Exposure to morphine-associated cues increases mu opioid receptor mRNA expression in the nucleus accumbens of Wistar Kyoto rats.

The Wistar-Kyoto (WKY) rat has been proposed as a model of anxiety vulnerability as it exhibits pronounced behavioral inhibition, passive avoidance, exaggerated startle response, enhanced HPA-axis activation, and active avoidance that is resistant to extinction. Accumulating evidence suggests that WKY rats respond differently to rewarding stimuli when compared to outbred strains of rat. Conditioned responding to drug-associated cues is linked with alterations in the activation of mu opioid receptors (MOR) and kappa opioid receptors (KOR) in the nucleus accumbens (NAc).

Dietary Fructose and GLUT5 Transporter Activity Contribute to Antipsychotic-Induced Weight Gain.

Receptors for antipsychotics in the hypothalamus contribute to antipsychotics-induced weight gain; however, many of these receptors are also expressed in the intestine. The role of these intestinally-expressed receptors, and their potential modulation of nutrient absorption, have not been investigated in the context of antipsychotics-induced weight gain. Here we tested the effect of dietary fructose and intestinal fructose uptake on clozapine-induced weight gain in mice.

Dopamine D3 Receptor Mediates Preadolescent Stress-Induced Adult Psychiatric Disorders.

Several studies have shown that repeated stressful experiences during childhood increases the likelihood of developing depression- and anxiety-related disorders in adulthood; however, the underlying mechanisms are not well understood. We subjected drd3-EGFP and drd3-null mice to daily, two hour restraint stress episodes over a five day period during preadolescence (postnatal day 35 to 39), followed by social isolation. When these mice reached adulthood (post-natal day > 90), we assessed locomotor behavior in a novel environment, and assessed depression-related behavior in the Porsolt Forced Swim test.

Investigating the Role of Hippocampal BDNF in Anxiety Vulnerability Using Classical Eyeblink Conditioning.

Dysregulation of brain-derived neurotrophic factor (BDNF), behavioral inhibition temperament (BI), and small hippocampal volume have been linked to anxiety disorders. Individuals with BI show facilitated acquisition of the classically conditioned eyeblink response (CCER) as compared to non-BI individuals, and a similar pattern is seen in an animal model of BI, the Wistar-Kyoto (WKY) rat. The present study examined the role of hippocampal BDNF in the facilitated delay CCER of WKY rats.

Identification of key residues involved in the activation and signaling properties of dopamine D3 receptor.

The dopamine D3 receptor exhibits agonist-dependent tolerance and slow response termination (SRT) signaling properties that distinguish it from the closely-related D2 receptors. While amino acid residues important for D3 receptor ligand binding have been identified, the residues involved in activation of D3 receptor signaling and induction of signaling properties have not been determined. In this paper, we used cis and trans isomers of a novel D3 receptor agonist, 8-OH-PBZI, and site-directed mutagenesis to identify key residues involved in D3 receptor signaling function.

Post-transcriptional regulation of dopamine D1 receptor expression in caudate-putamen of cocaine-sensitized mice.

The dopamine D1 receptor is centrally involved in mediating the effects of cocaine and is essential for cocaine-induced locomotor sensitization. Changes in D1 receptor expression have been reported in various models of cocaine addiction; however, the mechanisms that mediate these changes in D1 receptor expression are not well understood. Using preadolescent drd1a-EGFP mice and a binge cocaine treatment protocol we demonstrate that the D1 receptor is post-transcriptionally regulated in the caudate-putamen of cocaine-sensitized animal.

Chronic levodopa treatment alters expression and function of dopamine D3 receptor in the MPTP/p mouse model of Parkinson's disease.

Chronic treatment with levodopa or antipsychotics results in manifestation of side-effects such as dyskinesia which correlates with changes in expression and function of receptors and signaling proteins. Previous studies have suggested a role for the dopamine D3 receptor in Parkinson's disease (PD) and tardive dyskinesia. Yet the expression and signaling function of D3 receptor in these disorders is not well understood.

Overexpression of the dopamine D3 receptor in the rat dorsal striatum induces dyskinetic behaviors.

L-DOPA-induced dyskinesias (LID) are motor side effects associated with treatment of Parkinson's disease (PD). The etiology of LID is not clear; however, studies have shown that the dopamine D3 receptor is upregulated in the basal ganglia of mice, rats and non-human primate models of LID. It is not known if the upregulation of D3 receptor is a cause or result of LID.

In vitro and in vivo characterization of the agonist-dependent D3 dopamine receptor tolerance property.

The D3 dopamine receptor has the highest affinity for dopamine, many antipsychotics as well as agonists used to treat Parkinson's disease and related disorders. We and others have reported that the D3 receptor exhibits a tolerance property wherein repeated agonist stimulation of the receptor results in a progressive loss of agonist-induced signaling response. Recently we reported that the D3 receptor tolerance property is agonist dependent and identified a novel agonist, ES609, which does not elicit D3 receptor tolerance.

Preadolescent drd1-EGFP mice exhibit cocaine-induced behavioral sensitization.

In adult mice, repeated cocaine administration induces behavioral sensitization measured as increased horizontal locomotor activity. Cocaine-induced locomotor sensitization has been well characterized in adult mice. In adult animals, the D1 dopamine receptor is important for mediating effects of cocaine.

MicroRNA expression profile and functional analysis reveal that miR-382 is a critical novel gene of alcohol addiction.

Alcohol addiction is a major social and health concern. Here, we determined the expression profile of microRNAs (miRNAs) in the nucleus accumbens (NAc) of rats treated with alcohol. The results suggest that multiple miRNAs were aberrantly expressed in rat NAc after alcohol injection.

Interaction of D₃ preferring agonist (-)-N⁶-(2-(4-(biphenyl-4-yl)piperazin-1-yl)ethyl)-N⁶-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264) with cloned human D₂L, D₂S, and D₃ receptors: potent stimulation of mitogen-activated protein kinases and G protein-coupled inward rectifier potassium channels.

This study aims to determine the effect of the novel D(3) dopamine receptor agonist, D-264, on activation of D(3) and D(2) dopamine receptor signal transduction pathways and cell proliferation. AtT-20 neuroendocrine cells stably expressing human D(2S), D(2L), and D(3) dopamine receptors were treated with D-264 and the coupling of the receptors to mitogen-activated protein kinase (MAPK) and G protein-coupled inward rectifier potassium (GIRK) channels was determined using Western blotting and whole-cell voltage clamp recording, respectively. D-264 potently activated MAPK signaling pathway coupled to D(2S), D(2L), and D(3) dopamine receptors.

MicroRNA 142-3p mediates post-transcriptional regulation of D1 dopamine receptor expression.

The D1 dopamine receptor subtype is expressed in the brain, kidney and lymphocytes. D1 receptor function has been extensively studied and the receptor has been shown to modulate a wide range of physiological functions and behaviors. The expression of D1 receptor is known to change during development, disease states and chronic treatment; however, the molecular mechanisms that mediate the changes in D1 receptor expression under these circumstances are not well understood.

Soluble interleukin-6 receptor induces motor stereotypies and co-localizes with gp130 in regions linked to cortico-striato-thalamo-cortical circuits.

Soluble cytokine receptors are normal constituents of body fluids that regulate peripheral cytokine and lymphoid activity and whose levels are increased in states of immune activation. Soluble interleukin-6 receptor (sIL-6R) levels positively correlate with disease progression in some autoimmune conditions and psychiatric disorders. Particularly strong links between levels of sIL-6R and the severity of psychotic symptoms occur in schizophrenia, raising the possibility that sIL-6R is involved in this disease.

Molecular characterization of individual D3 dopamine receptor-expressing cells isolated from multiple brain regions of a novel mouse model.

Among dopamine receptors, the expression and function of the D3 receptor subtype is not well understood. The receptor has the highest affinity for dopamine and many drugs that target dopamine receptors.In this paper, we examined, at the single cell level, the characteristics of D3 receptor-expressing cells isolated from different brain regions of male and female mice that were either 35 or 70 days old.

The extracellular cAMP-adenosine pathway regulates expression of renal D1 dopamine receptors in diabetic rats.

Activation of D1 dopamine receptors expressed in the kidneys promotes the excretion of sodium and regulates sodium levels during increases in dietary sodium intake. A decrease in the expression or function of D1 receptors results in increased sodium retention which can potentially lead to the development of hypertension. Studies have shown that in the absence of functional D1 receptors, in null mice, the systolic, diastolic, and mean arterial pressures are higher.

Development of tolerance in D3 dopamine receptor signaling is accompanied by distinct changes in receptor conformation.

The D3 but not D2 dopamine receptors exhibit a tolerance property in which agonist-induced D3 receptor response progressively decreases upon repeated agonist stimulation. We have previously shown that the D3 receptor tolerance property is not mediated by receptor internalization, persistent agonist binding or a decrease in receptor binding affinity. In this paper, we test the hypothesis that alterations in D3 receptor conformation underlie the tolerance property.

Brain-derived neurotrophic factor facilitates maturation of mesenchymal stem cell-derived dopamine progenitors to functional neurons.

The generation of dopamine (DA) neurons from stem cells holds great promise in the treatment of Parkinson's disease and other neural disease associated with dysfunction of DA neurons. Mesenchymal stem cells (MSCs) derived from the adult bone marrow show plasticity with regards to generating cells of other germ layers. In addition to reduced ethical concerns, MSCs could be transplanted across allogeneic barriers, making them desirable stem cells for clinical applications.

L-lysine uptake in giant vesicles from cardiac ventricular sarcolemma: two components of cationic amino acid transport.

Cationic L-amino acids enter cardiac-muscle cells through carrier-mediated transport. To study this process in detail, L-[(14)C]lysine uptake experiments were conducted within a 10(3)-fold range of L-lysine concentrations in giant sarcolemmal vesicles prepared from rat cardiac ventricles. Vesicles had a surface-to-volume ratio comparable with that of an epithelial cell, thus representing a suitable system for initial uptake rate studies.

Bioisosteric heterocyclic versions of 7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol: identification of highly potent and selective agonists for dopamine D3 receptor with potent in vivo activity.

In the current report, we extend the SAR study on our hybrid structure 7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol further to include heterocyclic bioisosteric analogues. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (Ki). Functional activity of selected compounds in stimulating GTPgammaS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors.

Further structure-activity relationships study of hybrid 7-{[2-(4-phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol analogues: identification of a high-affinity D3-preferring agonist with potent in vivo activity with long duration of action.

This paper describes an extended structure-activity relationships study of aminotetralin-piperazine-based hybrid molecules developed earlier for dopamine D2/D3 receptors. Various analogues as positional isomers have been developed where location of the phenolic hydroxyl group has been varied on the aromatic ring. Between two catechol derivatives, compound 6e with a two methylene linker length exhibited higher affinity and selectivity for D3 over D2 receptors over compound 6f with four methylene linkers (D2/D3 = 50.

The tolerance property of human D3 dopamine receptor is determined by specific amino acid residues in the second cytoplasmic loop.

The D2 and D3 dopamine receptor subtypes are structurally homologous and couple to the same signal transduction pathways. Nevertheless, their evolutionary conservation suggests that the two subtypes might exhibit unique signaling characteristics. We previously determined that D3 but not D2S dopamine receptor exhibits a tolerance property in which the D3 receptor-activated G-protein coupled inward rectifier potassium currents progressively decreases upon repeated agonist stimulation.

Specification of a dopaminergic phenotype from adult human mesenchymal stem cells.

Dopamine (DA) neurons derived from stem cells are a valuable source for cell replacement therapy in Parkinson disease, to study the molecular mechanisms of DA neuron development, and for screening pharmaceutical compounds that target DA disorders. Compared with other stem cells, MSCs derived from the adult human bone marrow (BM) have significant advantages and greater potential for immediate clinical application. We report the identification of in vitro conditions for inducing adult human MSCs into DA cells.

Extracellular cAMP inhibits D1 dopamine receptor expression in CAD catecholaminergic cells via A2a adenosine receptors.

The expression of D1 dopamine (DA) receptor gene is regulated during development, aging, and pathophysiology. The extracellular factors and signaling mechanisms that modulate the expression of D1 DA receptor have not been well characterized. Here, we present novel evidence that endogenous D1 DA receptor expression is inhibited by extracellular cAMP in the Cath.