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

Xi, Zheng‐Xiong; Zheng, Yang; Li, Shi‐Jiang; Li, Xia; Dillon, Christopher P.; Peng, Xiao‐Qing; Spiller, Krista; Gardner, Eliot L.

doi:10.1016/j.neuropharm.2007.08.004

Cited by 44 publications

(63 citation statements)

References 36 publications

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“…Previous experiments reported observing sedation at slightly higher doses; however, we attributed the observed differences to changes in the locomotion experimental design (Xi et al, 2007;Xu et al, 2013). Coadministration of L-THP with LDN prevented the reduction of locomotion produced by L-THP alone; yet LDN alone did not alter locomotor behavior at such a low dose, suggesting that LDN coadministration may block the sedative effects of L-THP.…”

Section: Discussionmentioning

confidence: 63%

“…(B) Effect of coadministration of L-THP and LDN. (Xi et al, 2007). The increase in cocaine self-administration is attributed to the partial blockade of postsynaptic DA receptors, which decrease the rewarding properties of cocaine and lead to a compensatory increase in drug-taking.…”

Section: Discussionmentioning

confidence: 99%

“…The cocaine self-administration procedures, surgeries, and training schedules were the same as previously reported (Xi et al, 2007). Animals were prepared for selfadministration experiments by surgical catheterization of right external jugular vein.…”

Section: Methodsmentioning

confidence: 99%

“…Clinically, a pilot study conducted to assess the utility of L-THP for the treatment of heroin addiction determined that 30 mg L-THP given twice daily increased heroin abstinence over 3 months by 63% (Yang et al, 2008). However, L-THP also produces significant sedative effects in a dose-dependent manner (Xi et al, 2007;Xu et al, 2013), which may limit its utility in treatment of drug addiction.…”

Section: Introductionmentioning

confidence: 99%

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Combination of Levo-Tetrahydropalmatine and Low Dose Naltrexone: A Promising Treatment for Prevention of Cocaine Relapse

Sushchyk

Wang

2016

Journal of Pharmacology and Experimental Therapeutics

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Relapse to drug use is often cited as the major obstacle in overcoming a drug addiction. Whereas relapse can occur for a myriad of reasons, it is well established that complex neuroadaptations that occur over the course of addiction are major factors. Cocaine, as a potent dopamine transporter blocker, specifically induces alterations in the dopaminergic as well as other monoaminergic neurotransmissions, which lead to cocaine abuse and dependence. Evidence also suggests that adaptations in the endogenous opioids play important roles in pathophysiology of cocaine addiction. Following this evidence, we investigated a combination medication, levotetrahydropalmatine (L-THP) and low dose naltrexone (LDN), targeting primarily dopaminergic and endogenous opioid systems as a cocaine-relapse-prevention treatment. In the present study Wistar rats were used to assess the effects of L-THP and LDN on cocaine self-administration, drug-seeking behavior during cocaine reinstatement, spontaneous locomotion, and effects on the endogenous opioid system. We determined that the combination of L-THP and LDN reduces drug-seeking behavior during reinstatement more potently than L-THP alone. Additionally, the combination of L-THP and LDN attenuates the sedative locomotor effect induced by L-THP. Furthermore, we revealed that treatment with the combination of L-THP and LDN has an upregulatory effect on both plasma b-endorphin and hypothalamic POMC that was not observed in L-THP-treated groups. These results suggest that the combination of L-THP and LDN has great potential as an effective and well-tolerated medication for cocaine relapse prevention.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combination of Levo-Tetrahydropalmatine and Low Dose Naltrexone: A Promising Treatment for Prevention of Cocaine Relapse

Sushchyk

Wang

2016

Journal of Pharmacology and Experimental Therapeutics

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“…It is an alkaloid, isolated from a Chinese herbal medicine called Corydalis yanhusuo, and has been used in China for 40 year as an analgesic. Primarily a modest dopamine receptor antagonist, L-THP also interacts with several other neurotransmitter receptors, such as the serotonin receptor, 5-hydroxytryptamine (5-HT) [2], the Gamma Amino Butyric Acid (GABA) receptors [3] and the alpha-1 adrenergic receptor [4–6]. The effectiveness of L-THP as a non-opioid analgesic and sedative/anxiolytic agent resulted in the approval of purified L-THP for this indication by the Chinese State Food and Drug Adminisration (SFDA) and has led to extensive investigation of the pharmacological properties of L-THP.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of l-tetrahydropalmatine and cocaine in human plasma by simple UPLC–FLD method: Application in clinical studies

Yu¹,

Hassan²,

Ibrahim³

et al. 2014

Journal of Chromatography B

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Currently, there are no FDA approved medications for treatment of cocaine addiction underscoring the dire need to develop such a product. There is an accumulating body of evidence that L-tetrahydropalmatine (L-THP), a non-selective dopamine antagonist, can be used for the treatment of cocaine addiction. Indeed, the FDA recently approved its usage in a Phase I study in cocaine abusers and it was indispensable to develop a simple and sensitive method for the simultaneous determination of L-THP and cocaine in human plasma. We developed a UPLC-FLD method for quantitation of these molecules using an ACQUITY BEH C18 column (2.1 × 50mm, 1.7um) and a mobile phase that consisted of 5 mM ammonium phosphate (PH=4.75), methanol, and acetonitrile (v:v:v, 78:16:6). Venlafaxine was used as the internal standard while hexane was used for the liquid-liquid extraction. The flow rate was 0.4ml/min with fluorescence detection using an excitation wavelength of 230nm and emission detection wavelength of 315nm. This method was selective, linear and sensitive with a lower limit of quantification of 2.5 ng/mL for both cocaine and L-THP. The intra-day precision of cocaine and L-THP was <9.50% while the accuracy was <4.29%. The inter-day precision of cocaine and L-THP was <9.14%, and the accuracy was <12.49%. The recovery for cocaine and L-THP ranged from (43.95 - 50.02%) and (54.65 - 58.31%), respectively. In comparison to forty reported cocaine quantitation methods this method is simple, sensitive and cost-effective and can be used for simultaneous quantitation of L-THP and cocaine. This method meets the FDA guidelines and can be used in current and future clinical studies.

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Pharmacokinetics and Safety Assessment ofl-Tetrahydropalmatine in Cocaine Users: A Randomized, Double-Blind, Placebo-Controlled Study

Hassan

Kelly

Honick

et al. 2016

The Journal of Clinical Pharmacology

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Cocaine use disorder (CUD) remains a significant public health challenge. Levo-tetrahydropalmatine (L-THP), a well-tolerated and non-addictive compound, shows promise for the management of CUD. Its pharmacologic profile includes blockade at dopamine and other monoamine receptors and attenuation of cocaine self-administration, reinstatement, and rewarding properties in rats. This study evaluated the safety of L-THP in human cocaine users and its influence on the safety and pharmacokinetics (PK) of cocaine. Twenty-four cocaine-using adult men were randomized to receive L-THP (30 mg BID orally) or placebo double-blind for 4 days, with an intranasal cocaine (40 mg) challenge on the fourth day. Safety and tolerability were evaluated using vital signs, EKG, clinical laboratory tests, and standardized self-report instruments. Peripheral venous blood was collected periodically and later assayed for L-THP and cocaine using highly sensitive and specific ultra-performance liquid chromatography-fluorescence detection (UPLC-FLD) methods. Twenty subjects completed the study, of whom 19 provided complete PK data. The short 3.5-day course of L-THP was safe and well tolerated and did not affect cocaine’s PK or its acute cardiovascular effects. The cocaine AUC0→∞ was 211.5 and 261.4 h*ng/ml, and the Cmax was 83.3 and 104.5 ng/ml for the L-THP and placebo groups respectively. In addition there were no significant difference in the number of side effects reported in each group (L-THP group: 22 [48%], Placebo group: 24 [52%]), or vital signs including, heart rate, blood pressure, complete blood count or EKG. These findings suggest that oral THP has promise for further development as a treatment for CUD.

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

Cited by 44 publications

References 36 publications

Combination of Levo-Tetrahydropalmatine and Low Dose Naltrexone: A Promising Treatment for Prevention of Cocaine Relapse

Combination of Levo-Tetrahydropalmatine and Low Dose Naltrexone: A Promising Treatment for Prevention of Cocaine Relapse

Simultaneous determination of l-tetrahydropalmatine and cocaine in human plasma by simple UPLC–FLD method: Application in clinical studies

Pharmacokinetics and Safety Assessment ofl-Tetrahydropalmatine in Cocaine Users: A Randomized, Double-Blind, Placebo-Controlled Study

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