Behavioral-electrophysiological observation of the involvement of dopamine D1 receptor of the rat anterior cingulate cortex in the regulation of pain-related emotion / 生理学报

The present study was aimed to explore the involvement of dopamine D1 receptor of the anterior cingulate cortex (ACC) in the regulation of chronic inflammatory pain-related emotion. On the first day, the rats were acclimated to the environment and the baseline indices were measured. On the second day, the rats were administered with the dopamine D1 receptor antagonist SCH-23390 or agonist SKF38393 in the ACC, and then they were subcutaneously injected with complete Freund's adjuvant (CFA, 0.08 mL) in the left hind paw to establish conditioned place avoidance (CPA) response after pairing with specific environment. On the third day, the CPA response and the firing frequency of ACC neurons were observed synchronously, and the open-field behavior, mechanical pain behavior and paw withdrawal latency (PWL) tests were also observed subsequently. In other experiments, rats were given subcutaneous injection of normal saline (NS) on the left hind paw after SCH-23390 or SKF-38393 was administered in the ACC, and then the same observations were performed. The results showed that: (1) Compared with the control group, the PWL and mechanical pain thresholds of rats injected with CFA on the left hind paw were significantly decreased (P < 0.05); (2) The residence time of rats injected with CFA in the "pain environment" and open field center was significantly shortened (P < 0.05); (3) Pre-injection of antagonist SCH-23390 in ACC (10 μg) alleviated the anxiety-like negative behavior response induced by CFA (P < 0.05) and reversed CFA-induced increases of discharge frequency of ACC neurons (P < 0.05); (4) Pre-injection of agonist SKF-38393 in the ACC (10 μg) induced CPA-like behavioral response in rats injected with NS in the left hind paw, and increased the firing frequency of ACC neurons (P < 0.05); (5) Immunofluorescence detection showed that dopamine D1 receptor and NMDA receptor were co-expressed in the same neuron. These results suggest that inhibition of dopamine D1 receptor in ACC can alleviate the negative emotional response induced by persistent pain.

Gap Junction Contributions to the Goldfish Electroretinogram at the Photopic Illumination Level

Understanding how the b-wave of the electroretinogram (ERG) is generated by full-field light stimulation is still a challenge in visual neuroscience. To understand more about the origin of the b-wave, we studied the contributions of gap junctions to the ERG b-wave. Many types of retinal neurons are connected to similar and different neighboring neurons through gap junctions. The photopic (cone-dominated) ERG, stimulated by a small light beam, was recorded from goldfish (Carassius auratus) using a corneal electrode. Data were obtained before and after intravitreal injection of agents into the eye under a photopic illumination level. Several agents were used to affect gap junctions, such as dopamine D1 and D2 receptor agonists and antagonists, a nitric oxide (NO) donor, a nitric oxide synthase (NOS) inhibitor, the gap junction blocker meclofenamic acid (MFA), and mixtures of these agents. The ERG b-waves, which were enhanced by MFA, sodium nitroprusside (SNP), SKF 38393, and sulpiride, remained following application of a further injection of a mixture with MFA. The ERG b-waves decreased following NG-nitro-L-arginine methyl ester (L-NAME), SCH 23390, and quinpirole administration but were enhanced by further injection of a mixture with MFA. These results indicate that gap junction activity influences b-waves of the ERG related to NO and dopamine actions.

Activation of hippocampal D1 dopamine receptor inhibits glutamate-mediated depression induced by chronic unpredictable mild stress in rats / 生理学报

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.

Differential DAergic Control of D1 and D2 Receptor Agonist Over Locomotor Activity and GABA Level in the Striatum

The basal ganglia, a group of nuclei, are associated with a variety of functions, including motor control. The striatum, which is the major input station of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. The striatum is made up 96% of medium spiny neurons which are GABAergic cells. GABAergic cells are known to contain DA receptors which divide into two main branches- the D1 receptor (D1R)-expressing direct pathway and the D2 receptor (D2R)-expressing indirect pathway. The role of these two efferent pathways has not been clear in control of motor behaviors. To establish the influence of the different DA subtypes on GABAergic systems in the striatum, D1 selective receptor agonist (SKF 38393) and D2 selective receptor agonist (Quinpirole) were administered to mice. SKF 38393 and quinpirole were administered intraperitoneally in a volume of 0, 1, 5, 10 (mg/kg) and motor activity was assessed for 60 min immediately after the injection of DA agonists. Mice were sacrificed after behavioral test and the striatum in the brain were dissected for analysis of GABA level with HPLC. Both SKF 38393 and quinpirole dose-dependently increased locomotor activity but, GABA level in the striatum was clearly different in two agonists. These findings provide insight into the selective contributions of the direct and indirect pathways to striatal GABAergic motor behaviors.

Differential distributions and trafficking properties of dopamine D1 and D5 receptors in nerve cells / 神经科学通报·英文版

<p><b>OBJECTIVE</b>To explore the possible differential trafficking properties of the dopamine D1-like receptor subtypes, D1 receptor and D5 receptor.</p><p><b>METHODS</b>To visualize distributions of dopamine D1-like receptor subtypes at subcellular level, the yellow and cyan variants of green fluorescent protein (GFP) were used to tag D1 and D5 receptors. After transfection with the tagged dopamine receptors, the neuroblastoma cells NG108-15 were treated with D1 agonist SKF38393 or acetylcholine (ACh). Then we observed the subcellular distributions of the tagged receptors under the confocal microscopy and tried to determine trafficking properties by comparing their distribution patterns before and after the drug treatment.</p><p><b>RESULTS</b>In resting conditions, D1 receptors located in the plasma membrane of NG108-15 cells, while D5 receptors located in both plasma membrane and cytosol. With the pre-treatment of SKF38393, the subcellular distribution of D1 receptors was changed. The yellow particle-like fluorescence of tagged D1 receptors appeared in the cytosol, indicating that D1 receptors were internalized into cytosol from the cell surface. Same situation also occurred in ACh pre-treatment. In contrast, the subcellular distribution of D5 receptors was not changed after SKF38393 or ACh treatment, indicating that D5R was not translocated to cell surface. Interestingly, when D1 and D5 receptors were co-expressed in the same cell, both kept their distinct subcellular distribution patterns and the trafficking properties.</p><p><b>CONCLUSION</b>Our present study reveals that in NG108-15 nerve cells, dopamine D1 and D5 receptors exhibit differential subcellular distribution patterns, and only D1 receptor has a marked trafficking response to the drug stimulation. We further discuss the potential role of the differential trafficking properties of D1-like receptors in complex modulation of DA signaling.</p>

Lesion of Subthalamic Nucleus in Parkinsonian Rats: Effects of Dopamine D1 and D2 Receptor Agonists on the Neuronal Activities of the Substantia Nigra Pars Reticulata

OBJECTIVE: It was hypothesized that dopamine agonist administration and subthalamic nucleus (STN) lesion in the rat might have a synergistic effect on the neuronal activities of substantia nigra pars reticulata (SNpr) as observed in patients with Parkinson's disease. The effects of SKF38393 (a D1 receptor agonist) and Quinpirole (a D2 receptor agonist) were compared in parkinsonian rat models with 6- hydroxydopamine (6-OHDA) after STN lesion. METHODS: SKF38393 and Quinpirole were consecutively injected intrastriatally. SNpr was microrecorded to ascertain the activity of the basal ganglia output structure. The effect of SKF38393 or Quinpirole injection on the firing rate and firing patterns of SNpr was investigated in medial forebrain bundle (MFB) lesioned rats and in MFB+STN lesioned rats. RESULTS: The administration of SKF38393 decreased SNpr neuronal firing rates and the percentage of burst neurons in the MFB lesioned rats, but did not alter them in MFB+STN lesioned rats. The administration of Quinpirole significantly decreased the spontaneous firing rate in the MFB lesioned rats. However, after an additional STN lesion, it increased the percentage of burst neurons. CONCLUSION: This study demonstrated that dopamine agonists and STN lesion decreased the hyperactive firing rate and the percentage of burst neurons of SNpr neurons in 6-OHDA lesioned rats, respectively. Quinpirole with STN lesion increased a percentage of burst neurons. To clear the exact interactive mechanism of D1 and D2 agonist and the corresponding location, it should be followed a study using a nonselective dopamine agonist and D1, D2 selective antagonist.

[Effects of Dopamine administration on anxiety in male rat]

Anxiety is a common disease in the society. Several neurotransmitters. The aim of this study was to investigate indirect effect of dopamine on anxiety in rat. In this experimental study, eight male rats were divided into control and experimental groups. The control group received saline and the tested groups received different IP doses of drugs haloperidol [dopamine receptor antagonist], SKF38393 [dopamineD1 receptor agonist] and quinpirol [dopamine D2receptor agonist]. For studying of anxiety-like and antianxiety effects Vogels conflict test and Elevate plus-maze [EP-M] test were used. Injection of different doses of haloperidol in rats could increase the number of times of passing through place of received shock by apparatus in comparison with control group in Vogels test. In EP-M test, injection of 0.04 mg/kg of haloperidol increased the number of entrance to open arm and time spent on arm comparing to the control group. Quinpirol diminished the number of times of passing through place of receiving shock in comparison with control group in Vogels test. In EP-M test in dose 1 mg/kg number of entrance to open arm and the time spent on arm decreased comparing to the control group. The findings of this study showed that by increasing the doses of haloperidol, the effect of this antagonist has been significant and diminished anxiety. The SKF38393 and Quinpirol by occupying their own dopamine receptor D1, D2 had an effect like endogenous dopamine and made the rats anxious

D2-dopamine receptor and alpha2-adrenoreceptor-mediated analgesic response of quercetin.

Quercetin, a bioflavonoid (100-300 mg/kg) produced dose dependent increase in tail-flick latency, the analgesic effect being sensitive to reversal by naloxone (1 mg/kg). Prior treatment with haloperidol (1 mg/kg), D1/D2 receptor antagonist haloperidol, sulpiride (50 mg/kg), a selective D2 receptor antagonist, yohimbine (5 mg/kg), a alpha2-adrenoreceptor antagonist but not by SCH 23390 a, selective D1 receptor antagonist blocked this response. Apomorphine (1 mg/kg) a mixed D1/D2 dopamine receptor agonist, and quinpirole (0.5 mg/kg), a selective D2 receptor agonist also produced antinociception, that was reversed by haloperidol (1 mg/kg), sulpiride (50 mg/kg), but not by yohimbine (5 mg/kg). The antinociceptive action of quercetin (200 mg/kg) was potentiated by D2 agonist quinpirole (0.2 mg/kg). Dopamine D1 receptor agonist SKF38393 (10 and 15 mg/kg) failed to alter the antinociceptive effect of quercetin (200 mg/kg). Quercetin (200 mg/kg) reversed reserpine (2 mg/kg-4 hr) induced hyperalgesia, which was reversed by sulpiride but not by yohimbine. Thus, a role of dopamine D2 and alpha2-adrenoreceptors is postulated in the antinociceptive action of quercetin.

Effects of D1 and D2 dopamine receptor agonists and antagonists on cerebral ischemia/reperfusion injury / 生理学报

Gerbil forebrain ischemia/reperfusion(I/R) injury model was used to study the effects of D(1) and D(2) receptor agonists and antagonists on neuronal apoptosis of hippocampal CA1 area. All animals were tested for habituation deficits in an open field test on the 1st, 3rd and 7th days after reperfusion. The animals were then killed, and brains underwent paraffin embedding for hematoxylin-eosin staining, in situ terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling (TUNEL) staining and immunohistochemistry (bax, bcl-2). The result of open field test showed that the I/R group was significantly impaired (higher activity scores) when compared with the control group. Pretreatment with pergolide significantly reduced this habituation impairment. Forebrain ischemia for 5 min resulted in extensive CA1 apoptosis on the 3rd and 7th days after I/R injury. About 95% neurons in hippocampal CA1 area entered apoptosis and only 2%-7% pyramidal neurons stayed alive due to an inhibition of bcl-2 expression and an increase in bax expression. Pretreatment of pergolide attenuated neuronal damage caused by transient ischemia. Infusion of pergolide could induce the expression of bcl-2 and reduce the expression of bax. Pretreatment with SKF38393, SCH23390 and spiperone had no effects on these changes in this transient I/R injury model. All these results indicate that pergolide plays an important role in the protection of hippocampal neurons from apotosis through upregulating the expression of bcl-2 protein and reducing the expression of bax protein.

The Effects of Dopamin D-1 Agonist (SKF-38393) on Expression of Substance-P & Enkephalin mRNA in the Striatum of Hemiparkinsonian Rat Model

BACKGROUND: The selective D1 dopamine agonist has been known to play a stimulatory role in substance-P synthesis in the striatum, but its effect on the enkephalin mRNA expression has not been well known in the striatum of unilateral 6-hydroxydopamine(OHDA)-lesioned rat. So we investigated the effect of selective D1 dopaminergic agonist on substance-P, enkephalin mRNA expression in the striatum with different time interval. METHODS: The lesioned rats were divided into two groups (treated and non-treated). Each group was subdivided according to time course after lesioning (2nd, 4th and 8th week). Dopamine 1 receptor agonist, SKF-38393 (5 mg/kg/ip) and the same volume of saline was injected to treated and nontreated group respectively. The levels of enkephalin and substance-P mRNA were determined by in situ-hydridization and the expression of mRNA levels were compared between the groups. RESULTS: The expression of striatal enkephalin mRNA was increased on lesioned side in all groups. Especially, SKF-38393 enhanced the striatal expression of enkephalin mRNA after lesioning 2nd week. After lesioning 4th week and 8th week, the effect of SKF-38393 was not significant. The striatal expression of substance-P mRNAs was significantly decreased on the lesioned side, especially at the 2nd weeks. This decrement of substance-P mRNA was reversed by SKF-38393 at the 2nd week. CONCLUSIONS: These data show that the selective D1 agonist SKF-38393 have an agonistic effect on direct pathway but antagonistic effect on indirect pathway in early course of Parkinsonian rat model.

The Effects of Dopamin D-1 Agonist (SKF-38393) on Expression of Substance-P & Enkephalin mRNA in the Striatum of Hemiparkinsonian Rat Model

BACKGROUND: The selective D1 dopamine agonist has been known to play a stimulatory role in substance-P synthesis in the striatum, but its effect on the enkephalin mRNA expression has not been well known in the striatum of unilateral 6-hydroxydopamine(OHDA)-lesioned rat. So we investigated the effect of selective D1 dopaminergic agonist on substance-P, enkephalin mRNA expression in the striatum with different time interval. METHODS: The lesioned rats were divided into two groups (treated and non-treated). Each group was subdivided according to time course after lesioning (2nd, 4th and 8th week). Dopamine 1 receptor agonist, SKF-38393 (5 mg/kg/ip) and the same volume of saline was injected to treated and nontreated group respectively. The levels of enkephalin and substance-P mRNA were determined by in situ-hydridization and the expression of mRNA levels were compared between the groups. RESULTS: The expression of striatal enkephalin mRNA was increased on lesioned side in all groups. Especially, SKF-38393 enhanced the striatal expression of enkephalin mRNA after lesioning 2nd week. After lesioning 4th week and 8th week, the effect of SKF-38393 was not significant. The striatal expression of substance-P mRNAs was significantly decreased on the lesioned side, especially at the 2nd weeks. This decrement of substance-P mRNA was reversed by SKF-38393 at the 2nd week. CONCLUSIONS: These data show that the selective D1 agonist SKF-38393 have an agonistic effect on direct pathway but antagonistic effect on indirect pathway in early course of Parkinsonian rat model.

Augmentation of Regional Cerebral Blood Flow Response by Repeated Administration of Methamphetamine in Rat / 대한정신약물학회지

OBJECTIVES: It was aimed to observe the regional cerebral blood flow (rCBF) response on methamphetamine challenge test in rats which were subjected to repeated administration of methamphetamine, and to investigate the mechanism(s) of changes in rCBF response in relation to the dopaminergic receptors and cyclic AMP. METHODS: Male Sprague-Dawley rats received daily injections of methamphetamine (0.3 mg/kg, i.p.) for 10 days, and were then allowed a 4-day drug-free period. Naive and methamphetamine-pretreated rats were challenged with topical application of methamphetamine on the surface of parietal cortex through a cranial window. The changes in rCBF were measured by laser-Doppler flowmetry. RESULTS: Acute topical application of methamphetamine dose-dependently increased rCBF with little effect on mean arterial blood pressure. The methamphetamine-induced increases in rCBF were significantly blocked by SCH23390, a D1-like receptor antagonist, but not by sulpiride, a D2-like receptor antagonist. Repeated administration of methamphetamine induced progressive augmentation of rCBF in response to the challenge of methamphetamine. Repeated administration of methamphetamine in combination with SKF38393, a D1-like receptor agonist, as well as with SCH23390 significantly attenuated the development of augmentation of rCBF response to methamphetamine. The augmentation of rCBF response was markedly inhibited by pretreatment with 2',3'-dideoxyadenosine, a specific adenylyl cyclase inhibitor, and Rp-cAMPS, a protein kinase A inhibitor, respectively. CONCLUSION: Based on these results, it is suggested that repeated administration of methamphetamine induces an augmentation of rCBF in response to the challenge of methamphetamine, and that D1-like receptor-mediated cyclic AMP plays a critical role in the development of augmentation of methamphetamine-induced rCBF response.

Differntial effect of NMDA antagonists on D1 & D2 mediated rotation responses in 6- hydroxydopamine (6-OHDA) lesioned rat

BACKGROUND & OBJECTIVES: Glutamate is a major neurotrammitter in corticostriatal, subthalamopallidal, and subthalamonigral pathways and interacts with other neurotrammitters. The study was done to investigate the effects of NMDA blockade on dopaminergic responses. METHODS: We made a unilateral Parkinson model in rats by injecting 6-hydroxydopamine into the substantia nigra. Rotational behavior was observed using apomorphine (mixed Dl/D2 agonist, 0. 5 mg/kg), SKF 38393 (Dl agonist, 1. 5 mg/kg), LY-171555 (D2 agonist, 0. I mg/kg), MK-801 (uncompetitive NMDA blocker, 0. 067 mg/kg), and memantine (non competitive NMDA blocker, 10 mg/kg). RESULTS: Contralateral rotation was induced by apomorphine (total turns for 2 hours, 1160+/-154), SKF 38393 (total turns for 3 hours, 1374+/-400), and LY 171555 (total turns for 3 hours 2316+/-395). NMDA antagonists per se induced mild ipsilateral rotation (MK 801; 587+/-131, memantine; 166+36). Apomorphine induced rotation was potentiated by MK 801 (1683+/-186, p<0.05) and memantine (170+/-264, p<0.05). SKF 38393 induced rotation tended to be potetiated by MK-801 (2451+/-741, p=0.08) and memantine (1794+/-450, p=0.21), though not statistically significant. However, LY 171555 induced rotation was reduced by MK-801 (1153+/-284, p<0.05) ad memantine (22.1+/-42.5, p<0.05). CONCLUSION: NMDA blockers act synergistically with Dl- and antagonistically with D2-mediated behavioural responses, suggesting that glutamate has different interactions with Dl- and D2 pathway.

Dose-response functions of apomorphine, SKF 38393, LY 171555, haloperidol and clonidine on the self-stimulation evoked from lateral hypothalamus and ventral tegmentum.

The experimental animals were implanted with two bipolar electodes, one in the lateral hypothalamus including medial forebrain bundle (LH-MFB) and other in ipsilateral ventral tegmental area-substantia nigra (VTA-SN) and were trained to press a pedal for self-stimulation. This provided the scope to compare directly the effect of a given dose of a drug on the two reward regions in the same animal in the same testing situation. The current intensity was set to produce intracranial self-stimulation (ICSS) response rates of 50% less than the maximal shaping response rates for the respective animals (M60). Following systemic (intraperitoneal) administration of apomorphine (a dopamine receptor D1/D2 mixed agonist), SKF 38393 (D1 > D3 > D2 agonist), LY 17155 or quinpirole (D3 > D2 and D1) agonist), haloperidol (a DA-D2 antagonist), and clonidine (noradrenaline receptor alpha 2 agonist), the ICSS response rates evoked from LH-MFB and VTA-SN were compared with vehicle or saline-treated animals on the basis of dose-response functions. A dose-dependent inhibitory effect at M50 was observed with apomorphine (0.01-1.00 mg/kg) and haloperidol (0.05-0.30 mg/kg) for both the sites of stimulation. These doses of haloperidol did not produce any motor deficits like catalepsy and muscular rigidity. The dose-response and time-effect functions of SKF 38393 and LY 171555 at M50 showed the facilitation and suppression of ICSS of VTA-SN and LH-MFB respectively. Clonidine (0.05-0.25 mg/kg) also produced inhibitory effect on ICSS rates, but this suppression was of different magnitude with respect to the site of stimulation. These doses of clonidine were in the range that did not prevent active pedal pressing responses. ED50 (the dose required to reduce the ICSS response rate 50% of the rate after administration of vehicle) for LY 171555 was 0.8 and 4.4 mg/kg for the ICSS of VTA-SN and LH-MFB respectively and thus statistically different ED50 for apomorphine was 0.27 and 0.36 mg/kg; and for haloperidol was 0.75 and 0.90 mg/kg for LH-MFB and VTA-SN respectively and thus not different significantly. ED50 for clonidine was 0.25 and 0.08 mg/kg for VTA-SN and LH-MFB respectively and thus statistically different. The two-way analysis of variance (ANOVAR) of interaction of dose-response function of alpha 2 agonist with respect to LH-MFB and VTA-SN showed significant independence in their suppressive effects.

Specificity of Dopamine-2 Receptor Agonist on Eyeball Growth in Chicken Model of Myopia

The authors examined the specificity of the dopamine-2 receptor for eyeball growth of the experimental myopic chicken eyes. Two day-old white Leghorn chickens were monocularly deprived of vision by lid suture of the right eyes. We measured the axial lengths of chicken's eyes by ultrasonography at the 2nd day and the 4th weeks. The right eyes of the first group were instillated with 0.04cc of tris buffer solution, those of the second and third group were instillated with 0.04cc of 0.02% SKF38393 hydrochloride solution and 0.02% bromocriptine solution individually. All solutions were instillated into the right eyes two times per day during 4 weeks. At the 2nd day of the age, the axial lengths of the first group's eyeballs were 7.83 +/- 0.14mm in the right, 7.87 +/- 0.15mm in the left eyes, 7.78 +/- 0.16mm in the right eyes, 7.77 +/- 0.11mm in the left eyes of the second group and 7.89 +/- 0.12mm in the right eyes, 7.87 +/- 0.12mm in the left eyes of the third group. Each group was not statistically different (p>0.05). But at the four weeks of the age, the axial lengths of the lid sutured right chicken eyeball were 11.39 +/- 0.27mm in the first group, 11.40 +/- 0.40mm in the second group and 11.20 +/- 0.40mm in the third group, The third group was statistically different from the first or 2nd group (p<0.05). The growth of the axial lengths of the right chicken eyeballs from the 2nd day to the 4th week of the age was 3.50 +/- 0.35mm in the first, 3.63 +/- 0.42mm in the second and 3.21 +/- 0.29mm in the third group. The right eyes of the third group were found significantly less growth than those of other groups. These results suggest that dopamine-2 receptor playa role in eyeball growth.

On the characterization of dopamine-induced contractile response of rat anococcygeus muscle preparation.

Presence of specific dopamine (DA) receptors and their characterization was attempted in rat anococcygeus muscle preparation. Dopamine (10(-6) M) and B-HT 920 (10(-6) M) produced concentration dependent contractions of the rat anococcygeus muscle preparation. The response of DA was shifted towards right in presence of haloperidol (10(-6) M; pA2 = 6.8) and sulpiride (10(-4) M) in a competitive manner. Alpha 2 antagonists yohimbine (10(-5) M) and idazoxan (10(-5) M) blocked the response to DA in a competitive manner, while alpha 1 antagonist prazosin (10(-5) M) completely blocked the response to DA. SCH 23390 (10(-5) M), a D1 DA antagonist potentiated the response to DA. Reserpinization (5 mg/kg, 24 hr prior) brought about a shift towards the right, and this response was similarly blocked by haloperidol, sulpiride and yohimbine without affecting the maximum response. Desipramine (10(-5) M) blocked the response of DA in a non-competitive manner. Pretreatment of animals with desipramine (10 mg/kg) followed by reserpine, brought about a reversal of action of reserpine. The response to B-HT 920 (10(-6) M), was blocked similarly by haloperidol and yohimbine. However, the effect of desipramine was more pronounced when compared to DA per se. SKF 38393, a D1 DA agonist, potentiated the response to B-HT 920. The findings suggest the presence of both D1 and D2 DA receptors in rat anococcygeus muscle and that DA also acts on adrenergic receptors to produce a contractile response of this muscle preparation.

Dopamine receptor mediated antidepressant action of B-HT 920 in mice.

Possible involvement of dopaminergic (DAergic) system in forced swimming-induced immobility (despair behaviour) was investigated in mice. B-HT 920 (0.05 and 0.1 mg/kg), a post-synaptic DAergic agonist, produced a dose dependent reduction in immobility period, which was sensitive to blockade by haloperidol (0.5 mg/kg) and sulpiride (100 mg/kg). This effect was also blocked by alpha 2 antagonist yohimbine (5 mg/kg). SKF 38393 (5 mg/kg), a D1-DA agonist potentiated the action of B-HT 920. Reserpinization (2 mg/kg, 24 hr prior) produced despair immobility in mice. When a low dose of B-HT 920 (0.05 mg/kg) was given to reserpinized animals, the duration of immobility period was further increased. But on the other hand, a higher dose (0.1 mg/kg) of it reduced reserpine-induced immobility. Desipramine (5 and 10 mg/kg), elicited a dose dependent reduction in the immobility period, which was sensitive to blockade by sulpiride (100 mg/kg). Desipramine (10 mg/kg) showed a diphasic response in combination with B-HT 920, i.e., a potentiation of the response due to a low dose of B-HT 920 (0.05 mg/kg) and an antagonism of the response due to a higher dose of B-HT 920 (0.1 mg/kg), respectively. SKF 38393 (5 mg/kg), potentiated the action of desipramine (5 mg/kg). SKF 38393 (5 mg/kg) further potentiated the action of desipramine (5 mg/kg) and B-HT 920 (0.05 mg/kg). These observations suggests that B-HT 920 reduces behavioural immobility by DAergic mechanism and desipramine also modulates D2-DA receptors in its anti-depressant action.

Concomitant D1 dopamine receptor activation (SKF 38393) unmasks D2 dopaminergic actions of B-HT 920 in mice.

The present study attempts to demonstrate D1/D2 dopamine (DA) receptor interactions during stereotyped behaviour in mice. B-HT 920 [2-amino-6-allyl-5, 6, 7, 8-tetrahydro-4H-thiazolo-(4, 5-d)-azepine] (0.05-1.0 mg/kg), a selective D2-DA agonist, induced mild per se stereotypy consisting mainly of sniffing and rearing responses. Apomorphine, a mixed D1/D2 agonist, also produced typical stereotypic response in mice. The stereotypic response of B-HT 920 was blocked by D2-DA antagonist, sulpiride (50 mg/kg). The effect of apomorphine was not influenced by co-treatment with SKF 38393. Simultaneous administration of B-HT 920 (0.1-0.5 mg/kg) with SKF 38393 (5 mg/kg), a selective D1-DA agonist, elicited dramatic increase in stereotyped behaviours in naive as well as in 24 hr reserpinised (2 mg/kg) mice. Co-treatment of apomorphine (0.5 mg/kg) with B-HT 920 (0.1, 0.25 mg/kg) also resulted in a clearly synergistic effect on stereotyped behaviour. These potentiated responses were reduced or blocked by haloperidol, a D2-DA antagonist. The data suggest that in presence of concomitant stimulation of D1-DA receptors. B-HT 920 exhibits full expression of postsynaptic D2-DA receptor mediated behavioural effects.

Anorectic effect of SK & F 38393, a new dopamine agonist in rats.

Anorectics are clinically used in the management of obesity to accept dietary restriction through decreased desire of food intake. The present study, indicates that the drug SK & F 38393 a dopamine agonist given to albino rats at the doses of 1 mg/kg and 5 mg/kg caused decreased food intake. Central side effects observed with amphetamine and other related drugs were not observed with this drug. The drug thus may be used as an anorectic agent without central side effects.