Dopamine internalization via Uptake and stimulation of intracellular D-receptor-dependent calcium mobilization and CDP-diacylglycerol signaling.

Dopamine stimulates CDP-diacylglycerol biosynthesis through D-like receptors, particularly the D subtype most of which is intracellularly localized. CDP-diacylglycerol regulates phosphatidylinositol-4,5-bisphosphate-dependent signaling cascades by serving as obligatory substrate for phosphatidylinositol biosynthesis. Here, we used acute and organotypic brain tissues and cultured cells to explore the mechanism by which extracellular dopamine acts to modulate intracellular CDP-diacylglycerol.

Dopamine-sensitive signaling mediators modulate psychostimulant-induced ultrasonic vocalization behavior in rats.

The mesolimbic dopamine system plays a major role in psychostimulant-induced ultrasonic vocalization (USV) behavior in rodents. Within this system, psychostimulants elevate synaptic concentrations of dopamine thereby leading to exaggerated activation of postsynaptic dopamine receptors within the D1-like and D2-like subfamilies. Dopamine receptor stimulation activate several transmembrane signaling systems and cognate intracellular mediators; downstream activation of transcription factors then conveys the information from receptor activation to appropriate modulation of cellular and physiologic functions.

Intracellular endothelin type B receptor-driven Ca2+ signal elicits nitric oxide production in endothelial cells.

Endothelin-1 exerts its actions via activation of ET(A) and ET(B) G(q/11) protein-coupled receptors, located in the plasmalemma, cytoplasm, and nucleus. Although the autocrine/paracrine nature of endothelin-1 signaling has been extensively studied, its intracrine role has been largely attributed to interaction with receptors located on nuclear membranes and the nucleoplasm. Because ET(B) receptors have been shown to be targeted to endolysosomes, we used intracellular microinjection and concurrent imaging methods to test their involvement in Ca(2+) signaling and subsequential NO production.

Agonist-selective effects of opioid receptor ligands on cytosolic calcium concentration in rat striatal neurons.

Background: Buprenorphine is an opioid receptor ligand whose mechanism of action is incompletely understood.

Methods: Using Ca(2+) imaging, we assessed the effects of buprenorphine, β-endorphin, and morphine on cytosolic Ca(2+) concentration [Ca(2+)](i), in rat striatal neurons.

Results: Buprenorphine (0.

Differential subcellular distribution of rat brain dopamine receptors and subtype-specific redistribution induced by cocaine.

We investigated the subcellular distribution of dopamine D(1), D(2) and D(5) receptor subtypes in rat frontal cortex, and examined whether psychostimulant-induced elevation of synaptic dopamine could alter the receptor distribution. Differential detergent solubilization and density gradient centrifugation were used to separate various subcellular fractions, followed by semi-quantitative determination of the relative abundance of specific receptor proteins in each fraction. D(1) receptors were predominantly localized to detergent-resistant membranes, and a portion of these receptors also floated on sucrose gradients.

Building capacity for public and population health research in Africa: the consortium for advanced research training in Africa (CARTA) model.

Background: Globally, sub-Saharan Africa bears the greatest burden of disease. Strengthened research capacity to understand the social determinants of health among different African populations is key to addressing the drivers of poor health and developing interventions to improve health outcomes and health systems in the region. Yet, the continent clearly lacks centers of research excellence that can generate a strong evidence base to address the region's socio-economic and health problems.

Pharmacology of signaling induced by dopamine D(1)-like receptor activation.

Dopamine D(1)-like receptors consisting of D(1) and D(5) subtypes are intimately implicated in dopaminergic regulation of fundamental neurophysiologic processes such as mood, motivation, cognitive function, and motor activity. Upon stimulation, D(1)-like receptors initiate signal transduction cascades that are mediated through adenylyl cyclase or phosphoinositide metabolism, with subsequent enhancement of multiple downstream kinase cascades. The latter actions propagate and further amplify the receptor signals, thus predisposing D(1)-like receptors to multifaceted interactions with various other mediators and receptor systems.

Antidepressant stimulation of CDP-diacylglycerol synthesis does not require monoamine reuptake inhibition.

Background: Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked.

Brain-derived neurotrophic factor signaling modulates cocaine induction of reward-associated ultrasonic vocalization in rats.

Cocaine exhibits high liability for inducing addictive behaviors, but the mechanisms of neuroplasticity underlying the behavioral effects remain unclear. As a crucial mediator of neuroplasticity in diverse functional models, brain-derived neurotrophic factor (BDNF) could contribute to the mechanisms of addiction-related neuroplasticity. Here, we addressed the hypothesis that cocaine increases synaptic dopamine, which induces BDNF protein expression to initiate addiction-related behavior in the rat.

Dopamine D1-like receptor activation induces brain-derived neurotrophic factor protein expression.

Recent studies showed that dopamine or D1 receptor-selective agonists increased brain-derived neurotrophic factor (BDNF) mRNA and protein expression in neuronal cultures, and this action was blocked by SCH23390. Moreover, SKF38393 activated Trk receptors and downstream signaling in striatal neurons. This study examined whether dopamine agonists induce the expression of BDNF protein in rat brain tissue.

D5 dopamine receptors are required for dopaminergic activation of phospholipase C.

Dopamine activates phospholipase C in discrete regions of the mammalian brain, and this action is believed to be mediated through a D(1)-like receptor. Although multiple lines of evidence exclude a role for the D(1) subtype of D(1)-like receptors in the phosphoinositide response, the D(5) subtype has not been similarly examined. Here, mice lacking D(5) dopamine receptors were tested for dopamine agonist-induced phosphoinositide signaling both in vitro and in vivo.

Maternal cocaine administration in mice alters DNA methylation and gene expression in hippocampal neurons of neonatal and prepubertal offspring.

Previous studies documented significant behavioral changes in the offspring of cocaine-exposed mothers. We now explore the hypothesis that maternal cocaine exposure could alter the fetal epigenetic machinery sufficiently to cause lasting neurochemical and functional changes in the offspring. Pregnant CD1 mice were administered either saline or 20 mg/kg cocaine twice daily on gestational days 8-19.

Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain.

Background: Major depression is a serious mood disorder affecting millions of adults and children worldwide. While the etiopathology of depression remains obscure, antidepressant medications increase synaptic levels of monoamine neurotransmitters in brain regions associated with the disease. Monoamine transmitters activate multiple signaling cascades some of which have been investigated as potential mediators of depression or antidepressant drug action.