The aim of the present study was to reveal the role of cortical-striatum postsynaptic dopamine D2 receptor (D2R) in improving motor behavioral dysfunction in Parkinson's disease (PD) mice by exercise. C57/BL6 male adult mice were randomly divided into control, PD and PD plus exercise groups. The mice were injected with 6-OHDA in striatum to establish a unilateral injury PD model. The exercise intervention program was uniform speed running (16 m/min, 40 min/d, 5 d per week for 4 weeks). Autonomic activity of mice was tested by open field test. Cortical-striatum synaptic transmission efficiency was assessed by peak amplitude of field excitatory postsynaptic potential (fEPSP) recorded from in vitro brain slides. Meanwhile, the effects of D2R agonist on autonomic activity and cortical-striatal synaptic transmission were observed. The results showed that, compared with PD group, PD plus exercise group exhibited significantly increased autonomic motor distance and proportion of fast-moving (P < 0.05), as well as decreased maximum amplitude of fEPSP under increasing stimulation intensity (0.75-3.00 pA) (P < 0.05) and slope of stimulus-response curve. Compared with PD mice without D2R agonist, the movement distance and rapid movement ratio of PD mice treated with D2R agonist were increased significantly (P < 0.05), whereas fEPSP peak amplitude (P < 0.05) and the slope of stimulus-response curve were decreased. These results indicate that either early exercise intervention or D2R agonist treatment can inhibit the abnormal increase of cortical-striatum synaptic transmission and improve the autonomic motor ability in PD mice, suggesting that the cortical-striatum synaptic D2R may be an important molecular target for exercise to improve the autonomic motor ability of PD mice.
Animals ; Corpus Striatum ; physiology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidopamine ; Parkinson Disease ; physiopathology ; therapy ; Physical Conditioning, Animal ; Random Allocation ; Receptors, Dopamine D2 ; agonists ; physiology ; Synaptic Transmission

Dopamine plays an important role in cognitive functions including decision making, attention, learning and memory in the anterior cingulate cortex (ACC). However, little is known about dopamine receptors (DAR) expression patterns in ACC neurons, especially GABAergic interneurons. The aim of the present study was to investigate the expression of the most abundant DAR subtypes, D1 receptors (D1Rs) and D2 receptors (D2Rs), in major types of GABAergic interneurons in rat ACC, including parvalbumin (PV)-, calretinin (CR)-, and calbindin D-28k (CB)-containing interneurons. Double immunofluorescence staining and confocal scanning were used to detect protein expression in rat brain sections. The results showed a high proportion of PV-containing interneurons express D1Rs and D2Rs, while a low proportion of CR-positive interneurons express D1Rs and D2Rs. D1R- and D2R-expressing PV interneurons are more prevalently distributed in deep layers than superficial layers of ACC. Moreover, we found the proportion of D2Rs expressed in CR cells is much greater than that of D1Rs. These regional and interneuron type-specific differences of D1Rs and D2Rs indicate functionally distinct roles for dopamine in modulating ACC activities via stimulating D1Rs and D2Rs.
Animals ; Calbindin 1 ; physiology ; Calbindin 2 ; physiology ; Calcium-Binding Proteins ; physiology ; Dopamine ; physiology ; Gyrus Cinguli ; cytology ; Interneurons ; physiology ; Parvalbumins ; physiology ; Rats ; Receptors, Dopamine D1 ; physiology ; Receptors, Dopamine D2 ; physiology

OBJECTIVETo observe the long-term changes in anxiety-like behavior and tyrosine hydroxylase (TH) expression in the substantia nigra (SN) after hypoxic-ischemic brain damage (HIBD) in a neonatal rat model and to further explore the relationship between dopamine (DA) level and long-term anxiety-like behavior using the DA receptor (DAR) antagonist.

METHODSSeven-day-old (P7) neonatal Sprague-Dawley (SD) rats were randomized into normal control, sham-operated, HIBD and HIBD+DAR antagonist groups. HIBD model was prepared by ligating the right common carotid artery and 8% hypoxia exposure. The rats in the sham-operated group were sham-operated and were not subjected to right common carotid artery ligation and hypoxia exposure. The DAR antagonist was injected intraperitoneally before and after inducing HIBD. The same amount of normal saline was given to the other three groups as a control. Anxiety-like behavior was evaluated by elevated plus maze test, and TH expression in the SN was measured by immunohistochemistry on P14, P21, and P28.

RESULTSOn P21 and P28, the time spent in the open arms and the percentage of open arms entries in the HIBD group were significantly increased compared with those in the normal control, sham-operated and HIBD+DAR antagonist groups (P<0.05); in addition, the HIBD+DAR antagonist group showed a significantly longer time spent in the open arms than the normal control group (P<0.05). On P14, P21, and P28, TH expression in the HIBD and HIBD+DAR antagonist groups was significantly lower than that in the normal control and sham-operated groups, and TH level in the HIBD group was significantly lower than that in the HIBD+DAR antagonist group (P<0.05).

CONCLUSIONSDAR antagonist allows the restoration of anxiety-like behavior and alleviates the damage to dopaminergic neurons in SD rats after HIBD.

Animals ; Animals, Newborn ; Anxiety ; etiology ; prevention & control ; Dopamine Antagonists ; therapeutic use ; Hypoxia-Ischemia, Brain ; complications ; Maze Learning ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine ; physiology ; Substantia Nigra ; enzymology ; Tyrosine 3-Monooxygenase ; analysis

OBJECTIVETo study the effects of dopamin receptors-2 (DR2) on myocardial ischemic postconditioning and explore its underlying mechanisms.

METHODSThe myocardial ischemic postconditioning (PC) model was established in cultured primary rat neonatal cardiomyocytes which were then randomly assigned in the following groups: Nomial control group, Isehemia/reperfusion (L'R) group, PC (ischemic postconditioning) group, PC + Bro (Bromocriptine, a DB2 antagonist) group, PC + Hal (Haloperidol, a DB2 repressor) and PC + Hal + Bro groups. The lactate dehydrogenase (LDH) and superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in cell medium were analyzed by colorunetry. The cell ultrastructure changes were observed by transmission electron microscope. The cell apoptosis was analyzed using flowcytometiy. The protein expression level of D112 and activity of p-p38 and p-JNK were detected by Western blot.

RESULTSCompared with the nonnal control group, hR increased the protein expression level of DB2, enhanced LDH activity and MDA content, promoted cell injury and apoptosis, decreased SOD activity, up-regulated the activity of p-p38 and p-JNK. Compared with the hR group, although PC further increased the expression of DR2 protein, it decreased LDH activity and MDA content, cell injury and apoptosis, increased SOD activity, down-regulated activity of p-p38 and p-JNK. Bromocriptine treatment further enhanced PC-induced canlioprotective effect, yet Hal addition attenuated this enhancing effect exerted by bromocriptine.

CONCLUSIONThe activation of DB2 is involved in the protective effect of ischemic postconditioning on myocardial ischemia/reperfusion injury through down-regulating the activity of p-p38 and p-JNK.

Animals ; Apoptosis ; Cells, Cultured ; Ischemic Postconditioning ; JNK Mitogen-Activated Protein Kinases ; metabolism ; Myocardial Reperfusion Injury ; prevention & control ; Myocytes, Cardiac ; pathology ; Rats ; Rats, Wistar ; Receptors, Dopamine D2 ; physiology ; p38 Mitogen-Activated Protein Kinases ; metabolism

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by severe loss of substantia nigra dopamine (DA) neurons. The target region of substantia nigra DA neurons is the dorsal striatum. According to the classic model, activation of DA receptors on striatal medium spiny neurons (MSNs) modulates their intrinsic excitability. Activation of D1 receptors makes MSNs in the direct "Go" pathway more excitable, whereas activation of D2 receptors makes MSNs in the indirect "NoGo" pathway less excitable. Therefore increased DA increases the responsiveness of the Go pathway while decreases the responsiveness of the NoGo pathway. Both mechanisms increase motor output. Conversely, diminished DA will favor the inhibitory NoGo pathway. Therefore, DA has direct, "on-line" effect on motor performance. However, in addition to modulating the intrinsic excitability of MSNs "on-line", DA also modulates corticostriatal plasticity, therefore could potentially produce cumulative and long-lasting changes in corticostriatal throughput. Studies in my lab suggest that DA blockade leads to both direct motor performance impairment and D2 receptor dependent NoGo learning ("learned" motor inhibition) that gradually deteriorates motor performance. NoGo learning is experience dependent and task specific. It is different from blocked learning since NoGo learning impairs future performance even after DA is restored. More recent data from my lab suggest that NoGo learning in the absence of DA arises from increased LTP at the indirect pathway corticostriatal synapses and contributes significantly to PD-like motor symptoms. Our data and hypotheses suggest a novel therapeutic strategy for PD that targets directly signaling molecules for corticostriatal plasticity (e.g. the cAMP pathway and downstream signaling molecules) and prevents aberrant plasticity under conditions of DA denervation.
Corpus Striatum ; cytology ; Dopamine ; physiology ; Dopaminergic Neurons ; pathology ; Humans ; Neuronal Plasticity ; Parkinson Disease ; physiopathology ; Receptors, Dopamine D1 ; physiology ; Receptors, Dopamine D2 ; physiology ; Substantia Nigra ; pathology

The present study was to investigate the role of dopamine D1 receptors and its relationship with glutamate, N-methyl-D-aspartic acid (NMDA) receptor and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor in depression induced by chronic unpredictable mild stress (CUMS). CUMS-induced depression model was established in Sprague-Dawley rats, and intrahippocampal microinjections of D1 dopamine receptor agonist SKF38393, non-competitive NMDA receptor antagonist MK-801 and AMPA receptor antagonist NBQX were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by measurement of weight changes, sucrose preference test, open-field test and tail suspension test. The concentration of glutamic acid and the expression of its receptors' subunits were detected by HPLC and Western blot, respectively. The results showed that, compared with control group, CUMS rats showed depression-like behavioral changes, higher concentration of glutamic acid, lower expressions of NMDA receptor (NR1) and AMPA receptor (GluR2/3) in hippocampus. Pretreatment with injection of SKF38393 could rescue such depression effect of CUMS, decrease the concentration of glutamic acid, and increase the expressions of NMDA receptor (NR1), AMPA receptor (GluR2/3) in hippocampus. Pretreatment with MK-801 could enhance the antidepressant effect of SKF38393, while NBQX weakened. These results suggest that agonists of D1 dopamine receptor could reduce the concentration of glutamic acid in hippocampus, and its antidepressant effect may be mediated by AMPA receptor partially.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine ; pharmacology ; Animals ; Depression ; etiology ; physiopathology ; Dizocilpine Maleate ; pharmacology ; Excitatory Amino Acid Antagonists ; Glutamates ; metabolism ; Hippocampus ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA ; metabolism ; Receptors, Dopamine D1 ; agonists ; physiology ; Stress, Physiological ; physiology

OBJECTIVETo investigate the role of dopamine-1 receptor in the modulation of basic respiration rhythm.

METHODSNewborn SD rat (0-3 days, n=20) brain stem slices containing the medial region of the nucleus retrofacialis (mNRF) were prepared with the hypoglossal nerve roots retained. The respiratory rhythmical discharge activity (RRDA) of the hypoglossal nerve was recorded using suction electrodes on these preparations, and the effects of dopamine-1 receptor on RRDA were investigated by application of the specific agonist of dopamine-1 receptor A68930 at different concentrations (0, 1, 2, and 5 micromol/L) in the perfusion solution.

RESULTSThe respiratory cycles (RC) and the expiratory time (TE) decreased progressively with gradual increment of the integrated amplitude (IA) after A68930 administration, and their changes were the most conspicuous at 5 min after the administration. A68930 at the concentrations of 2 and 5 micromol/L resulted in the most obvious changes in RC, TE, and IA (P<0.05), but IA exhibited no significant variation at 1 min after perfusion with 2 micromol/L A68930 (P>0.05). RC and TE were gradually shortened after treatment with increasing concentrations of A68930, which also caused gradual increment of IA, and at the concentration of 5 micromol/L, RC, TE, and IA all showed the most obvious changes (P<0.01).

CONCLUSIONSDopamine-1 receptor plays a role in the modulation of RRDA in isolated neonatal rat brainstem slice. A68930 may increase the frequency of respiration by shortening TE and enhance the respiratory activity by increasing the amplitude of inspiratory discharge of the respiratory neurons.

Animals ; Animals, Newborn ; Cell Separation ; Chromans ; pharmacology ; Dopamine Agonists ; pharmacology ; In Vitro Techniques ; Medulla Oblongata ; cytology ; physiology ; Neurons ; cytology ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine ; physiology ; Respiration ; drug effects

PURPOSE: Itopride hydrochloride (itopride) inhibits acetylcholinesterase (AChE) and antagonizes dopamine D(2) receptor, and has been used as a gastroprokinetic agent. However, its prokinetic effect on the small bowel or colon has not yet been thoroughly investigated. The aim of this study was to investigate the effects of itopride on motor functions of the ileum and colon in guinea pigs. MATERIALS AND METHODS: The distal ileum was excised and the activity of peristaltic contraction was determined by measuring the amplitude and propagation velocity of peristaltic contraction. The distal colon was removed and connected to the chamber containing Krebs-Henseleit solution (K-H solution). Artificial fecal matter was inserted into the oral side of the lumen, and moved toward the anal side by intraluminal perfusion via peristaltic pump. Colonic transit times were measured by the time required for the artificial feces to move a total length of 10cm with 2-cm intervals. RESULTS: In the ileum, itopride accelerated peristaltic velocity at higher dosage (10(-10)-10(-6)M) whereas neostigmine accelerated it only with a lower dosage (10(-10)-10(-9)M). Dopamine (10(-8)M) decelerated the velocity that was recovered by itopride infusion. Itopride and neostigmine significantly shortened colonic transit at a higher dosage (10(-10)-10(-6)M). Dopamine (10(-8)M) delayed colonic transit time that was also recovered after infusion of itopride. CONCLUSION: Itopride has prokinetic effects on both the ileum and colon, which are regulated through inhibitory effects on AChE and antagonistic effects on dopamine D(2) receptor.
Animals ; Benzamides/*pharmacology ; Benzyl Compounds/*pharmacology ; Cholinesterase Inhibitors/pharmacology ; Colon/*drug effects/physiology ; Dopamine/pharmacology ; Dose-Response Relationship, Drug ; Gastrointestinal Motility/*drug effects ; Guinea Pigs ; Ileum/*drug effects/physiology ; Neostigmine/pharmacology ; Receptors, Dopamine D1/antagonists & inhibitors/physiology

To explore the role of D(1)-dopamine receptor in the modulation of basic respiratory rhythm, neonatal (0-3 d) Sprague-Dawley rats of either sex were used. The medulla oblongata slice was prepared and the surgical procedure was performed in the modified Kreb's solution (MKS) with continuous ventilating 95% O2 and 5% CO2 and ended in 3 min. A 600-700 mum single transverse slice containing the hypoglossal nerve roots and some parts of the ventral respiratory group was cut. The preparation was quickly transferred to a recording chamber and continuously perfused with oxygen-saturated MKS at a rate of 4-6 mL/min at 27-29 degrees C. Ten medulla oblongata slice preparations were randomly divided into two groups. In group I, the preparations were perfused with perfusion solution containing D(1)-dopamine receptor specific agonist cis-(+/-)-1-(Aminomethyl)-3,4-dihydro-3-phenyl-1H-2-Benzopyran-5,6-Diolhy-drochlo-ride (A68930, 5 mumol/L) for 10 min first; after washing out, the preparations were then perfused with perfusion solution containing D(1)-dopamine receptor specific antagonist R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390, 2 mumol/L) for 10 min. In group II, after perfusion with A68930 for 10 min, the preparations were perfused with additional A68930 + SCH-23390 for 10 min. Respiratory rhythmical discharge activity (RRDA) of the rootlets of hypoglossal nerve was recorded by suction electrodes. The results showed that A68930 shortened the respiratory cycle (RC) and expiratory time (TE) with an increase in the integral amplitude (IA). However, SCH-23390 significantly prolonged RC and TE, and decreased IA with a decrease in inspiratory time (TI). Moreover, the effect of A68930 on the respiratory rhythm was partially reversed by additional application of A68930 + SCH-23390. These results indicate that D(1)-dopamine receptor is possibly involved in the modulation of the RRDA in the isolated neonatal rat brainstem slice.
Animals ; Animals, Newborn ; Benzazepines ; pharmacology ; Biological Clocks ; Chromans ; pharmacology ; Female ; In Vitro Techniques ; Male ; Medulla Oblongata ; physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine ; physiology ; Respiration

BACKGROUNDCocaine addiction may involve complex neuroadaptations, including many changes of genes expression. Dopamine D3 receptors play an important role in cocaine addiction; however, its role in cocaine induced gene expression change is poorly understood. To identify the changes in gene expression induced by repeated cocaine exposure through D3 dopamine receptors, we compared the expression of four molecules: Janus kinase 2 (Jak2), g-aminobutanoic acid receptor subunit alpha 1 (GABAAalpha1), glutamate receptor AMPA3 alpha 3 (GluR 3) and stromal cell derived factor 1 (SDF1). These four have been implicated in mediating the actions of cocaine in the nucleus accumbens (NAc) and caudoputamen (CPu) in mice after acute and repeated cocaine exposure.

METHODSFor the acute and repeated injections, the mice were divided into four groups: 30 mg/kg cocaine, nafadotride 0.5 mg/kg + cocaine 30 mg/kg, nafadotride 0.5 mg/kg, and saline as the basal group. The expression of Jak2, GABAAalpha1, GluR 3 and SDF1 were assayed by Western blot, quantitative real-time RT-PCR and immunohistochemistry.

RESULTSTwenty-four hours after seven consecutive days of repeated cocaine exposure, the expression of GABAAalpha1 decreased in cocaine group compared with basal line and further decreased in the cocaine + nafadotride group and remained at basal level in the nafadotride group. Similarly, the Jak2 expression decreased in cocaine group compared with base line. However, the levels of Jak2 increased in cocaine + nafadotride group compared with cocaine group, while remained at basal level in nafadotride group.

CONCLUSIONSGABAAalpha1 and Jak2 may be involved in chronic cocaine induced neuroadaptations. D3 dopamine receptors play an important role in the expression of these genes.

Animals ; Brain ; drug effects ; metabolism ; Cocaine ; pharmacology ; Female ; Gene Expression Regulation ; drug effects ; Immunohistochemistry ; Janus Kinase 2 ; analysis ; genetics ; Male ; Mice ; Receptors, Dopamine D3 ; physiology ; Receptors, GABA-A ; analysis ; genetics ; Reverse Transcriptase Polymerase Chain Reaction