A D2 Class Dopamine Receptor Transactivates a Receptor Tyrosine Kinase to Inhibit NMDA Receptor Transmission

Kotecha, Suhas A.; Oak, James N.; Jackson, Michael; Perez, Yaël; Orser, Beverley A.; Tol, Hubert H.M. Van; MacDonald, John F.

doi:10.1016/s0896-6273(02)00859-0

Cited by 205 publications

(166 citation statements)

References 66 publications

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“…As shown in Figure 7, the effects of quinpirole were persistent and not recoverable. The persistent action of quinpirole on NMDA receptor-mediated currents is in agreement with the action of quinpirole in the hippocampus and prefrontal cortex (Beazely et al, 2006;Kotecha et al, 2002). Because NT-induced DA release is dramatically reduced in Ntsr1-KO mice (Leonetti et al, 2004), it is unlikely that DA release from DA/NTergic fibers is increased in Ntsr1-KO mice.…”

Section: Ntsr1 Regulates Amygdala Ltpsupporting

confidence: 73%

Heightened Amygdala Long-Term Potentiation in Neurotensin Receptor Type-1 Knockout Mice

Amano

Wada

Yamada

et al. 2008

Neuropsychopharmacol

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Neurotensin receptor type-1 (Ntsr1) is the main receptor subtype that underlies neurotensin (NT)-mediated modulation of the dopamine (DA) system. Although NT and DA coexist in the basolateral nucleus of the amygdala (BLA), the function of Ntsr1 in the amygdala is not well characterized. In the present study, we utilized Ntsr1 knockout (Ntsr1-KO) mice to examine the role of Ntsr1 in the amygdala. In acute brain slices of Ntsr1-KO mice, synaptic currents elicited in BLA pyramidal neurons by electrical stimulation of the lateral nucleus of the amygdala (LA) were greatly potentiated by tetanic stimulation (BLA-long-term potentiation (LTP)). Such potentiation was not evident in pyramidal neurons of wild-type mice. In the presence of an antagonist of Ntsr1, SR48692, BLA-LTP was consistently observed in the neurons of wild-type mice, suggesting that both inherited deletion and acute pharmacological blockade of Ntsr1 induce BLA-LTP. BLA-LTP in Ntsr1-KO mice was impaired by sulpiride, a DA D 2 -like receptor antagonist. Conversely, quinpirole, a D 2 -like receptor agonist, induced pronounced BLA-LTP in wild-type mice, suggesting the upregulation of D 2 -like receptor activity in Ntsr1-KO mice. The ratio of NMDA receptor-mediated to non-NMDA receptor-mediated synaptic currents in Ntsr1-KO mouse BLA neurons was approximately double that measured in wild-type mouse neurons. Furthermore, quinpirole potentiated NMDA receptormediated synaptic currents in the BLA of wild-type mice. These results suggest that, without Ntsr1, synaptic responses from the LA to BLA pyramidal neurons undergo LTP in response to tetanus stimulation through facilitation of D 2 -like receptor-induced activation of NMDA receptors.

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Section: Ntsr1 Regulates Amygdala Ltpsupporting

confidence: 73%

Heightened Amygdala Long-Term Potentiation in Neurotensin Receptor Type-1 Knockout Mice

Amano

Wada

Yamada

et al. 2008

Neuropsychopharmacol

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“…Dopamine and D 2 agonists can decrease N-methyl-D-aspartate (NMDA)-mediated pain through activation of a receptor tyrosine kinase (23). Yunus (24) has proposed that dopamine agonists act as analgesics, but they may also play a more complex role, possibly a central autonomic regulatory role.…”

Section: Discussionmentioning

confidence: 99%

A randomized, double‐blind, placebo‐controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications

Holman¹,

Myers²

2005

Arthritis & Rheumatism

254

120

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Objective. To assess the efficacy and safety of pramipexole, a dopamine 3 receptor agonist, in patients with fibromyalgia.Methods. In this 14-week, single-center, doubleblind, placebo-controlled, parallel-group, escalatingdose trial, 60 patients with fibromyalgia were randomized 2:1 (pramipexole:placebo) to receive 4.5 mg of pramipexole or placebo orally every evening. The primary outcome was improvement in the pain score (10-cm visual analog scale [VAS]) at 14 weeks. Secondary outcome measures were the Fibromyalgia Impact Questionnaire (FIQ), the Multidimensional Health Assessment Questionnaire (MDHAQ), the pain improvement scale, the tender point score, the 17-question Hamilton Depression Inventory (HAM-d), and the Beck Anxiety Index (BAI). Patients with comorbidities and disability were not excluded. Stable dosages of concomitant medications, including analgesics, were allowed.Results. Compared with the placebo group, patients receiving pramipexole experienced gradual and more significant improvement in measures of pain, fatigue, function, and global status. At 14 weeks, the VAS pain score decreased 36% in the pramipexole arm and 9% in the placebo arm (treatment difference -1.77 cm). Forty-two percent of patients receiving pramipexole and 14% of those receiving placebo achieved >50% decrease in pain. Secondary outcomes favoring pramipexole over placebo included the total FIQ score (treatment difference -9.57) and the percentages of improvement in function (22% versus 0%), fatigue (29% versus 7%), and global (38% versus 3%) scores on the MDHAQ. Compared with baseline, some outcomes showed a better trend for pramipexole treatment than for placebo, but failed to reach statistical significance, including improvement in the tender point score (51% versus 36%) and decreases in the MDHAQ psychiatric score (37% versus 28%), the BAI score (39% versus 27%), and the HAM-d score (29% versus 9%). No end points showed a better trend for the placebo arm. The most common adverse events associated with pramipexole were transient anxiety and weight loss. No patient withdrew from the study because of inefficacy or an adverse event related to pramipexole.Conclusion. In a subset of patients with fibromyalgia, ϳ50% of whom required narcotic analgesia and/or were disabled, treatment with pramipexole improved scores on assessments of pain, fatigue, function, and global status, and was safe and well-tolerated.Abnormal autonomic arousal (1-4), altered sleep stage architecture (5), chronic pain, and fatigue characterize fibromyalgia syndrome. The pathogenesis of fibromyalgia is a matter of debate, but centrally mediated abnormalities of sensory processing play an important role (6). Clinicians have tried various pharmacotherapies, including such agents as antidepressants, antiepileptics, muscle relaxants, antiinflammatories, sedative hypnotics, analgesics, and nutriceuticals (7). As a central neurotransmitter, dopamine influences human behavior, autonomic arousal, and sleep (8). Discovery of dopamine receptor subtypes (D 1-5 ) and thei...

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“…15 Dopamine D4 receptor activation can modulate many intracellular signaling cascades in heterologous expression systems, 1 and has been shown to inhibit adenylyl cyclase, 16,17 inhibit GABAa currents, 18 and stimulate extracellular regulated kinase (ERK) and depress NMDA channel activity via transactivation of the plateletderived growth factor receptor-b in the central nervous system. 19 The biological role of this receptor is less well established, but studies with D4-deficient mice and selective D4 receptor antagonists support a role of this receptor in attention and cognition. 14,15,20,21 To date, 36 variants of the polymorphic 48 bp repeat sequence have been identified in humans, and these repeat sequences can be combined into many allelic variants.…”

Section: Introductionmentioning

confidence: 99%

The human dopamine D4 receptor repeat sequences modulate expression

2003

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Genetic studies have implicated a polymorphic repeat sequence in exon 3 of the human dopamine D4 receptor in various behavioral and psychiatric disorders. Functionally various repeat variants are nearly identical, but whether these have different effects on gene expression has not been studied. To study the role of the repeat sequences on expression independently from its structural and functional effects at the protein level, we introduced these sequences immediately upstream of the promoter and in the 3 0 untranslated region of a luciferase reporter vector. In this report, we demonstrate that the repeat sequence can both modulate promoter activity and alter expression post-transcriptionally. The repeat sequence can serve as a substrate for a nuclear binding factor and all the three repeat variants can suppress promoter activity. Placement of the three repeat variants downstream from the luciferase gene in the expression vector shows, however, that the D4.7 repeat sequence has significantly suppressed expression of the reporter compared to the D4.2 and D4.4 repeats, likely via mechanisms involving RNA stability or translational efficiency. These data indicate that the various D4 repeat sequences have different effects on expression, which may explain its potential role in behavioral disorders.

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A D2 Class Dopamine Receptor Transactivates a Receptor Tyrosine Kinase to Inhibit NMDA Receptor Transmission

Cited by 205 publications

References 66 publications

Heightened Amygdala Long-Term Potentiation in Neurotensin Receptor Type-1 Knockout Mice

Heightened Amygdala Long-Term Potentiation in Neurotensin Receptor Type-1 Knockout Mice

A randomized, double‐blind, placebo‐controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications

The human dopamine D4 receptor repeat sequences modulate expression

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