D2 Receptor Pathways Research Articles

Assessment of Quercetin Antiemetic Properties: In Vivo and In Silico Investigations on Receptor Binding Affinity and Synergistic Effects.

Quercetin (QUA), a flavonoid compound, is ubiquitously found in plants and has demonstrated a diverse range of biological activities. The primary objective of the current study is to assess the potential antiemetic properties of QUA using an in vivo and in silico approach. In this experiment, 4-day-old chicks were purchased to induce emesis by orally administering copper sulfate pentahydrate (CuSO4·5H2O) at a dose of 50 mg/kg (orally). Domperidone (DOM) (6 mg/kg), Hyoscine (HYS) (21 mg/kg), and Ondansetron (OND) (5 mg/kg) were treated as positive controls (PCs), and distilled water and a trace amount of Tween 80 mixture was employed as a negative control (NC). QUA was given orally at two distinct doses (25 and 50 mg/kg). Additionally, QUA (50 mg/kg) and PCs were administered separately or in combination to assess their antagonistic or synergistic effects on the chicks. The binding affinity of QUA and referral ligands towards the serotonin receptor (5HT3), dopamine receptors (D2 and D3), and muscarinic acetylcholine receptors (M1-M5) were estimated, and ligand-receptor interactions were visualized through various computational tools. In vivo findings indicate that QUA (25 and 50 mg/kg) has a significant effect on reducing the number of retches (16.50 ± 4.65 and 10.00 ± 4.19 times) and increasing the chick latency period (59.25 ± 4.75 and 94.25 ± 4.01 s), respectively. Additionally, QUA (50 mg/kg) in combination with Domperidone and Ondansetron exhibited superior antiemetic effects, reducing the number of retches and increasing the onset of emesis-inducing time. Furthermore, it is worth noting that QUA exhibited the strongest binding affinity against the D2 receptor with a value of -9.7 kcal/mol through the formation of hydrogen and hydrophobic bonds. In summary, the study found that QUA exhibited antiemetic activity in chicks, potentially by interacting with the D2 receptor pathway.

Dopamine relieves inflammatory responses through the D2 receptor after electroacupuncture at ST36 in a mouse model of chronic obstructive pulmonary disease.

To detect the role of dopamine in the anti-inflammatory effect of electroacupuncture (EA) at ST36 in a mouse model of chronic obstructive pulmonary disease (COPD). Twenty-eight male BALB/c mice were randomly divided into the control group, model group, sham EA (sham) group or ST36 EA (ST36) group in a 1:1:1:1 ratio (n = 7 each). The COPD mouse model was established through cigarette smoke (CS) exposure for 12 weeks. During the last 2 weeks, EA was applied at a sham point location or ST36 before CS exposure. Lung function, histopathological changes, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), inflammatory cytokines in BALF, plasma, lung tissue homogenate (LTH), and plasma dopamine levels were detected in the different groups. Furthermore, the role of different dopamine receptors was explored through intraperitoneal injections of non-specific dopamine receptor antagonist chlorpromazine, specific dopamine D1 receptor antagonist SCH 23390 and specific dopamine D2 receptor antagonist eticlopride hydrochloride prior to ST36 EA and CS exposure. EA at ST36 improved lung function, alleviated lung and systemic inflammatory responses by reducing inflammatory cells and cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-8 and IL-1β in BALF, plasma and lung tissue in this COPD mouse model. Plasma dopamine was greatly increased after EA at ST36, negatively correlated with lung histological lesions and inflammatory cytokine levels, and positively correlated with mice body weight and lung function indicators. Chlorpromazine and eticlopride hydrochloride inhibited the anti-inflammatory effect of EA at ST36, while SCH 23390 showed no neutralizing effect. EA at ST36 could alleviate inflammation in this mouse model of COPD through the dopamine D2 receptor pathway.

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement.

SUMMARYAlthough midbrain dopamine (DA) circuits are central to motivated behaviors, our knowledge of how experience modifies these circuits to facilitate subsequent behavioral adaptations is limited. Here we demonstrate the selective role of a ventral tegmental area DA projection to the amygdala (VTADA→amygdala) for cocaine-induced anxiety but not cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach reveals a persistent elevation in spontaneous and task-related activity of inhibitory GABAergic cells from the bed nucleus of the stria terminalis (BNST) and downstream VTADA→amygdala cells that can be detected even after a single cocaine exposure. Activity in BNSTGABA→midbrain cells is related to cocaine-induced anxiety but not reward or sensitization, and silencing this projection prevents development of anxiety during protracted withdrawal after cocaine administration. Finally, we observe that VTADA→amygdala cells are strongly activated after a challenge exposure to cocaine and that activity in these cells is necessary and sufficient for reinstatement of cocaine place preference.

Dopamine D2 receptors in the nucleus accumbens modulate erectile function in a rat model of nonorganic erectile dysfunction.

BackgroundThe central molecular mechanisms of nonorganic erectile dysfunction remains unknown.ObjectiveThis study aimed to investigate the association of dopaminergic neurons projecting to the nucleus accumbens of male rats with nonorganic erectile dysfunction.Materials/methodsNonorganic erectile dysfunction was induced by chronic mild stress. The sucrose consumption test, sexual behavior test, and apomorphine test were carried out to select depression‐like rats with erectile dysfunction. These rats were considered as nonorganic erectile dysfunction model rats. Dopamine D1/D2 receptor agonist/antagonist was infused into the nucleus accumbens to observe the effect on sexual behavior. Dopaminergic projections to the nucleus accumbens were labeled with both the retrograde tracer FluoroGold injected into the nucleus accumbens and tyrosine hydroxylase. The expression level of tyrosine hydroxylase in dopaminergic neurons projecting to the nucleus accumbens in the ventral tegmental area was measured. The expression levels of dopamine D1/D2 receptors and tyrosine hydroxylase in the nucleus accumbens were also measured.ResultsNonorganic erectile dysfunction was proved by the sucrose consumption test, sexual behavior test, and apomorphine test in model rats. After central infusion of the dopamine D2 receptor agonist into the nucleus accumbens, the recovery of erectile function, sexual arousal, and motivation were indicated by increased intromission ratio and decreased mount latency. Decreased expression levels of dopamine D2 receptors and tyrosine hydroxylase in the nucleus accumbens and decreased expression level of tyrosine hydroxylase in the dopaminergic neurons projecting to the nucleus accumbens were observed in model rats.DiscussionThese results suggest the impairment of dopaminergic neurons projecting to the nucleus accumbens and dopamine D2 signaling in the nucleus accumbens, causing the suppression of erectile function, sexual arousal, and motivation.ConclusionThese results suggest that the impaired dopamine D2 receptor pathway in the nucleus accumbens may be one of the main pathway involved in the development of nonorganic erectile dysfunction in the present model.

Differential dopamine modulation of spinal reflex amplitudes is associated with the presence or absence of the autonomic nervous system

The spinal cord contains a highly collateralized network of descending dopamine (DA) fibers that stem from the dorso-posterior hypothalamic A11 region in the brain, however, the modulatory actions of DA have generally only been assessed in lumbar segments L2-L5. In contrast to these exclusively sensorimotor segments, spinal cords segments T1-L2 and, in mouse, L6-S2, additionally contain the intermediolateral (IML) nucleus, the origin of autonomic nervous system (ANS).Here, we tested if the different spinal circuits in sensorimotor and IML-containing segments react differently to the modulation of the monosynaptic reflex (MSR) by DA. Bath-application of DA (1 μM) led to a decrease of MSR amplitude in L3-L5 segments; however, in IML-containing segments (T10-L2, and S1/2) the MSR response was facilitated. We did not observe any difference in the response between thoracic (sympathetic) and lumbosacral (parasympathetic) segments. Application of the D2-receptor agonists bromocriptine or quinpirole mimicked the effects of DA, while blocking D2 receptor pathways with raclopride or application with the D1-receptor agonist SKF 38393 led to an increase of the MSR in L3-L5 segments and a decrease of the MSR in IML-containing segments. In contrast, in the presence of the gap-junction blockers, carbenoloxone and quinine, DA modulatory actions in IML-containing segments were similar to those of sensorimotor L3-L5 segments.We suggest that DA modulates MSR amplitudes in the spinal cord in a segment-specific manner, and that the differential outcome observed in ANS segments may be a result of gap junctions in the IML.

BTBD9 and dopaminergic dysfunction in the pathogenesis of restless legs syndrome.

Restless legs syndrome (RLS) is characterized by an urge to move legs, usually accompanied by uncomfortable sensations. RLS symptoms generally happen at night and can be relieved by movements. Genetic studies have linked polymorphisms in BTBD9 to a higher risk of RLS. Knockout of BTBD9 homolog in mice (Btbd9) and fly results in RLS-like phenotypes. A dysfunctional dopaminergic system is associated with RLS. However, the function of BTBD9 in the dopaminergic system and RLS is not clear. Here, we made use of the simple Caenorhabditis elegans nervous system. Loss of hpo-9, the worm homolog of BTBD9, resulted in hyperactive egg-laying behavior. Analysis of genetic interactions between hpo-9 and genes for dopamine receptors (dop-1, dop-3) indicated that hpo-9 and dop-1 worked similarly. Reporter assays of dop-1 and dop-3 revealed that hpo-9 knockout led to a significant increase of DOP-3 expression. This appears to be evolutionarily conserved in mice with an increased D2 receptor (D2R) mRNA in the striatum of the Btbd9 knockout mice. Furthermore, the striatal D2R protein was significantly decreased and Dynamin I was increased. Overall, activities of DA neurons in the substantia nigra were not altered, but the peripheral D1R pathway was potentiated in the Btbd9 knockout mice. Finally, we generated and characterized thedopamine neuron-specific Btbd9 knockout mice and detected anactive-phase sleepiness, suggesting that dopamine neuron-specific loss of Btbd9 is sufficient to disturb the sleep. Our results suggest that increased activities in the D1R pathway, decreased activities in the D2R pathway, or both may contribute to RLS.

Experimental evidence for a role of dopamine in avian personality traits.

There is increasing interest in the genetic and physiological bases of behavioural differences among individuals, namely animal personality. One particular dopamine (DA) receptor gene (the dopamine receptor D4 gene) has been used as candidate gene to explain personality differences, but with mixed results. Here, we used an alternative approach, exogenously manipulating the dopaminergic system and testing for effects on personality assays in a social bird species, the common waxbill (Estrilda astrild). We treated birds with agonists and antagonists for DA receptors of both D1 and D2 receptor pathways (the latter includes the D4 receptor) and found that short-term manipulation of DA signalling had an immediate effect on personality-related behaviours. In an assay of social responses (mirror test), manipulation of D2 receptor pathways reduced time spent looking at the social stimulus (mirror image). Blocking D2 receptors reduced motor activity in this social assay, while treatment with a D2 receptor agonist augmented activity in this social assay but reduced activity in a non-social behavioural assay. Also, in the non-social assay, treatment with the D1 receptor antagonist markedly increased time spent at the feeder. These results show distinct and context-specific effects of the dopaminergic pathways on waxbill personality traits. Our results also suggest that experimental manipulation of DA signalling can disrupt a behavioural correlation (more active individuals being less attentive to mirror image) that is habitually observed as part of a behavioural syndrome in waxbills. We discuss our results in the context of animal personality, and the role of the DA system in reward and social behaviour.

Dopaminergic Modulation of Goal-Directed Behavior in a Rodent Model of Attention-Deficit/Hyperactivity Disorder.

Aside from its clinical symptoms of inattention, impulsivity and hyperactivity, patients with Attention/Deficit-Hyperactivity Disorder (ADHD) display reward and motivational impairments. These impairments may reflect a deficit in action control, that is, an inability to flexibly adapt behavior to changing consequences. We previously showed that spontaneously hypertensive rats (SHR), an inbred rodent model of ADHD, show impairments in goal-directed action control, and instead are predominated by habits. In this study, we examined the effects of specific dopamine receptor sub-type (D1 and D2) agonists and antagonists on goal-directed behavior in SHR and the normotensive inbred control strain Wistar-Kyoto (WKY) rats. Rats acquired an instrumental response for different-flavored food rewards. A selective-satiety outcome devaluation procedure followed by a choice test in extinction revealed outcome-insensitive habitual behavior in SHR rats. Outcome-sensitive goal-directed behavior was restored in SHR rats following injection prior to the choice test of the dopamine D2 receptor agonist Quinpirole or dopamine D1 receptor antagonist SCH23390, whereas WKY rats showed habitual responding following exposure to these drugs. This novel finding indicates that the core behavioral deficit in ADHD might not be a consequence of dopamine hypofunction, but rather is due to a misbalance between activation of dopamine D1 and D2 receptor pathways that govern action control.

Dopamine D2 receptors in the basolateral amygdala modulate erectile function in a rat model of nonorganic erectile dysfunction.

Nonorganic erectile dysfunction is a problem with unknown central mechanisms. Changes in brain activity in the amygdala have been observed in human patients. This study aimed to investigate the dopamine system in the basolateral amygdala of male rats with nonorganic erectile dysfunction. We applied chronic mild stress to induce nonorganic erectile dysfunction. After exposure to chronic mild stress, the sucrose consumption test, sexual behaviour test and apomorphine test were used to select depression-like rats with erectile dysfunction as nonorganic erectile dysfunction model rats. The sexual behaviour of these rats after central infusion of a dopamine D1/D2 receptor agonist/antagonist was observed. The expression levels of dopamine D1/D2 receptors and tyrosine hydroxylase in the basolateral amygdala were also measured. The result of the sucrose consumption test, sexual behaviour test and apomorphine test indicated a successful nonorganic erectile dysfunction model. Central infusion of a dopamine D2 receptor agonist increased intromission ratio in model rats. Lower expression levels of tyrosine hydroxylase and the dopamine D2 receptor in the basolateral amygdala were observed in rats with nonorganic erectile dysfunction. These results suggest that impairment of the dopamine D2 receptor pathway in the basolateral amygdala may contribute to the development of nonorganic erectile dysfunction.

What Do Animal Studies Tell Us about the Mechanism of Myopia-Protection by Light?

: Human studies have provided strong evidence that exposure to time outdoors is protective against the onset of myopia. A causal factor may be that the light levels outdoors (30,000-130,000 lux) are much higher than light levels indoors (typically less than 500 lux). Studies using animal models have found that normal animals exposed to low illuminance levels (50 lux) can develop myopia. The myopia and axial elongation, produced in animals by monocular form deprivation, is reduced by light levels in the 15,000 to 25,000 range. Myopia induced with a negative-power lens seems less affected, perhaps because the lens provides a powerful target for the emmetropization mechanism. Animal studies suggest that raising the light levels may have their effect by increasing retinal dopamine activity, probably via the D2 receptor pathway, altering gene expression in the retina and reducing the signals that produce axial elongation.

Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

Inhibitors of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the mammalian striatum, enhance activity in direct (dopamine D1 receptor-expressing) and indirect (D2 receptor-expressing striatal output) pathways. The ability of such agents to act to potentiate D1 receptor signaling while inhibiting D2 receptor signaling suggest that PDE10A inhibitors may have a unique antipsychotic-like behavioral profile differentiated from the D2 receptor antagonist-specific antipsychotics currently used in the treatment of schizophrenia. To evaluate the functional consequences of PDE10A inhibitor modulation of D1 and D2 receptor pathway signaling, we compared the effects of a PDE10A inhibitor (TP-10) on D1 and D2 receptor agonist-induced disruptions in prepulse inhibition (PPI), a measure of sensorimotor gating disrupted in patients with schizophrenia. Our results indicate that, in rats: (1) PDE10A inhibition (TP-10, 0.32-10.0mg/kg) has no effect on PPI disruption resulting from the mixed D1/D2 receptor agonist apomorphine (0.5mg/kg), confirming previous report; (2) Yet, TP-10 blocked the PPI disruption induced by the D2 receptor agonist quinpirole (0.5mg/kg); and attenuated apomorphine-induced disruptions in PPI in the presence of the D1 receptor antagonist SCH23390 (0.005mg/kg). These findings indicate that TP-10 cannot block dopamine agonist-induced deficits in PPI in the presence of D1 activation and suggest that the effect of PDE10A inhibition on D1 signaling may be counterproductive in some models of antipsychotic activity. These findings, and the contribution of TP-10 effects in the direct pathway on sensorimotor gating in particular, may have implications for the potential antipsychotic efficacy of PDE10A inhibitors.

Brain Imaging, Other Advances Reveal Drugs’ Effects on Brain

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessBrain Imaging, Other Advances Reveal Drugs’ Effects on BrainAaron LevinAaron LevinSearch for more papers by this authorPublished Online:12 Jun 2013https://doi.org/10.1176/appi.pn.2013.6b36AbstractNew understanding of how drugs of abuse affect dopamine reward circuitry is providing insights into potential new therapies.Nora Volkow, M.D.: Increasing—and sometimes surprising—advances in research are fueling a better understanding of the mechanisms of drug addiction and potential treatments.David Hathcox“The universe of a person who is addicted is narrowed to the drug, and that is the challenge and the incredible opportunity we have as psychiatrists to help these individuals,” said Nora Volkow, M.D., director of the National Institute on Drug Abuse, at APA’s 2013 annual meeting in San Francisco last month.Research in recent years using brain imaging techniques has provided new insights into the mechanism of addiction while simultaneously unsettling elements of what once was the common wisdom, she said.All drugs of abuse increase dopamine, which is crucial for their effect, she said. They also trigger neuroplasticity changes that result in addiction, but more dopamine does not explain addiction.Among both lab animals and humans, voluntary initiation of drug use leads to a subsequent loss of control and development of addiction among about 10 percent of subjects. The lab rats and mice are useful for refuting old stereotypes.Some people still consider addiction moral turpitude, she said. “But how can you develop the same phenotype in a rat, which has no moral precepts?”Other ideas about addiction have also changed in recent years, she said. Once it was thought that addicts were overly sensitive to dopaminergic effects, but now it appears that they have an attenuated response in the dopamine system to drug consumption.Repeated drug use leads to less D2 receptor pathway signaling, inhibiting sensitivity to reward, she said.This makes evolutionary sense as the reward value of dopamine signaling shifts from consumption of drugs or food to expectation and stimulus.“As in addiction, it motivates your behavior to get that reward,” she said. “Once consumed, it doesn’t matter. You don’t need to motivate behavior then.”For example, simply showing videos to addicts of people using cocaine releases dopamine in the striatum and provokes a desire for the drug. This may also explain why it is better for psychiatrists to help patients avoid settings where they risk taking drugs, rather than having to intervene once they have started using again.Yet another discovery is that addiction is not solely a property of the limbic system but also involves the prefrontal cortex, said Volkow. D1 and D2 receptors there are important for normal executive function. However, D2 expression is lower during addiction to cocaine, methamphetamine, alcohol, heroin, and nicotine (but not marijuana). Reduced D2 receptor signaling in addiction decreases inhibitory control in the prefrontal area, letting up on the neural “brakes” on compulsive drug use.“That’s why the process of addiction becomes so ingrained and why patients go to tremendous effort to get drugs at such a horrific price,” she said. Awareness of deficits in the prefrontal cortex can help psychiatrists treat addicted individuals using approaches that allow them to assert better self-control, extinguish conditioned responses to drugs, and enhance the value of alternative rewards.A third insight has come from genetic studies of smoking. Three alleles for nicotine receptors—α5, α3, and β4—are heavily concentrated in the habenula, a region that has been targeted by deep brain stimulation for treatment of depression.“That may be related to the antidepressant properties of smoking,” she speculated.Nevertheless, no single area of the brain is implicated in addiction, she said. “Multiple circuits are disrupted as they are in other mental illnesses, like schizophrenia, ADHD, and mood disorders.”Perhaps as a consequence, the treatment of addiction requires a multipronged approach to strengthen brain circuits that have been impaired by the use of drugs, she said. Thus, in addition to research into behavioral and medical treatments, NIDA also is funding a search for vaccines to produce antibodies that would bind to cocaine, heroin, methamphetamine, and other addictive substances in the bloodstream and prevent their entry into the brain.“These are some of the most exciting areas of science in the field of drug addiction,” said Volkow. ■An extended discussion of addiction and reward circuitry by Nora Volkow and colleagues is posted at http://www.pnas.org/content/108/37/15037.full. To watch a video interview with Volkow, go to http://www.youtube.com/watch?v=zXzU9uFF5G0. ISSUES NewArchived

The dopaminergic system and aggression in laying hens

The dopaminergic system is involved in the regulation of aggression in many species, especially via dopamine (DA) D1 and D2 receptor pathways. To investigate heritable differences in this regulation, 2 high aggressive strains [Dekalb XL (DXL) and low group egg productivity and survivability (LGPS)] and one low aggressive strain (low group egg productivity and survivability; HGPS) of laying hens were used in the study. The HGPS and LGPS lines were diversely selected using group selection for high and low group production and survivability. The DXL line is a commercial line selected through individual selection based on egg production. Heritable differences in aggressive propensity between the strains have been previously assessed. The birds were pair housed within the same strain and labeled as dominant or subordinate based on behavioral observation. For both experiments 1 and 2, behavioral analysis was performed on all 3 strains whereas neurotransmitter analysis was performed only on the most aggressive (DXL) and least aggressive (HGPS) strains. In experiment 1, the subordinate birds were treated with D1 agonist, D2 agonist, or saline controls (n = 12). In experiment 2, the dominant birds from a separate flock were treated with D1 antagonist, D2 antagonist, or saline controls (n = 12). Treatment-associated changes in aggressive behaviors and central neurotransmitters were measured. Aggression was increased in all strains in response to D1 agonism but increased only in the less aggressive HGPS birds with D2 agonism. Aggression was decreased and hypothalamic serotonin and epinephrine were increased in birds from all strains treated with D2 receptor antagonist. The D1 receptor antagonism elicited different behavioral and neurotransmitter responses based on the aggressive phenotype of the genetic strains. Aggressive strains DXL and LGPS but not the HGPS strain decreased aggressiveness following antagonism of the D1 receptor. The data show evidence for distinct neurotransmitter regulation of aggression in high and low aggressive strains of hens through different receptor systems. These chicken lines could provide new animal models for the biomedical investigation of the genetic basis of aggression.

Evidence for normal cortical inhibition in first-degree relatives of schizophrenic patients: A preliminary report

length of both apical ( wt:994.5 microm, n=6; KO: 600.6 microm, n=4) and basal dendrites (wt: 1268.3 microm, n=6; KO: 906.4 microm, n=4) of pyramidal neurons was significantly reduced in D2 receptor knockout animals. In addition the number of dendritic intersections was reduced (wt: 49.8, n=6; KO: 33.0, n=4). Interestingly, the mean total axonal length was increased in KO animals (wt: 341.1 microm, n=6; KO: 842.3 microm, n=4). These results indicate that the D2 receptor pathway is critically involved in the maturation of parvalbumin positive interneurons and inhibitory transmission in the prefrontal cortex of the mouse.