute migraine in the emergency department, but few have adequate medical evidence to support their use. Opioids, which are less effective than other medications used for the acute treatment of migraine and also carry the risk of adverse CNS side effects, habituation, and addiction, have been prescribed for migraine in the emergency department at an increasing rate over the last decade, which is a worrisome trend. Very few patients with migraine derive sustained relief from pain after emergency department treatment, and most have a high frequency of headache recurrence.
SUMMARY
Treatment of status migrainosus and intractable migraine should focus on adequate fluid hydration and combination IV therapy with multiple nonopioid medications from multiple drug classes. Dopamine receptor antagonists appear to have some of the highest medical evidence for efficacy.
Topics: Disease Management; Dopamine Antagonists; Emergency Service, Hospital; Headache Disorders; Humans; Inpatients; Migraine Disorders
PubMed: 26252587
DOI: 10.1212/CON.0000000000000191 -
The European Journal of Neuroscience Aug 2022Dopamine (DA) modulates cognition in part via differential activation of D1 and D2 receptors within the striatum and prefrontal cortex, yet evidence for cognitive...
Dopamine (DA) modulates cognition in part via differential activation of D1 and D2 receptors within the striatum and prefrontal cortex, yet evidence for cognitive impairments stemming from DA blockade or deficiency is inconsistent. Given the predominance of D1 over D2 receptors (R) in the prefrontal cortex of primates, D1-R blockade should more strongly influence frontal executive function (including working memory), while D2-R blockade should impair processes more strongly associated with the dorsal striatum (including cognitive flexibility, and learning). To test how systemic DA blockade disrupts cognition, we administered D1-R and D2-R like antagonists to healthy monkeys while they performed a series of cognitive tasks. Two selective DA receptor antagonist drugs (SCH-23390 hydrochloride: D1/D5-R antagonist; or Eticlopride hydrochloride: D2/D3-R antagonist) or placebo (0.9% saline) were systemically administered. Four tasks were used: (1) 'visually guided reaching', to test response time and accuracy, (2) 'reversal learning', to test association learning and attention, (3) 'self-ordered sequential search' to test spatial working memory, and (4) 'delayed match to sample' to test object working memory. Increased reach response times and decreased motivation to work for liquid reward was observed with both the D1/D5-R and D2/D3-R antagonists at the maximum dosages that still enabled task performance. The D2/D3-R antagonist impaired performance in the reversal learning task, while object and spatial working memory performance was not consistently affected in the tested tasks for either drug. These results are consistent with the theory that systemic D2/D3-R antagonists preferentially influence striatum processes (cognitive flexibility) while systemic D1/D5-R administration is less detrimental to frontal executive function.
Topics: Animals; Dopamine; Dopamine D2 Receptor Antagonists; Learning; Motivation; Primates; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 35746869
DOI: 10.1111/ejn.15743 -
Behavioural Brain Research Jan 2021Considering the extent of drug use and its relapse rate worldwide, in the present study, we explored the role of intra-CA1 administration of D1-like and D2-like receptor...
Considering the extent of drug use and its relapse rate worldwide, in the present study, we explored the role of intra-CA1 administration of D1-like and D2-like receptor antagonists on the expression and extinction of morphine-induced CPP. To induce morphine CPP, adult male Wistar rats received a daily subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Different doses of SCH23390 (0.25, 1 or 4 μg/0.5 μl saline), as a selective D1-like receptor antagonist, and sulpiride (0.25, 1, or 4 μg/0.5 μl DMSO), as a selective D2-like receptor antagonist, were bilaterally microinjected into the CA1 region in the expression and extinction phases 1 h before CPP evaluation. Conditioning scores and locomotor activities were recorded during the tests. Results indicated that the injection of the antagonists into the CA1 region dose-dependently attenuated the expression of the morphine-induced CPP and sulpiride revealed prominent behavioral results compared to SCH23390 in the expression phases. Furthermore, microinjections of SCH23390 and sulpiride shortened the extinction phase of the morphine-induced CPP without changing the locomotor activity. The results indicated the involvement of D1- and D2-like receptors within the CA1 region in the expression and extinction of rewarding properties of morphine.
Topics: Animals; Behavior, Animal; Benzazepines; CA1 Region, Hippocampal; Conditioning, Classical; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Extinction, Psychological; Locomotion; Male; Morphine; Narcotics; Rats; Rats, Wistar; Receptors, Dopamine D1; Reward; Sulpiride
PubMed: 32976861
DOI: 10.1016/j.bbr.2020.112924 -
Cell Host & Microbe Oct 2022The gastrointestinal tract facilitates food digestion, with the gut microbiota playing pivotal roles in nutrient breakdown and absorption. However, the microbial...
The gastrointestinal tract facilitates food digestion, with the gut microbiota playing pivotal roles in nutrient breakdown and absorption. However, the microbial molecules and downstream signaling pathways that activate food digestion remain unexplored. Here, by establishing a food digestion system in C. elegans, we discover that food breakdown is regulated by the interaction between bacterial outer membrane proteins (OMPs) and a neural-immune pathway. E. coli OmpF/A activate digestion by increasing the neuropeptide NLP-12 that acts on the receptor CCKR. NLP-12 is homologous to mammalian cholecystokinin, known to stimulate dopamine, and we found that loss of dopamine receptors or addition of a dopamine antagonist inhibited OMP-mediated digestion. Dopamine and NLP-12-CKR-1 converge to inhibit PMK-1/p38 innate immune signaling. Moreover, directly inhibiting PMK-1/p38 boosts food digestion. This study uncovers a role of bacterial OMPs in regulating animal nutrient uptake and supports a key role for innate immunity in digestion.
Topics: Animals; Bacterial Outer Membrane Proteins; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cholecystokinin; Dopamine; Dopamine Antagonists; Escherichia coli; Escherichia coli Proteins; Immunity, Innate; Mammals; Receptors, Dopamine
PubMed: 36057258
DOI: 10.1016/j.chom.2022.08.004 -
Neuroscience Sep 2022Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the...
Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the accumbens reduces the proportion of reward-predictive cues to which rats respond with cued approach. Recent evidence indicates that accumbens dopamine also promotes wakefulness and arousal, but the relationship between dopamine's roles in arousal and reward seeking remains unexplored. Here, we show that the ability of systemic or intra-accumbens injections of the D1 antagonist SCH23390 to reduce cued approach to reward depends on the animal's state of arousal. Handling the animal, a manipulation known to increase arousal, was sufficient to reverse the behavioral effects of the antagonist. In addition, SCH23390 reduced spontaneous locomotion and increased time spent in sleep postures, both consistent with reduced arousal, but also increased time spent immobile in postures inconsistent with sleep. In contrast, the ability of the D2 antagonist haloperidol to reduce cued approach was not reversible by handling. Haloperidol reduced spontaneous locomotion but did not increase sleep postures, instead increasing immobility in non-sleep postures. We place these results in the context of the extensive literature on dopamine's contributions to behavior, and propose the arousal-motor hypothesis. This novel synthesis, which proposes that two main functions of dopamine are to promote arousal and facilitate motor behavior, accounts both for our findings and many previous behavioral observations that have led to disparate and conflicting conclusions.
Topics: Animals; Arousal; Dopamine; Dopamine Antagonists; Haloperidol; Nucleus Accumbens; Rats; Receptors, Dopamine D1; Reward
PubMed: 35853563
DOI: 10.1016/j.neuroscience.2022.07.008 -
Pharmacology, Biochemistry, and Behavior Nov 2015Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A...
Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS.
Topics: Acetylcholine; Animals; Benzopyrans; Brain Chemistry; Cerebral Cortex; Dopamine; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Fluorenes; Haloperidol; Male; Mice; Mice, Inbred C57BL; Nootropic Agents; Oxazines; Phencyclidine; Piperazines; Piperidines; Rats, Long-Evans; Receptors, Dopamine D3
PubMed: 26383990
DOI: 10.1016/j.pbb.2015.09.011