(−)-Stepholidine: a potential novel antipsychotic drug with dual D1 receptor agonist and D2 receptor antagonist actions

Jin, Guo-Zhang; Zhu, Zhang; Fu, Yu

doi:10.1016/s0165-6147(00)01929-5

Cited by 83 publications

(84 citation statements)

References 15 publications

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“…In addition, it also lowered BSR Ymax levels, suggesting that at 10 mg/kg, l-THP does produce sedation, locomotor inhibition and aversive effects in experimental animals, as reported previously (Jin, 1987;Jin et al, 2002;Mantsch et al, 2007). However, the same high dose (10 mg/kg) of l-THP increased cocaine selfadministration under FR reinforcement, suggesting that the reduction in PR cocaine selfadministration and cocaine-enhanced BSR is unlikely due to sedation or locomotor inhibition.…”

Section: Discussionsupporting

confidence: 81%

“…Stephanie (Jin, 1987;Jin et al, 2002). l-THP, as a traditional sedative-analgesic agent, has been used for more than 40 years in China for the treatment of chronic pain and anxious insomnia (Jin, 1987;Jin et al, 2002).…”

Section: Levo-tetrahydropalmatine (L-thp) Is a Purified Active Ingredmentioning

confidence: 99%

“…l-THP, as a traditional sedative-analgesic agent, has been used for more than 40 years in China for the treatment of chronic pain and anxious insomnia (Jin, 1987;Jin et al, 2002). Recent studies have demonstrated that l-THP is a non-selective D 1 and D 2 (and possibly D 3 ) receptor antagonist (Jin et al, 1986;Xu et al, 1989;Guo et al, 1997;Mantsch et al, 2007).…”

Section: Levo-tetrahydropalmatine (L-thp) Is a Purified Active Ingredmentioning

confidence: 99%

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Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: Experiments with self-administration and brain-stimulation reward in rats

Zheng

et al. 2007

Neuropharmacology

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It was recently reported that levo-tetrahydropalmatine (l-THP), a dopamine (DA) D 1 and D 2 receptor antagonist purified from the Chinese herb Stephanie, appears to be effective in attenuating cocaine self-administration, cocaine-triggered reinstatement and cocaine-induced conditioned place preference in preclinical animal models. The present study was designed to contrast l-THP's effects on cocaine self-administration under fixed-ratio (FR) and progressive-ratio (PR) reinforcement, and to study l-THP's effects on cocaine-enhanced brain stimulation reward (BSR). Systemic administration of l-THP produced dose-dependent, biphasic effects, i.e., low-to-moderate doses (1, 3, 10 mg/kg) increased, while a high dose (20 mg/kg) inhibited cocaine self-administration behavior under FR2 reinforcement. The increased cocaine self-administration is likely a compensatory response to a reduction in cocaine's rewarding effects, because the same low doses of l-THP dosedependently attenuated cocaine self-administration under PR reinforcement and also attenuated cocaine-enhanced BSR. These attenuations of PR cocaine self-administration and cocaine-enhanced BSR are unlikely due to l-THP-induced sedation or locomotor inhibition, because only 10 mg/kg, but not 1-3 mg/kg of l-THP inhibited locomotion, sucrose self-administration and asymptotic operant performance in the BSR paradigm. In vivo microdialysis demonstrated that l-THP slightly elevates extracellular nucleus accumbens DA by itself, but dose-dependently potentiates cocaine-augmented DA, suggesting that a postsynaptic, rather than presynaptic, DA receptor antagonism underlies l-THP's actions on cocaine reward. Together, the present data, combined with previous findings, support the potential use of l-THP for treatment of cocaine addiction.

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Section: Discussionsupporting

confidence: 81%

Section: Levo-tetrahydropalmatine (L-thp) Is a Purified Active Ingredmentioning

confidence: 99%

Section: Levo-tetrahydropalmatine (L-thp) Is a Purified Active Ingredmentioning

confidence: 99%

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Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: Experiments with self-administration and brain-stimulation reward in rats

Zheng

et al. 2007

Neuropharmacology

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“…2A), indicating that the double-labeled vesicles were internalized. However, under the same experimental conditions, l-stepholidine (100 nmol/L, 40 min), which possesses D1 agoinst/D2 antagonist dual actions [14] , failed to induce the redistribution of D1R-YFP (data not shown).…”

mentioning

confidence: 78%

神经细胞中多巴胺d1和d5受体不同亚细胞分布和胞内转运的特性

Jin

2009

Neurosci. Bull.

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Objective To explore the possible differential trafficking properties of the dopamine D1-like receptor subtypes, D1 receptor and D5 receptor. Methods 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. Results 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. Conclusion 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.

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“…Subsequent studies show that SPD binds directly to D1-like receptors (Ki ¼ 13 nM, Xu et al, 1989) and acts as a partial D1 agonist (Dong et al, 1997;Zou et al, 1997; see also reviews by Jin et al, 1987Jin et al, , 2002. Results also show that SPD binds to D2-like receptors as well (Ki ¼ 85 nM) and acts as a full D2 antagonist (Dong et al, 1997;Zou et al, 1997; see also reviews by Jin et al, 1987Jin et al, , 2002. To our knowledge, SPD is the first compound known to have mixed D1 agonist/D2 antagonist properties.…”

Section: Introductionmentioning

confidence: 99%

Effects of l-Stepholidine on Forebrain Fos Expression: Comparison with Clozapine and Haloperidol

Jin

Chen

et al. 2004

Neuropsychopharmacol

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l-Stepholidine (SPD) is a tetrahydroprotoberberine alkaloid and a mixed dopamine D1 agonist/D2 antagonist. Preliminary clinical trials suggest that SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. Here, we report that SPD mimics the effect of the atypical antipsychotic drug clozapine, preferentially increasing Fos expression in corticolimbic areas. Thus, at 10 mg/kg (i.p.), SPD induced Fos expression in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral septal nucleus (LSN) without significantly affecting the dorsolateral striatum (DLSt). At higher doses (20-40 mg/kg), SPD also increased Fos expression in the DLSt. The increase, however, was less pronounced than the increase seen in the NAc. Within the NAc, SPD also induced more Fos expression in the shell than in the core. In all subcortical areas examined, the Fos expression induced by SPD was mimicked by the D2 antagonist sulpiride and reversed by the D2 agonist quinpirole, suggesting that the effect is due to blockade of D2-like receptors by SPD. In the mPFC, however, the effect was not mimicked by sulpride or reversed by quinpirole. It was also not mimicked by the D1 agonist SKF38393 or SKF38393 plus sulpride, and not reversed by the D1 antagonist SCH23390. These results suggest that, in the mPFC, SPD may induce Fos expression through a non-DA mechanism. Whether the mechanism involves an interaction of SPD with other neurotransmitters such as 5-HT and norepinephrine remains to be determined.

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(−)-Stepholidine: a potential novel antipsychotic drug with dual D1 receptor agonist and D2 receptor antagonist actions

Cited by 83 publications

References 15 publications

Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: Experiments with self-administration and brain-stimulation reward in rats

Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: Experiments with self-administration and brain-stimulation reward in rats

神经细胞中多巴胺d1和d5受体不同亚细胞分布和胞内转运的特性

Effects of l-Stepholidine on Forebrain Fos Expression: Comparison with Clozapine and Haloperidol

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