Effects of Ovariectomy and 17β-Estradiol Replacement on the Activity of Dopamine D2 Receptors in the Selection of Macronutrients Carbohydrates, Lipids and Proteins in Females Rats

17β-estradiol modulates the activity of D2 receptors in the regulation of food intake and body weight. The functional lack of 17β-estradiol in postmenopausal women could create a dietary imbalance and cause body weight gain. This study aimed to better understand the interferences that could exist between 17β-estradiol, D2 receptors and the selection of carbohydrate, fat and protein consumption, as well as their consequences on body weight gain by using an animal model of the menopause. Ovariectomy exacerbates the consumption of foods rich in lipids. Thus confirming an inhibitory action of 17β-estradiol (E2) on the consumption of these types of foods. This consumption stimulates body weight gain, which is promoted by the high caloric content of these foods and not by the amount consumed. Our results showed a direct involvement of D2 receptors in food choice. This choice would be made according to the two (2) isoforms of the D2 receptors. The D2/BR isoform directs towards a high carbohydrate consumption, without causing a gain in body weight. While D2/SUL, promotes high fat food consumption, causing an increase in body weight. In women, 17β-estradiol modulates the activity ratio between these two D2 receptor isoforms to ensure energy and homeostatic balance, stabilizing food intake and body weight.

Modeling of Dopamine D2 Receptor and its Agonist DOCK Analyses

A model of transmembrane helices of dopamine D2 receptor was constructed using the X ray coordinates of bacteriorhodopsin (BR) as a template. Based on the results from the model and the site directed mutagenesis experience, the binding pocket, including nine amino acid residues beside indispensable Asp86, Ser141 and Ser144 residues, was defined. In order to testify the 3D structure of dopamine D2 receptor and specially test the binding sites, two sets of D2 receptor agonists (one was rigid and the other flexible) were selected for docking. A good result of correlation between logIC 50 and binding energy E b indicates that the predicted model is reliable for the investigation of the receptor ligand interaction and design of new active molecules.

Effects of Ovariectomy and 17<i>β</i>-Estradiol Replacement on Dopamine D2 Receptors in Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

Background: Mechanisms underlying overeating-induced obesity in post-menopausal woman include functional lack of 17β-estradiol dysregulating dopamine D2 receptors, thereby inducing food addiction, glucose craving or alcohol dependence through reward circuitry. This study aimed at further understanding 17β-estradiol and dopamine D2 receptors interferences in the etiology of woman obesity. Method: Seventy-two Wistar female rats weighing 200 - 205 g, individually-housed, were divided into non-ovariectomized control (C = 6 groups) and ovariectomized rats (OVX = 6 groups) which were concurrently subjected to the following treatments: Non-drug-treated (DMSO vehicle), 17β-estradiol (E2, 5 μg/kg, s.c.), sulpiride (SUL, 20 mg/kg, i.p.), bromocriptine (BR, 0.1 mg/kg, i.p.), E2 + SUL or E2 + BR, designating the 6 constitutive groups of either control or ovariectomy. Within each experimental group, consumption of different solutions (10% alcohol, 10% sucrose and water) as well as food intake and body weight were daily measured, for 10 consecutive days. Results: This study indicated that D2S was a specific inducer of alcohol and food intakes, but reduced sugar consumption. In addition, 17β- estradiol regulated the body weight set point, modulating D2S functions towards increased food intake at lower weights and decreased food intake at higher weights. D2S met the slow genomic actions induced by 17β-estradiol. Conversely, D2L inhibited alcohol and food intakes, but induced specifically sugar consumption, thereby regulating blood glucose levels and promoting energy expenditure in reducing body weight. Indeed, 17β-estradiol exerted a tonic inhibition on D2L which was released by OVX, exacerbating sugar intake and increasing body weight. D2L mediated the rapid metabolic effects of 17β-estradiol. Conclusion: Our results supported physiological data reporting that activation of the mostly expressed presynaptically D2S-class autoreceptors decreased dopamine release stimulating food intake, whereas activation of the predominantly postsynaptic isoform D2L receptors increased dopamine activity inhibiting food intake. Our studies indicated that 17β-estradiol acted on the two types of D2 receptors showing opposite functions to equilibrate energy intake vs. expenditure for weight set point regulation. Our data also supported biochemical findings reporting that 17β-estradiol induced D2 genes transcriptional regulation, thereby involving both types of D2 receptors in the etiology of obesity. The combined dysregulated effects of D2L and D2S receptors, as 17β-estradiol was lacking, would be causal factors underlying the etiology of obesity.

Down-regulation of dopamine D2 receptor associates with impaired reversal learning induced by morphine withdrawal

OBJECTIVE Cognitive inflexibility plays a critical role in the compulsive drug taking,a central characteristic of drug addictions,yet its underlying neurochemical mechanisms are not well understood.The present study examined the impact of morphine withdrawal on reversal learning.METHODS Reversal learning was tested in a four-choices digging task.Some brain tissues were harvested 2 h after the behavioral experiment for the further measurement.RESULTS We found that after long-term abstinence for a month from chronic morphine exposure,mice exhibited a profound reversal learning deficit.We further found that dopamine D2 receptor(D2R)system in the frontal-striatal circuit is significantly down-regulated,at both receptor and downstream signals levels.Subsequent pharmacological experiments demonstrated that aripiprazole,a D2R partial agonist,prevented the D2R downregulation and rescued the reversal learning deficit.CONCLUSION Together,our findings provide valuable insights into the causal relationship between D2R system in the frontal-striatal circuit and the cognitive inflexibility caused by abused drugs and offer a promising possibility of an effective therapeutic intervention for drug addictions.

Effects of 17<i>β</i>-Estradiol on Dopamine D2 Receptors in Thiamine-Deficient Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

Our previous studies showed that 17β-estradiol (E2) modulated dopamine D2 receptor in regulating body weight set-point. The aim of this study was to understand whether thiamine deficiency influenced the E2 modulation on dopamine D2 receptors, using bromocriptine mesylate (BR) and sulpiride (SUL) as selective central dopamine-D2 receptors agonist and antagonist respectively. We studied the E2-dopamine D2 receptors interferences in a 10-day thiamine-deficient female rats for which consumptions of water, sugar, alcohol and food were daily-recorded and their consequences on body weights assessed. Our results showed that the volume of water daily ingested doubled in thiamine-deficient female rats (OXT), while sugar and alcohol consumptions collapsed with decreased weight and food consumption. On the one hand, thiamine potentiated D2/BR activity (bromocriptine-activated D2 receptors) to induce sugar intake and inhibited the same D2/BR receptors to induce water intake. On the other hand, thiamine promoted D2/SUL receptors (sulpiride-inhibited D2 receptors) for enhanced alcohol intake, increased food consumption and weight gain. Taking together, thiamine modulated the actions of 17β-estradiol on both D2/BR and D2/SUL receptors activities.

Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats

Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.

Effect of total isoflavones from pueraria lobata on the expressions of preproenkephalin, prodynorphin and D2 dopamine receptor mRNA in PC12 cells induced by MPP^+

Objective： The aim of the study was to observe the effect of total isoflavones from pueraria Iobata （TIP） on D2 dopamine receptor mRNA, preproenkephalin mRNA and prodynorphin mRNA expressions in Parkinson＇s disease （PD） model cells induced by 1-methyl-4-phenylpyridinium ion （MPP^＋）. Methods： TIP was dissolved in 0.1 M NaOH and added to the culture medium at a final concentrations of 50 mg/L, 100 mg/L and 200 mg/L. Some cells （control） were exposed to 0.001 M NaOH. TIP was added to PC12 cells 30 min prior to the administration of MPP^＋. TIP and MPP^＋ remained in the culture medium for 96 h. D2 dopamine receptor mRNA, preproenkephalin mRNA and prodynorphin mRNA expressions were assayed by real-time quantitative reverse transcription-PCR. Results： The D2 dopamine receptor mRNA and preproenkephalin mRNA expressions were up-regulated in MPP^＋ group compared with the control group, and prodynorphin mRNA expression was down-regulated in that. The D2 dopamine receptor mRNA expression being down-regulated and prodynorphin mRNA expression being up-regulated in TIP group compared with the MPP^＋ group. And there was no effect of TIP on preproenkephalin gene expression in PC12 cells induced by MPP^＋. Conclusion： The results suggest that TIP down-regulates the D2 dopamine receptor mRNA expression, up-regulates prodynorphin mRNA expression and not affects preproenkephalin gene expression in PC12 cells induced by MPP^＋.

Effects of septal nucleus lesion on dopamine D_2 receptor expression in the prefrontal lobe, striatum, and brainstem in a rat model of schizophrenia

BACKGROUND： It has been demonstrated that the septal nucleus is involved in the pathogenesis of schizophrenia. Based on autopsies of schizophrenia patients, studies have shown a reduced number of septal nucleus neurons and glia. In addition, experimental rat models of schizophrenia have shown increased dopamine receptor D2 binding sites in the basal ganglia, septal nuclei, and substantia nigra. Previous studies have demonstrated that the septal nucleus modulates dopamine metabolic disorder and dopamine D2 receptor balance. OBJECTIVE： Dopamine D2 receptor expression in a rat model of schizophrenia, combined with antipsychotic drugs, was analyzed in the prefrontal lobe, striatum, and brainstem. In situ hybridization was used to observe the effects of stereotactic septal nucleus lesions on dopamine D2 receptor expression in the brains of methylamphetamine-treated rats. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed in the Laboratory of General Institute of Psychosurgery, Third Hospital of Chinese PLA from November 2005 to June 2006. MATERIALS： A total of 120 healthy, adult Sprague Dawley rats, weighing approximately 200 g, were included. Methylamphetamine （Sigma, USA） and an in situ hybridization detection kit for dopamine D2 receptor （Boster, China） were also used for this study. METHODS： All rats were randomly allocated to the following 4 groups, with 30 rats in each group： normal control, simple administration, septal nucleus lesion, and sham-operated groups. In the normal control group, rats were not administered or lesioned. In the remaining 3 groups, rats were intraperitoneally administered 10 mg/kg methylamphetamine, once per day, for 15 successive days to establish a schizophrenia model. Following successful model establishment, rats from the septal nucleus lesion group were subjected to stereotactic septal nucleus lesions. The cranial bone was exposed in rats from the sham-operated group, and the septal nucleus was not lesioned. MAIN OUTCOME MEASURES： At 7 days post-surgery, dopamine D2 receptor expression in the prefrontal lobe, striatum, and brainstem were detected by in situ hybridization. RESULTS： Dopamine D2 receptor expression in the rat prefrontal lobe, striatum, and brainstem was significantly higher in the simple administration group and sham-operated group, compared with the normal control group （P 〈 0.01）. In the septal nucleus lesion group, dopamine D2 receptor expression was significantly less than the simple administration and sham-operated groups, （P 〈 0.01）. There was no significant difference in dopamine D2 receptor expression between the simple administration and sham-operated groups （P 〉 0.05）. CONCLUSION： Septal nucleus lesions reduce dopamine D2 receptor expression in the prefrontal lobe, striatum, and brainstem in a rat model of schizophrenia, indicating that the septal nucleus modulates dopamine D2 receptor expression.

Paired related homeobox 1 transactivates dopamine D2 receptor to maintain propagation and tumorigenicity of glioma-initiating cells

GUoblastoma multiforme （GBM） is a highly invasive brain tumor with limited therapeutic means and poor prognosis. Recent stud- ies indicate that glioma-initiating ceUs/gUoma stem ceils （GICs/GSCs） may be responsible for tumor initiation, infiltration, and recurrence. GICs could aberrantly employ molecular machinery balancing self-renewal and differentiation of embryonic neural precursors. Here, we find that paired related homeobox 1 （PRRX1）, a homeodomain transcription factor that was previously reported to control skeletal development, is expressed in cortical neural progenitors and is required for their self-renewal and proper differentiation. Further, PRRX1 is overrepresented in gUoma samples and labels GlCs. Gtioma celts and GlCs depleted with PRRX1 could not propagate in vitro or form tumors in the xenograft mouse model. The GIC self-renewal function regulated by PRRX1 is mediated by dopamine D2 receptor （DRD2）. PRRX1 directly binds to the DRD2 promoter and transactivates its expression in GICs. Blockage of the DRD2 signaling hampers GIC self-renewal, whereas its overexpression restores the propagating and tumorigenic potential of PRRXl-depleted GlCs. Finally, PRRX1 potentiates GICs via DRD2-mediated extracetlutar signal-related kinase （ERK） and AKT activation. Thus, our study suggests that therapeutic targeting the PRRX1-DRD2-ERK/AKT axis in GICs is a promising strategy for treating GBMs.

Activation of Dopamine D2 Receptors Alleviates Neuronal Hyperexcitability in the Lateral Entorhinal Cortex via Inhibition of HCN Current in a Rat Model of Chronic Inflammatory Pain

Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus(LEC-DG)are considered responsible for the chronification of pain.However,the underlying alterations in fan cells,which are the predominant neurons in the LEC that project to the DG,remain elusive.Here,we investigated possible mechanisms using a rat model of complete Freund’s adjuvant(CFA)-induced inflammatory pain.We found a substantial increase in hyperpolarization-activated/cyclic nucleotide-gated currents(Ih),which led to the hyperexcitability of LEC fan cells of CFA slices.This phenomenon was attenuated in CFA slices by activating dopamine D2,but not D1,receptors.Chemogenetic activation of the ventral tegmental area-LEC projection had a D2 receptor-dependent analgesic effect.Intra-LEC microinjection of a D2 receptor agonist also suppressed CFA-induced behavioral hypersensitivity,and this effect was attenuated by pre-activation of the Ih.Our findings suggest that down-regulating the excitability of LEC fan cells through activation of the dopamine D2 receptor may be a strategy for treating chronic inflammatory pain.

The dopamine receptor D4 regulates the proliferation of pulmonary arteries smooth muscle in broilers by downregulating AT1R

The major cause of pulmonary vascular remodeling in broilers is abnormal proliferation of vascular smooth muscle cells(VSMCs),and one of the main causes of pulmonary hypertension syndrome(PHS)in broilers is pulmonary artery vascular remodeling.Forty Arbor Acres(AA)broilers were randomly divided into four groups(n=10):a control group(deionized water,Og/L NaCl),a freshwater group(FW,deionized water+1 g/L NaCl),highly salinized freshwater group 1(H-SFW-1,deionized water+2.5 g/L NaCl)and highly salinized freshwater group 2(H-SFW-2,deionized water+5 g/L NaCl).The results of in vivo experiments showed that vascular smooth muscle of the broilers could be significantly proliferated by intake of high-salinity fresh water(H-SFW-1&H-SFW-2),which significantly increased the content of angiotensin II(Ang II)and the expression of angiotensin II type 1(AT1)receptor protein.Meanwhile,it significantly decreased the expression of dopamine receptor D4(DRD4)protein.The results of in vitro experiments showed that exogenous Ang II induced the proliferation of primary VSMCs in broilers,which could be significantly inhibited by DRD4 agonists(D4A,HY-101384A)and enhanced by DRD4 inhibitors(D4I;HY-B0965).In addition,the results of immunoblotting and fluorescence quantitative PCR showed that AT1 receptors could be negatively regulated by DRD4 in VSMCs of broilers,either at the transcriptional or translational level.At the same time,the expression of AT1 receptor could be increased by DRD4 inhibition by D4I and decreased by DRD4 activation by D4A.The negative regulatory effect of DRD4 on AT1 receptor occurred in a dose-dependent manner.These results indicate that long-term intake of highly salinized fresh water can cause PHS in broilers,accompanied by varying degrees of proliferation of pulmonary artery smooth muscle.This mechanism may involve response of its receptor being induced by increased Ang II,while DRD4 can negatively regulate it.

-94 G/A polymorphism in the dopamine D1 receptor gene is associated with schizophrenia in a Chinese Han population from Shandong province

The correlation between -94 G/A polymorphism in the dopamine D1 receptor gone and schizophrenia remains poorly understood despite extensive research. This study sought to evaluate the genotypes and allele frequencies of the -94 G/A polymorphism in the dopamine D1 receptor gone by real-time PCR using TaqMan fluorescent probes. One hundred and sixty-two patients with schizophrenia and 101 healthy controls living in Shandong province of China were evaluated. Experimental results showed that the G/A genotype distribution was significantly higher in the schizophrenia patients than in healthy controls. The frequencies of G allele and A allele were not significantly different between the schizophrenia patients and the controls. Thus, the -94 G/A polymorphism in the dopamine D1 receptor gone was found to be associated with schizophrenia in a Chinese Han population from Shandong province.

Dopamine receptor D3R and D4R mRNA levels in peripheral lymphocytes in patients with schizophrenia correlate with severity of illness

Schizophrenia is a disease that affects many areas of the brain. The dopamine hypothesis is one of the most widely-accepted ideas in the pathophysiology of schizophrenia. Besides alterations in the dopaminergic system in the central nervous system, there have been several reports of changes in dopaminergic systems in the peripheral blood of schizophrenic patients. Several reports have shown that dopamine receptor expression by lymphocytes is altered in patients with schizophrenia, but the results have been conflicting. We therefore re-assessed D3R and D4R mRNA levels in 11 patients with schizophrenia and 12 healthy subjects and correlated levels with severity of symptoms. D3R and D4R expression in lymphocytes and granulocytes was measured by quantitative RT-PCR and the severity of symptoms and cognitive impairment were assessed using the PANSS and BACS-J. There were no significant differences in mean D3R or D4R mRNA levels in lymphocytes from schizophrenic patients and controls and no significant difference in mean D4R mRNA levels in granulocytes (D3R mRNA undetectable). In patients with schizophrenia, D3R expression was inversely correlated with the total PANSS score (r = 0.768, p = 0.009), while D4R expression was positively correlated with working memory scales (r = 0.895, p = 0.001). In conclusion, these results imply that lymphocyte D3R and D4R are involved in the mechanisms of the disorder and could be used as target markers in the treatment of schizophrenia.

Cell-type specific examination of central amygdala dopamine receptor 2 expressing neurons as a translational target for pharmacological enhancement of extinction

Behavioral and molecular characterization of cell-type specific populations governing fear learning and behavior is a promising avenue for the rational identification of potential therapeutics for fear-related disorders.Identification of cell-type specific changes in neuronal translation following fear learning allows for targeted pharmacological intervention during fear extinction learning,mirroring possible treatment strategies in humans.Here we identify the central amygdala(Ce A)Drd2-expressing population as a fear-supporting population that is molecularly distinct from other,previously identified fear-supporting CeA populations.Sequencing of actively translating transcripts of Drd2 neurons identifies m RNAs that are differentially regulated following fear learning including Npy5r,Rxrg,Sst5r,Fgf3,Erb B4,Fkbp14,Dlk1,Ssh3 and Adora2a.Direct pharmacological manipulation of NPY5R,RXR,and ADORA2A confirms their importance in fear behavior and validates the present approach of identifying pharmacological targets for the modulation of emotional learning.

Anti-post-traumatic stress disorder effect of dopamine D3 receptor antagonist

OBJECTIVE To explore the antipost-traumatic-stress-disorder(PTSD) effects and its probable mechanism of YQA14,a dopamine D3 receptor antagonist.METHODS Two PTSD animal models,the rat single prolonged stress(SPS) model and the mouse pre-shock model,were used in this experiment.In the SPS model,adult male Sprague-Dawley(SD) rats were randomly divided into control group,model group,positive group and YQA14 groups with different dosages.In the mouse pre-chock model,dopamine D3 receptor knockout(KO) and wild type(WT) mice were randomly divided into control group,model group,positive group and YQA14 group.After the establishment of animal models,the saline,sertraline(ig) and YQA14(ip)were administered to the animals in the control,model,positive control and test groups respectively.The open field test(OFT) was used to evaluate the locomotor activity while the contextual freezing(CF) measurement and elevated plus maze(EPM) test were used to evaluate the PTSD-like behaviors.RESULTS In the rat SPS model,neither SPS nor drug treatment affected the locomotor activity in rats.However,SPS rats showed significant PTSD-like behaviors with enhanced freezing time in CF(P<0.01) and decreased percentage of entries into open arms and time spent in open arms in EPM(P<0.05,P<0.01).Moreover,compared with the model group,the repeated administration of YQA14(3.125,6.25 and 12.5 mg·kg-1)significantly reduced the freezing time(P<0.01)and increased the percentages of entries into open arms and time spent in open arms(P<0.05).In the mouse pre-shock model,when both model groups showed significant higher freezing time compared with the respective control groups(P<0.05,P<0.01),YQA14 selectively alleviated the freezing time on WT mice(P<0.05) while had no effect on KO mice.In the EPM tests,the WT mice model group showed a significant reduction in the percentage of entries into open arms and time spent in open arms(P<0.05) while D3 R KO mice model group didn′ t show any reduction,compared with respective control groups.Furthermore,daily administration of YQA14 at 12.5 mg·kg-1 both significantly reduced the percentages of entries into and time spent in open arms(P<0.05) but not D3 R KO mice.None of the locomotor activity were significantly affected.CONCLUSION YQA14 could significantly alleviate the PTSD-like behaviors in rodents and the effects were mediated by the blockade of brain D3 receptors.

Dopamine receptor D4 gene (DRD4) is associated with gazing toward humans in domestic dogs (<i>Canis familiaris</i>)

Dogs show high social communicative ability in interactions with humans. We investigated the association between dogs’ social communicative behavior and the polymorphisms of a gene related to a neurotransmitter. We used an “unsolvable task”, in which an experimenter put a food reward into a container and closed it firmly so that dogs could not remove the reward. Human-directed gazing, possibly to request help, is a characteristic behavioral trait of dogs in such situations. The association between owner-directed gazing behavior in the unsolvable task and polymorphisms of three regions (exon1, exon3, intron2) in the dopamine receptor D4 gene (DRD4) was analyzed. We found that the genotype of DRD4 intron2 was significantly associated with the dogs’ gazing behavior. Dogs carrying shorter allele (P) looked at their owner more frequently, for longer, and earlier than dogs carrying longer allele (Q). This result suggests that polymorphism in DRD4 intron2 may affect social communication and cognition in dogs.

Dopamine D2 Receptor-Mediated Modulation of Rat Retinal Ganglion Cell Excitability

Ganglion cells(RGCs) are the sole output neurons of the retinal circuity. Here, we investigated whether and how dopamine D2 receptors modulate the excitability of dissociated rat RGCs. Application of the selective D2 receptor agonist quinpirole inhibited outward K^+ currents, which were mainly mediated by glybenclamide-and 4-aminopyridine-sensitive channels, but not the tetraethylammonium-sensitive channel. In addition,quinpirole selectively enhanced Nav1.6 voltage-gated Na^+ currents. The intracellular c AMP/protein kinase A,Ca^2+/calmodulin-dependent protein kinase Ⅱ, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathways were responsible for the effects of quinpirole on K^+ and Na^+ currents, while phospholipase C/protein kinase C signaling was not involved. Under current-clamp conditions, the number of action potentials evoked by positive current injection was increased by quinpirole. Our results suggest that D2 receptor activation increases RGC excitability by suppressing outward K+currents and enhancing Nav1.6 currents, which may affect retinal visual information processing.

Effects of L-Dopa and Dopamine D2 Agonists on Recollection and Familiarity in Idiopathic Nondementing Parkinson’s Disease

Idiopathic nondementing Parkinson’s disease (PD) is marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area. Recent brain imaging work implicates these structures in dopamine modulated networks subserving episodic memory. These findings are of relevance to PD because they suggest that dopamine depletion contributes to the disease-dependent decline in episodic memory, and therefore, this decline should, at least partially, be remediated by dopaminergic medication. Recognition memory (RM), recollection and familiarity during recognition was examined in 17 PD patients, 12 of whom were medicated with a D2 dopamine agonist (pramipexole or ropinirole) and l-dopa, with a further 5 PD control patients on l-dopa but no D2 agonist. Memory was tested “ON” and, following a period of medication withdrawal, “OFF” and compared to a group of 14 matched healthy volunteers (HV). The HVs were also tested twice in the absence of medication. The patients on the agonists PD showed significant impairments in recollection ON- and OFF-medication, whereas the l-dopa control patients exhibited a decline in OFF-recollection only. RM and familiarity were spared in both groups ON- and OFF-medication. These findings suggest that D2 dopamine agonists (combined with l-dopa) contribute to disease-dependent episodic memory impairment.

The role of dopamine D2 receptors in the amygdala in metabolic and behavioral responses to stress in male Swiss-Webster mice

OBJECTIVE： The D2 dopamine receptor is found in different parts of the amygdala. However, its contribution to stress is unknown. Thus, in the present study, we examined the effects of excitation and inhibition of D2 dopamine receptors in the amygdala on the metabolic and hormonal changes in response to stress. METHODS： Bilateral amygdala cannulation was carried out in Swiss-Webster mice （n = 7）. On recovery, different doses of the dopamine D2 receptor antagonist, sulpiride （1, 5 and 10μg/mouse） or the dopamine D2 receptor agonist, bromocriptine （1, 5 and 10μg/mouse） were injected into the amygdala. The animals were then placed in stress apparatus （communication box） where they received an electric shock （10 mV voltage, 10 Hz frequency and 60 s duration） after 30 rain. The animal＇s activities were recorded for 10 min before and 10 min after the stress induction. Locomotion, rearing and freezing were investigated. Metabolic changes, such as food and water intake and anorexia, were studied. RESULTS： The results show that stress increased the concentration of plasma corticosterone, which was followed by a decrease in locomotion and rearing and an increase in freezing behavior. Furthermore, both weight and water and food intake were reduced. Administration of bromocriptine led to a reduction of corticosterone at doses of 1 and 5 ~tg/mouse and an increase of corticosterone at 10 ~tg/mouse. Additionally, lower doses ofbromocriptine （1 and 5 ~tg/mouse） caused an increase in locomotion and rearing and a decrease in freezing behavior. Similar results were observed with sulpiride injection. CONCLUSION： D2 dopamine receptors can play a major role in the amygdala in stress. Both an agonist and an antagonist of the D2 receptor attenuate the metabolic and hormonal changes observed in response to stress

Estrogen affects neuropathic pain through upregulating N-methyl-D-aspartate acid receptor 1 expression in the dorsal root ganglion of rats

Estrogen affects the generation and transmission of neuropathic pain,but the specific regulatory mechanism is still unclear.Activation of the N-methyl-D-aspartate acid receptor 1（NMDAR1） plays an important role in the production and maintenance of hyperalgesia and allodynia.The present study was conducted to determine whether a relationship exists between estrogen and NMDAR1 in peripheral nerve pain.A chronic sciatic nerve constriction injury model of chronic neuropathic pain was established in rats.These rats were then subcutaneously injected with 17β-estradiol,the NMDAR1 antagonist D（-）-2-amino-5-phosphonopentanoic acid（AP-5）,or both once daily for 15 days.Compared with injured drug na？ve rats,rats with chronic sciatic nerve injury that were administered estradiol showed a lower paw withdrawal mechanical threshold and a shorter paw withdrawal thermal latency,indicating increased sensitivity to mechanical and thermal pain.Estrogen administration was also associated with increased expression of NMDAR1 immunoreactivity（as assessed by immunohistochemistry） and protein（as determined by western blot assay） in spinal dorsal root ganglia.This 17β-estradiol-induced increase in NMDAR1 expression was blocked by co-administration with AP-5,whereas AP-5 alone did not affect NMDAR1 expression.These results suggest that 17β-estradiol administration significantly reduced mechanical and thermal pain thresholds in rats with chronic constriction of the sciatic nerve,and that the mechanism for this increased sensitivity may be related to the upregulation of NMDAR1 expression in dorsal root ganglia.