scholarly journals Supersensitive presynaptic dopamine D2 receptor inhibition of the striatopallidal projection in nigrostriatal dopamine-deficient mice

2013 ◽  
Vol 110 (9) ◽  
pp. 2203-2216 ◽  
Author(s):  
Wei Wei ◽  
Li Li ◽  
Guoliang Yu ◽  
Shengyuan Ding ◽  
Chengyao Li ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
Movement Control ◽  
Gaba Release ◽  
Mutant Mice ◽  
Neuron Activity ◽  
Indirect Pathway ◽  
Axon Terminals ◽  
Low Concentrations

The dopamine (DA) D2 receptor (D2R)-expressing medium spiny neurons (D2-MSNs) in the striatum project to and inhibit the GABAergic neurons in the globus pallidus (GP), forming an important link in the indirect pathway of the basal ganglia movement control circuit. These striatopallidal axon terminals express presynaptic D2Rs that inhibit GABA release and thus regulate basal ganglion function. Here we show that in transcription factor Pitx3 gene mutant mice with a severe DA loss in the dorsal striatum mimicking the DA denervation in Parkinson's disease (PD), the striatopallidal GABAergic synaptic transmission displayed a heightened sensitivity to presynaptic D2R-mediated inhibition with the dose-response curve shifted to the left, although the maximal inhibition was not changed. Functionally, low concentrations of DA were able to more efficaciously reduce the striatopallidal inhibition-induced pauses of GP neuron activity in DA-deficient Pitx3 mutant mice than in wild-type mice. These results demonstrate that presynaptic D2R inhibition of the striatopallidal synapse becomes supersensitized after DA loss. These supersensitive D2Rs may compensate for the lost DA in PD and also induce a strong disinhibition of GP neuron activity that may contribute to the motor-stimulating effects of dopaminergic treatments in PD.

The Effect of PAOPA, a Novel Allosteric Modulator of Dopamine D2 Receptors, on Select Signaling Proteins Following Sub-Chronic Administration in the Rat

2020 ◽  
Vol 13 ◽  
Author(s):  
Ritesh Daya ◽  
Joella Ho ◽  
Sharon Thomson ◽  
Jayant Bhandari ◽  
Ram K. Mishra
Keyword(s):  
Frontal Cortex ◽  
Mechanism Of Action ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
D2 Receptors ◽  
Dopamine D2 ◽  
Therapeutic Mechanism ◽  
Clinical Models ◽  
G Protein Coupled

Background: Allosteric modulators of G-protein coupled receptors regulate receptor activity by binding to sites other than the active site and have emerged as a new and highly desirable class of drugs. PAOPA (3(R)-[(2(S)- pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide), a peptidomimetic analog of Prolyl-Leucyl-Glycinamide, is a potent dopamine D2 receptor allosteric modulator. PAOPA has shown therapeutic effects in pre-clinical models of schizophrenia and extrapyramidal dysfunction. Objective: in this study, we sought to examine the biomolecular underpinnings of PAOPA‘s therapeutic outcomes in preclinical models of schizophrenia. Method: Following sub-chronic (daily for 7 days) administration of PAOPA, we assessed levels of dopamine D2 receptors, receptor kinases (GRK2 (G protein-coupled receptor kinase 2) and Arrestin-3), and phosphorylated mitogenactivated protein kinase (MAPKs), namely, extracellular signal-regulated kinases (ERK1/2) in the hippocampus, medial pre-frontal cortex, nucleus accumbens, pre-frontal cortex, and dorsal striatum via protein quantification. Results: Following 7 days of daily PAOPA treatment, we observed decreased GRK2 and increased dopamine D2 receptor expression in the dorsal striatum. These findings potentially underscore PAOPA’s therapeutic mechanism of action for the positive-like symptoms of schizophrenia in pre-clinical animal models. Additionally, we observed a decline in GRK2 in the hippocampus and an increase in phosphorylated ERK1 in the pre-frontal cortex, suggestive of a role for PAOPA in treating cognitive and/or affective dysfunction in pre-clinical models. Conclusion: While further studies are required to elucidate PAOPA’s mechanism of action, this study builds on prior investigations and develops an early framework to describe the therapeutic mechanism of action of PAOPA.

scholarly journals Effect of Zishenpingchan Granule on Neurobehavioral Manifestations and the Activity and Gene Expression of Striatal Dopamine D1 and D2 Receptors of Rats with Levodopa-Induced Dyskinesias

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Qing Ye ◽  
Xiao-Lei Yuan ◽  
Jie Zhou ◽  
Can-xing Yuan ◽  
Xu-ming Yang
Keyword(s):  
Gene Expression ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
D2 Receptors ◽  
Striatal Dopamine ◽  
Control Group ◽  
Indirect Pathway ◽  
Dopamine D2 ◽  
D1 And D2 Receptors ◽  
Neurobehavioral Manifestations

This study was performed to observe the effects of Zishenpingchan granule on neurobehavioral manifestations and the activity and gene expression of striatal dopamine D1 and D2 receptors of rats with levodopa-induced dyskinesias (LID). We established normal control group, LID model group, and TCM intervention group. Each group received treatment for 4 weeks. Artificial neural network (ANN) was applied to excavate the main factor influencing variation in neurobehavioral manifestations of rats with LID. The results showed that overactivation in direct pathway mediated by dopamine D1 receptor and overinhibition in indirect pathway mediated by dopamine D2 receptor may be the main mechanism of LID. TCM increased the efficacy time of LD to ameliorate LID symptoms effectively mainly by upregulating dopamine D2 receptor gene expression.

Inhibitory interaction of cannabinoid CB1 receptor and dopamine D2 receptor agonists on voltage-gated currents of goldfish cones

2004 ◽  
Vol 21 (1) ◽  
pp. 69-77 ◽  
Author(s):  
SHIH-FANG FAN ◽  
STEPHEN YAZULLA
Keyword(s):  
Receptor Agonist ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Suppressive Effect ◽  
Cb1 Receptor ◽  
Membrane Currents ◽  
Cannabinoid Cb1 Receptor ◽  
Inhibitory Interaction ◽  
Dopamine D2 ◽  
Low Concentrations

Dopamine is a light-adaptive signal that desensitizes the retina, while cannabinoids reportedly increase photosensitivity. The presynaptic membrane of goldfish retinal cones has dopamine D2 receptors and cannabinoid CB1 receptors. This work focused on whether dopamine D2 receptor agonist quinpirole and cannabinoid CB1 receptor agonist WIN 55212-2 (WIN) interacted to modulate voltage-dependent membrane currents of cones. A conventional patch-clamp method was used to record depolarization evoked whole-cell outward currents (Iout) and an inward calcium current (ICa) from the inner segment of cones in goldfish retinal slices. WIN had biphasic actions: low concentrations (<1 μM) increased the currentsviaGs, while higher concentrations (>1 μM) decreased the currentsviaGi/Go. Neither dopamine nor the D2 agonist quinpirole (1–20 μM) had a significant effect on eitherIoutorICa. Quinpirole at 50 μM had a mild suppressive (∼20%) effect onIout. However, quinpirole (<10 μM) completely blocked the enhancement of both currents seen with 0.7 μM WIN. The effect of quinpirole was blocked by sulpiride and by pertussis toxin, indicating that quinpirole was actingviaa D2 receptor-Gi/o coupled mechanism. The suppressive action of 50 μM quinpirole (∼20%) was not additive with the suppressive effect of 3 μM WIN (∼40%). D2 agonistsviaGi/o oppose the action of low concentrations of CB1 agonists actingviaGs to modulate cone membrane currents, suggesting a role in shaping the cone light response and/or sensitivity to changes in ambient light conditions. The nonadditive effect of high concentrations of WIN and quinpirole suggests that both decrease membrane currentsviathe same transduction pathway, Gi/Go protein kinase A (PKA).

scholarly journals Individual differences in the proneness to have flow experiences are linked to dopamine D2-receptor availability in the dorsal striatum

NeuroImage ◽  
2013 ◽  
Vol 67 ◽  
pp. 1-6 ◽  
Author(s):  
Örjan de Manzano ◽  
Simon Cervenka ◽  
Aurelija Jucaite ◽  
Oscar Hellenäs ◽  
Lars Farde ◽  
...  
Keyword(s):  
Individual Differences ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
Dopamine D2 ◽  
Flow Experiences

scholarly journals Dopamine receptor 1 neurons in the dorsal striatum regulate food anticipatory circadian activity rhythms in mice

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Christian M Gallardo ◽  
Martin Darvas ◽  
Mia Oviatt ◽  
Chris H Chang ◽  
Mateusz Michalik ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
D1 Receptor ◽  
Circadian Oscillators ◽  
Food Anticipatory Activity ◽  
Dopamine Signaling ◽  
Anticipatory Activity ◽  
Dopamine Receptor 1 ◽  
Deficient Mice

Daily rhythms of food anticipatory activity (FAA) are regulated independently of the suprachiasmatic nucleus, which mediates entrainment of rhythms to light, but the neural circuits that establish FAA remain elusive. In this study, we show that mice lacking the dopamine D1 receptor (D1R KO mice) manifest greatly reduced FAA, whereas mice lacking the dopamine D2 receptor have normal FAA. To determine where dopamine exerts its effect, we limited expression of dopamine signaling to the dorsal striatum of dopamine-deficient mice; these mice developed FAA. Within the dorsal striatum, the daily rhythm of clock gene period2 expression was markedly suppressed in D1R KO mice. Pharmacological activation of D1R at the same time daily was sufficient to establish anticipatory activity in wild-type mice. These results demonstrate that dopamine signaling to D1R-expressing neurons in the dorsal striatum plays an important role in manifestation of FAA, possibly by synchronizing circadian oscillators that modulate motivational processes and behavioral output.

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