• The Korean Journal of Physiology and Pharmacology
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• 제13권3호
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• pp.147-151
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• 2009

Repeated psychostimulants induce electroencephalographic (EEG) changes, which reflect adaptation of the neural substrate related to dopaminergic pathways. To study the role of dopamine receptors in EEG changes, we examined the effect of apomorphine, the dopamine D1 receptor antagonist, SCH-23390, and the D2 receptor antagonist, haloperidol, on EEG in rats. For single and repeated apomorphine treatment groups, the rats received saline or apomorphine for 4 days followed by a 3-day withdrawal period and then apomorphine (2.5 mg/kg, i.p.) challenge after pretreatment with saline, SCH-23390, or haloperidol on the day of the experiment. EEGs from the frontal and parietal cortices were recorded. On the frontal cortex, apomorphine decreased the power of all the frequency bands in the single treatment group, and increased the theta (4.5 ${\sim}$ 8 Hz) and alpha (8 ${\sim}$ 13 Hz) powers in the repeated treatment group. Changes in both groups were reversed to the control values by SCH-23390. On the parietal cortex, single apomorphine treatment decreased the power of some frequency bands, which were reversed by haloperidol but not by SCH-23390. Repeated apomorphine treatment did not produce significant changes in the power profile. These results show that adaptation of dopamine pathways by repeated apomorphine treatment could be identified with EEG changes such as increases in theta and alpha power of the frontal cortex, and this adaptation may occur through changes in the D1 receptor and/or the D2 receptor.

• 약학회지
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• 제45권2호
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• pp.205-213
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• 2001

The dopaminergic receptors were consisted of two distinct subtypes, $D_1$and $D_2$, each having different function. The present study was attempted to investigate the effects of R(-)-2,10,11-trihydroxy-N-n-propylnoraporphine (TNPA), a dopamine $D_2$receptor agonist, on renal function in dog. TNPA (5.0~15.0 $\mu$g/kg), when given into the vein, produced a dose-dependently antidiuresis along with the decrease in osmolar clearance ( $C_{osm}$) and urinary excretion of sodium and potassium ( $E_{Na}$ , and $E_{K}$). It also increased reabsorption rates of sodium and potassium in renal tubules ( $R_{Na}$ , $R_{K}$) without any changes in glomerular filtration rate (GFR), renal plasma flow (RPF) and free water clearance ( $C_{H2o}$). TNPA (0.5~1.5 $\mu$g/kg/min) infused into a renal artery decreased urine flow both in the experimental and the control kidneys. TNPA (1.5~5.0 $\mu$g/kg) administered via the carotid artery also greatly exhibited antidiuresis even at intravenously ineffective doses. Changes of renal function by TNPA given into both the renal artery and the carotid artery were almost the same aspect to those induced by intravenous TNPA. These results obtained from the present study suggest that TNPA produces antidiuresis by increasing the reabsorption rates of electrolytes in renal tubules, mainly distal tubule, through changing of central function.unction.

• The Korean Journal of Physiology and Pharmacology
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• 제5권4호
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• pp.299-305
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• 2001

Activation of D1-like dopamine receptors by psychostimulants, such as amphetamine, upregulates the expression of immediate early gene and opioid peptide gene in the striatum. The genomic changes are regulated by phosphorylated transcription factors via complicated intracellular events. To evaluate temporal expression of the transcription factors by dopaminergic stimulation, the D1-like dopamine agonist, amphetamine or SKF82958, was systematically delivered. As intracellular markers in response to the agonist, phosphorylated cAMP response element-binding protein (pCREB), Fos-related antigens (FRA) and FosB immunoreactivity (IR) was compared at 20 and 120 min time points in the selected areas of the striatum. Semi-quantitative immunocytochemistry showed that amphetamine (5 mg/kg, i.p.) significantly increased pCREB-IR at 20 min, sustained up to 60 min and decreased at 120 min after the infusion. Like amphetamine, the full D1 agonist, SKF82958 (0.5 mg/kg, s.c.), also increased pCREB-IR at 20 min, but not at 120 min after the infusion in the dorsal striatum (caudoputaman, CPu) and shell of ventral striatum (nucleus accumbens, NAc). In contrast, FRA- and FosB-IR induced by SKF82958 was significantly increased at 120 min, but not at 20 min after the administration. These data indicate that SKF82958 mimics induction of CREB phosphorylation by amphetamine and differentially regulates temporal induction of pCREB, and FRA and FosB expression in the striatum.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.215-215
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• 1996

The present study examined chronic effects of transient focal cerebral ischemia on the substantia nigra, a remote exofocal area, using immunohistochenmical and receptor autoradiographic techniques. Transient focal cerebral ischemia was induced by middle cerebral artery (MCA) occlusion for 60 or 90 min followed by reperfusion using silicone-coated 4-0 nylon monofilament in male Wistar rats. After 1- or 2-week reperfusion following transient MCA occlusion, there were partial losses of tyrosine hydroxylase-immunoreactive dopaminergic neurons, incieases in glial fibrillary acidic protein-immunoreactive cells (gliosis), decreases in [$^3$H]YM-09151-2 binding for dopamine D$_2$ receptors, and marked atrophy in the ipsilateral substantia nigra. The precise mechanism(s) of exofocal damage to the substantia nigra is remained to be elucidated.

• 생물정신의학
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• 제4권2호
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• pp.198-210
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• 1997

To examine the double-faced thymoleptic(antidepressant and antimanic) effects of risperidone in mood disorders, this article reviews the psychotropic-induced mania, thymoleptic effects of antipsychotics, therapeutic effects of risperidone and risperidone(RIS)-induced mania(RIM) in mood disorders, risk factors of RIM, possible neurochemical mechanism of these thymoleptic effects, pathophysiological and clinical significance of thymoleptic effects, and suggestive clinical guideline of RIS in mood disorders. RIS appeared effective for bipolar disorder at a lower dose than that recommended for schizophrenia, especially in the cases of maintenance of mood stabilizers, and gradual titration from low doses. Manic induction/exacerbation can occur by chance during RIS treatment in mood disorders, schizoaffective disorders, and schizophrenias. The possible risk factors for RIM are refractory mood disorder, especially in bipolar I disorder with poor initial response ; refractory schizoaffective disorders, especially in bipolar type with poor initial response ; refractory chronic schizophrenias, especially with initial responses ; psychotic features ; higher initial doses ; rapid titration ; combined therapy with antidepressants in refractory depression ; and RIS monotherapy in mania/hypomania. RIS is a drug that preferentially block 5-HT2 receptors. The effects of low dose are due mainly to the blockade of 5-HT2 receptors. There are more gradual increase in D2 blockade with increasing dose and this D2 blocking properties become apparent at higher doses. This may be related to a modulation of dopaminergic transmission by 5-HT2 antagonism at lower doses with the direct action of RIS on DA receptors coming into play at higher dose. The serotonergic antagonistic effect may be important for its effects on depressive symptoms. This, together with adequate blo-ckade of D2 receptors, may not necessarily lead to destabilization of mood disorder, but rather to more therapeutic effects. Therefore, this dose-receptor affinity relationship with both antidepressant and antimanic effects according to treatment duration can explain a continuum of antidepressant effect, antimanic effect, behavioral stimulation, and manic/hypomanic induction/exacerbation. It was the recognition of a useful psychiatric side effects by a thoughtful observer with fertile minds that led to their ultimate utilization as psychotropic drugs, i.e., phenothiazine, MAOI, TCA, and lithium. And, in vivo pharmacological challenge by novel psychotropics, as a neurochemical probe, with more specific actions is a useful tool to select pharmacologically homogeneous subgroup of the same phenotypical(clinical) condition, to further study the unknown underlying pathogenesis of various mental illnesses. Finally, RIS may be a useful alternative or adjunctive drug for patients with mood disorders without psychotic features or refractory to treatment with standard antipsychotic drugs. The more conservative doses(tirated slowly from 1-3 mg/d) of RIS, and maintenance of mood stabilizer in the cases with risk factors of RIM are recommended in mood disorder.

• The Korean Journal of Physiology and Pharmacology
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• 제9권5호
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• pp.263-268
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• 2005

Striatum has important roles in motor control, habitual learning and memory. It receives glutamatergic inputs from neocortex and thalamus, and dopaminergic inputs from substantia nigra. We examined effects of dopamine (DA) on the corticostriatal synaptic transmission using in vitro extracellular recording technique in rat brain corticostriatal slices. Synaptic responses were elicited by stimulation of cortical glutamatergic inputs on the corpus callosum and recorded in the dorsal striatum. Corticostriatal population spike (PS) amplitudes were decreased ($39.4{\pm}7.9$%) by the application of $100{\mu}M$ DA. We applied receptor subtype specific agonists and antagonists and characterized the modulation of corticostriatal synaptic transmission by different DA receptor subtypes. $D_2$ receptor agonist (quinpirole), antagonist (sulpiride), and $D_1$ receptor antagonist (SKF 83566), but not $D_1$ receptor agonist (SKF 38393), induced significantly the reduction of striatal PS. Pretreatment neither with SKF 83566 nor sulpiride significantly affected corticostriatal synaptic inhibition by DA. However, the inhibition of DA was completely blocked by pretreatment with mixed solution of both SKF 83566 and sulpiride. These results suggest that DA inhibits corticostriatal synaptic transmission through both $D_1$ and $D_2$ receptors in concert with each other.

• 생물정신의학
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• 제3권2호
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• pp.240-244
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• 1996

흰쥐에 항정신병약물인 haloperidol을 장기간 투여한 뒤 줄무늬체와 후결절 조직에서의 DA $D_2$양 수용체의 변동에 대해 조사하였다. 약물투여군 4군에게 haloperidol을 각기 0.05, 0.15, 0.5, 1.5mg/kg/day이 되게끔 4주간 투여하였다. DA수용체의 변동은 [$^3H$]spiperone을 이용한 결합반응법을 통해 알아 보았다. 정상대조군에 비해 4주 동안 haloperidol을 투여받은 군 모두에서 줄무늬체에서의 DA 수용체의 최대 결합치가 증가한 것으로 나타났다. 기존의 연구에서 사용한 용량보다 대단히 낮은 0.05mg/kg/day을 투여받은 군 역시 유의한 증가를 보여 낮은 용량의 haloperidol이 DA계에 영향을 미치는 것을 알 수 있었다. 후결절조직의 최대결합치는 haloperidol투여군 모두에서 증가한 경향을 볼 수 있었으나 정상대조군에 비해 1.5mg/kg/day투여군에서 유의한 증가를 볼 수 있었다. 본 실혐의 결과로 미루어 낮은 용량의 haloperidol을 장기간 투여했을 때 뇌내 DA계에 수용체증식이 나타나며 항정신병 효과의 발현과도 관련성이 시사된다. 이러한 결과는 최근 거론되고 있는 항정신병약물의 저용량투여를 간접적으로 지지하는 것으로 생각되며 DA계의 연동을 알리는 다른 생물학적 지표와의 관련성을 살피면 흥미로운 결과를 얻을 것으로 기대된다.

• The Korean Journal of Pain
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• 제37권1호
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• pp.26-33
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• 2024

Background: Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity. Methods: Male Swiss mice (25-30 g) and male Wistar rats (180-220 g) were used for formalin and carrageenan tests, respectively. In the formalin test, paw licking time and in the carrageenan test, paw thickness were considered as indexes of pain behavior and inflammation respectively. Three doses of sitagliptin (2.5, 5, and 10 mg/kg) were used in these tests. Also, several antagonists and enzyme inhibitors were used to evaluate the role of adrenergic, serotonergic, dopaminergic, and opioid receptors as well as the NO/cGMP/K_ATP pathway in the antinociceptive effect of sitagliptin (5 mg/kg). Results: Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly (P < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT₂) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect. Conclusions: NO/cGMP/K_ATP, 5HT₃ and D₂ pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test.

• 대한약리학회지
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• 제21권1호
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• pp.49-61
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• 1985

가토 측뇌실내로 dopamine을 투여하면 항이뇨를 일으키고, 도파민 길항제 haloperidol은 소량에서는 항이뇨를, 대량에서는 이뇨와 Na 배설증가를 초래한다는 보고에 비추어, 본 연구에서는 중추를 통한 신장기능 조절에 관여하는 도파민 수용체의 역할을 구명코자, D-2 receptor agonist이고 D-1 antagonist인 bromocriptine(BRC)의 작용을 검토하였다. 측뇌실내로 BRC를 투여하면 20-600 ${\mu}g/kg$의 범위안에서 대략 용량에 비례하여 natriuresis와 이뇨가 나타났으나, 신혈류와 사구체 여과율은 증량에 따라 점차 감소하였다. 따라서 이뇨 및 Na 배설증가는 신세뇨관에서의 Na재흡수 감소에 의한 것임을 알수 있었다. 이러한 Na 배설증가는 $200{\mu}g/kg$에서 가장 현저하여 Na 배설분획은 약 10%에 달하였다. 그러나 $600{\mu}g/kg$ 에서는 일시적인 현저한 혈압상승에 따르는 급격한 감소로 인하여 일시적 폐뇨가 선행한 다음 이뇨 작용이 나타났다. BRC의 정맥내 투여시에는 전신혈압 하강에 따르는 신혈류역학의 감소와 아울러 항이뇨가 나타났으며, 이는 측피실내로 투여한 BRC의 작용은 전신순환내로 유입되어 초래될 수도 있는 직접신장작용에 기인한것이 아니고 중추를 통한 것임을 시사하였다. Dopamine 150 ${\mu}g/kg$을 측뇌실내로 투여한 후에도 BRC 200 ${\mu}g/kg$은 작용을 나타낼 수 있으나, dopamine 500 ${\mu}g/kg$에 의해서는 BRC의 작용이 소실 되었다. 24 시간전에 1 mg/kg의 reserpine으로 처리한 가토에서는 200 ${\mu}g/kg$ BRC의 작용이 오히려 더 빠르고 강화되었다. 일측신장 신경을 제거한 표본에서는, BRC투여로 대조신은 항이뇨를 나타냈으나 실험신(탈신경측)은 심한 이뇨와 Na배설 증가를 일으켰다. 이상의 실험결과는, 측뇌실내 BRC는 natriuretic factor를 유리시킴과 동시에 교감신경 긴장도를 증가시키는 것을 시사하였으며, 또한 가토 신장기능의 중추 도파민계를 통한 조절에 있어서 여러 도파민 수용체가 각각 다른 기능을 하고 있음을 시사하였다.

• Journal of Pharmaceutical Investigation
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• 제32권2호
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• pp.127-133
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• 2002

Levosulpiride is the 1evo-enantiomer form of racemic sulpiride, a benzamide derivative selectively inhibiting dopaminergic $D_2$ receptors at the trigger zone both in the central nervous system and in the gastrointestinal tract. The purpose of the present study was to evaluate the bioequiva1ence of two levosulpiride tablets, Levopride (SK Pharmaceutical Co., Ltd.) and Levopid (Dae Won Pharmaceutical Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). The levosulpiride release from the two levosulpiride tablets in vitro was tested using KP VII Apparatus II method with various different kinds of dissolution media (pH 1.2, 4.0, 6.8 buffer solution and water). Twenty eight normal male volunteers, $23.82{\pm}3.26$ years in age and $69.13{\pm}8.58$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 25 mg of levosulpiride was orally administered, blood was taken at predetermined time intervals and the concentrations of levosulpiride in serum were determined using HPLC method with fluorescence detector. The dissolution profiles of two levosulpiride tablets were very similar at all dissolution media. Besides, the pharmacokinetic parameters such as $AUC_t,\;C_{max}\;and\;T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters using logarithmically transformed $AUC_t\;and\;C_{max}$ and untransformed $T_{max}$. The results showed that the differences in $AUC_t,\;C_{max}\;and\;T_{max}$ between two tablets based on the Levopride were -1.17%, 1.20% and -1.09%, respectively. There were no sequence effects between two tablets in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log(0.8) to log(1.25) $(e.g.,\;log(0.93){\sim}log(1.07)\;and\;log(0.90){\sim}log(1.14)\;for\;AUC_t\;and\;C_{max}$, respectively). The 90% confidence interval using untransformed data was within ${\pm}20%$ $(e.g.,\;-19.47{\sim}16.20\;for\;T_{max})$. All parameters met the criteria of KFDA guideline for bioequivalence, indicating that Levopid tablet is bioequivalent to Levopride tablet.