• The Korean Journal of Physiology and Pharmacology
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• v.12 no.1
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• pp.13-23
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• 2008

The aim of the present study was designed to establish comparatively the inhibitory effects of $D_1$-like and $D_2$-like dopaminergic receptor agonists, SKF81297 and R(-)-TNPA on the release of catecholamines (CA) evoked by cholinergic stimulation and membrane depolarization from the isolated perfused model of the rat adrenal medulla. SKF81297 $(30{\mu}M)$ and R-(-)-TNPA $(30{\mu}M)$ perfused into an adrenal vein for 60 min, produced great inhibition in the CA secretory responses evoked by ACh $(5.32{\times}10^{-3}\;M)$, DMPP $(10^{-4}\;M)$, McN-A-343 $(10^{-4}\;M)$, high $K^+$ $(5.6{\times}10^{-2}\;M)$, Bay-K-8644 $(10{\mu}M)$, and cyclopiazonic acid $(10{\mu}M)$, respectively. For the release of CA evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid, the following rank order of inhibitory potency was obtained: SKF81297>R-(-)-TNPA. However, R(+)-SCH23390, a selectve $D_1$-like dopaminergic receptor antagonist, and S(-)-raclopride, a selectve $D_2$-like dopaminergic receptor antagonist, enhanced the CA secretory responses evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid only for $0{\sim}4$ min. The rank order for the enhancement of CA release evoked by high $K^+$, McN-A-343 and cyclopiazonic acid was R(+)-SCH23390>S(-)-raclopride. Also, the rank order for ACh, DMPP and Bay-K-8644 was S(-)-raclopride > R(+)-SCH23390. Taken together, these results demonstrate that both SKF81297 and R-(-)-TNPA inhibit the CA release evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors and the membrane depolarization from the isolated perfused rat adrenal gland without affecting the basal release, respectively, but both R(+)-SCH23390 and S(-)-raclopride facilitate the CA release evoked by them. It seems likely that the inhibitory effects of SKF81297 and R-(-)-TNPA are mediated by the activation of $D_1$-like and $D_2$-like dopaminergic receptors located on the rat adrenomedullary chromaffin cells, respectively, whereas the facilitatory effects of R(+)-SCH23390 and S(-)-raclopride are mediated by the blockade of $D_1$-like and $D_2$-like dopaminergic receptors, respectively: this action is possibly associated with extra- and intracellular calcium mobilization. Based on these results, it is thought that the presence of dopaminergic $D_1$ receptors may play an important role in regulation of the rat adrenomedullary CA secretion, in addition to well-known dopaminergic $D_2$ receptors.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2003.04a
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• pp.21-37
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• 2003

1. Stimulation of dopaminergic system by morphine was abolished in ${\mu}$-opioid receptor knockout mice. 2. Dopaminergic stimulation by opioid agonists, morphine, DPDPE, and U50488, acts independently. 3. Loss of ${\mu}$-opioid receptors is more sensitive to the response of NMDA-induced convulsion and increase in the expression of mRNA for NMDA receptors.

• Archives of Pharmacal Research
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• v.24 no.6
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• pp.613-617
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• 2001

The present study examined the hypothesis that NMDA, AMPA/Kainate, and metabotropic (mGlu) glutamate receptors contribute to a behavioral stimulation induced by activation of dopamine receptors by comparing responses in apomorphine-induced cage climbing behaviors in mice. MK-801, CNQX, and MCPG were served as the NMDA receptor, AMPA/Kainate receptor, and mGlu receptor antagonist, respectively, to elucidate the glutamatergic modulation in apomorphine-induced eopaminergic activation in mice. Drugs were administered intracerebroventricularly (i.c.v.) into the mouse brain 15 min before the apomorphine treatment (2 mg/kg, s.c.). 1.c.v. injection of MK-801 inhibited the apomorphine-induced cage climbing behavior dose-dependently. However, treatments with CNQX and MCPG did not any significant change in apomorphine-induced cage climbing behavior in mice. These results suggest that stimulation of NMDA type of glutamate receptors could contribute to the dopaminergic sti mutation, but not AMPA/Kainate and mGlu type glutamate receptors.

• The Korean Journal of Physiology and Pharmacology
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• v.11 no.5
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• pp.197-206
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• 2007

The aim of the present study was to investigate the effects of 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(SKF81297), a selective agonist of dopaminergic $D_1$ receptor, on the secretion of catecholamines(CA) evoked by cholinergic stimulation and membrane-depolarization in the isolated perfused rat adrenal gland, and also to elucidate the mechanism involved. SKF81297($10{\sim}100{\mu}M$) perfused into an adrenal vein for 60 min produced dose- and time-dependent inhibition of CA secretory responses evoked by ACh(5.32 mM), high $K^+$(56 mM), DMPP($100{\mu}M$) and McN-A-343($100{\mu}M$). Also, in adrenal glands loaded with SKF81297($30{\mu}M$), the CA secretory responses evoked by Bay-K-8644($10{\mu}M$), an activator of L-type $Ca^{2+}$ channels and cyclopiazonic acid($10{\mu}M$), an inhibitor of cytoplasmic $Ca^{2+}$-ATPase were also inhibited. However, in the presence of the dopamine $D_1$ receptor antagonist, (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-benzazepine-7-ol(SCH23390, $3{\mu}M$), which is a selective antagonist of dopaminergic $D_1$ receptor, the inhibitory responses of SKF81297($30{\mu}M$) on the CA secretion evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644, and cyclopiazonic acid were significantly reduced. Collectively, these experimental results suggest that SKF81297 inhibits the CA secretion from the rat adrenal medulla evoked by cholinergic stimulation(both nicotininc and muscarinic receptors) and membrane depolarization. This inhibitory of SKF81297 seems to be mediated by stimulation of dopaminergic $D_1$ receptors located on the rat adrenomedullary chromaffin cells, which are relevant to extra- and intracellular calcium mobilization. Therefore, it is thought that the presence of the dopaminergic $D_1$ receptors may be involved in regulation of CA release in the rat adrenal medulla.

• Journal of Pharmacopuncture
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• v.23 no.1
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• pp.1-7
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• 2020

Nicotine, primary component of tobaco produces craving and withdrawal effect both in humans and animals. Nicotine shows a close resemblance to other addictive drugs in molecular, neuroanatomical and pharmacological, particularly the drugs which enhances the cognitive functions. Nicotine mainly shows its action through specific nicotinic acetylcholine receptors located in brain. It stimulates presynaptic acetylcholine receptors thereby enhancing Ach release and metabolism. Dopaminergic system is also stimulated by it, thus increasing the concentration of dopamine in nuclear accumbens. This property of nicotine according to various researchers is responsible for reinforcing behavioral change and dependence of nicotine. Various researchers have also depicted that some non dopaminergic systems are also involved for rewarding effect of nicotinic withdrawal. Neurological systems such as GABAergic, serotonergic, noradrenergic, and brain stem cholinergic may also be involved to mediate the actions of nicotine. Further, the neurobiological pathway to nicotine dependence might perhaps be appropriate to the attachment of nicotine to nicotinic acetylcholine receptors, peruse by stimulation of dopaminergic system and activation of general pharmacological changes that might be responsible for nicotine addiction. It is also suggested that MAO A and B both are restrained by nicotine. This enzyme helps in degradation dopamine, which is mainly responsible for nicotinic actions and dependence. Various questions remain uninsurable to nicotine mechanism and require more research. Also, various genetic methods united with modern instrumental analysis might result for more authentic information for nicotine addiction.

• Archives of Pharmacal Research
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• v.19 no.1
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• pp.23-29
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• 1996

Changes in dopaminergic activities were investigated after the intracerebroventricular (icv) administration of ethylcholine aziridium (AF64A) in rats. The levels of dopamine (DA) and metabolites, the activities of tyrosine hydroxylase (TH) and monoamine oxidase (MAO), and the specific binding sites of dopamine receptros in striata, hippocampus, and frontal cortex were assessed 6 days after the AF64A treatment with 3 nmol/each ventrcle. In frontal cortex, the levels of DA and metabolities were significantly decreased without changes in metabolites/DA ratios in the AF64A-treated groups. In contrast, the ratios of metabolites/DA were significantly decreased in striatum and hippocampus in the AF64A treatment. The activity of TH in frontal cortex was significantly decreased. However, that in other areas was not changed. Also the activity of MAO-A was not changed in the studied brain regions. However, the activity of MAO-B in striatum was significantly increased with no change in other areas. The specific binding sites of dopamine D1 and D2 receptors were increased in AF64A-treated frontal cortex. However, those were not changed in striatum and hippocampus except the small decreased specific binding sites of dopamine D-1 receptors in striatum after AF64A treatment. These results indicate that the dopaminergic activity was altered in AF64A treatment. Furthermore, it suggest that the decreased dopaminergic activities in each brain regions might be differently affected by AF64A treatment.

• The Korean Journal of Physiology and Pharmacology
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• v.10 no.5
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• pp.273-282
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• 2006

The aim of the present study was to investigate the effects of R-(-)-2,10,11-trihydroxy-N-propylnoraporphine [R-(-)-TNPA], a selective agonist of dopaminergic $D_2$ receptor and S(-)-raclopride, a selective antagonist of dopaminergic $D_2$ receptor, on the secretion of catecholamines (CA) evoked by cholinergic stimulation and membrane-depolarization in the isolated perfused model of the rat adrenal gland, and also to establish its mechanism of action. R-(-)-TNPA $(10{\sim}100\;{\mu}M)$ perfused into an adrenal vein for 60 min produced dose- and time-dependent inhibition in CA secretory responses evoked by ACh (5.32 mM), high $K^+$ (56 mM), DMPP $(100\;{\mu}M)$ and McN-A-343 $(100\;{\mu}M)$. R-(-)-TNPA itself did also fail to affect basal CA output. Also, in adrenal glands loaded with R-(-)-TNPA $(30\;{\mu}M)$, the CA secretory responses evoked by Bay-K-8644 $(10\;{\mu}M)$, an activator of L-type $Ca^2+$ channels and cyclopiazonic acid $(10\;{\mu}M)$, an inhibitor of cytoplasmic $Ca^{2+}-ATPase$ were also inhibited. However, S(-)-raclopride $(1{\sim}10\;{\mu}M)$, given into an adrenal vein for 60 min, enhanced the CA secretory responses evoked by ACh, high $K^+$, DMPP and McN-A-343 only for the first period (4 min), although it alone has weak effect on CA secretion. Moreover, S(-)-raclopride $(3.0\;{\mu}M)$ in to an adrenal vein for 60 min also augmented the CA release evoked by BAY-K-8644 and cyclopiazonic acid only for the first period (4 min). However, after simultaneous perfusion of R-(-)-TNP A $(30\;{\mu}M)$ and S(-)-raclopride $(3.0\;{\mu}M)$, the inhibitory responses of R(-)-TNPA $(30\;{\mu}M)$ on the CA secretion evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644, and cyclopiazonic acid were significantly reduced. Taken together, these experimental results suggest that R-(-)-TNPA greatly inhibits the CA secretion from the perfused rat adrenal medulla evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) and membrane depolarization, but S(-)-raclopride rather enhances the CA release by them. It seems that this inhibitory of R-(-)-TNPA may be mediated by stimulation of inhibitory dopaminergic $D_2$ receptors located on the rat adrenomedullary chromaffin cells, while the facilitatory effect of S(-)-raclopride is due to the blockade of dopaminergic $D_2$ receptors, which are relevant to extra- and intracellular calcium mobilization. Therefore, it is thought that dopaminergic $D_2$ receptors may be involved in regulation of CA release in the rat adrenal medulla.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.247-247
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• 1996

Previous work in our laboratory has shown that noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced inhibition of apomorphine-induced cage climbing behavior in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine (DA) receptors: Therefore, in order to definitively establish the involvement of NMDA receptor in the apomorphine-induced dopaminergic response at the postsynaptic DA receptor, it is necessary to investigate whether or not the noncompetitive NMDA receptor antagonists would inhibit these phenomena not only in intact mice but also in the mice that are devoid of any involvement of indirect dopaminergic function. To minimize the risk of any indirect involvement of NMDA antagonists with DA neurons, vesicular DA stores were first depleted with reserpine.

• Journal of Microbiology and Biotechnology
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• v.33 no.10
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• pp.1268-1280
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• 2023

Echinacoside (ECH) is a naturally occurring phenylethanoid glycoside, isolated from Echinacea angustifolia, and this study aimed to analyze its effect on thermogenesis and its interaction with dopaminergic receptors 1 and 5 (DRD1 and DRD5) in 3T3-L1 white adipocytes and mice models. We employed RT-PCR, immunoblot, immunofluorescence, a staining method, and an assay kit to determine its impact. ECH showed a substantial increase in browning signals in vitro and a decrease in adipogenic signals in vivo. Additionally, analysis of the iWAT showed that the key genes involved in beiging, mitochondrial biogenesis, and ATP-dependent thermogenesis were upregulated while adipogenesis and lipogenesis genes were downregulated. OXPHOS complexes, Ca²⁺ signaling proteins as well as intracellular Ca²⁺ levelswere also upregulated in 3T3-L1 adipocytes following ECH treatment. This was collectively explained by mechanistic studies which showed that ECH mediated the beiging process via the DRD1/5-cAMP-PKA and subsequent downstream molecules, whereas it co-mediated the α1-AR-signaling thermogenesis via the DRD1/5/SERCA2b/RyR2/CKmt pathway in 3T3-L1 adipocytes. Animal experiments revealed that there was a 12.28% reduction in body weight gain after the ECH treatment for six weeks. The effects of ECH treatment on adipose tissue can offer more insights into the treatment of obesity and metabolic syndrome.

• Archives of Pharmacal Research
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• v.17 no.6
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• pp.398-404
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• 1994

The behavioral response, depamine metabolism, and characteristics of dopamine subtypes after developing the hyperlycemia were studied in the striata of rats. In animals developed hyperglycemia, the on-set duration of cataleptic behavior responded to SCH 23390 injection was delayed abd shortened, respectively. However, the cataleptic response to spiperone occurred significantly earlier in on-set and prolonged in duration. Dopamine metabolites, dihydroxyphenylacetic acid (DDPAC) and homovanillic acid (HVA), were significantly reduced in teh striata of hyeprglycemic rats. However, level of DA was significantly increased. It is noted that the ratios of DOPAC and HVA to DA were decreased, suggesting decreased tumover of DA. The affinity of striatal D-1 receptors was significantly increased without changes in the number of binding sites, while the maximum binding number of D-2 recptors was significantly increased without affecting its affinity in the diabetic rats. These results indicate that the dopaminergic activity in striatia was altered in hyperglycemic rats. Furthermore, it suggests that the upregulation of dopamine receptors might be due to the decreased dopamine matabolism.