(-)-Stepholidine Reduces Cue-induced Reinstatement of Cocaine Seeking and Cocaine Self-administration in Rats

Overview

Journal Drug Alcohol Depend

Publisher Elsevier

Specialty Psychiatry

Date 2018 Jun 8

PMID 29879681

Citations 8

Authors

M Manuszak

W Harding

S Gadhiya

R Ranaldi

Affiliations

Soon will be listed here.

Abstract

Background: Dopamine receptors are implicated in cocaine reward and seeking. We hypothesize that (-)-stepholidine, a dopamine D1/D2/D3 multi-receptor agent, would be effective in reducing cocaine reward and seeking in an animal model. We investigated the effects of (-)-stepholidine in cue-induced reinstatement of cocaine seeking and cocaine self-administration (reward).

Methods: Cue-induced reinstatement experiment: Rats were trained to press a lever reinforced by cocaine (1 mg/kg/injection) for 15 consecutive daily sessions, after which the response was extinguished by withholding cocaine and cocaine-paired cues (light and pump activation). This was followed by a cue-induced reinstatement test where subjects were exposed to two cocaine cue presentations and presses on the active lever produced cues. Subjects were treated with one of four (-)-stepholidine doses prior to the reinstatement test. Cocaine self-administration (reward) experiment: Rats were trained to self-administer cocaine under a progressive ratio schedule of reinforcement. After stable breakpoints were established, rats were injected with four doses of (-)-stepholidine prior to testing; each dose was injected prior to a separate test session with no-treatment sessions intervening to re-establish break points.

Results: (-)-Stepholidine significantly reduced cue-induced reinstatement of cocaine seeking in a dose-related manner. Additionally, (-)-stepholidine significantly reduced break points for cocaine reward. (-)-Stepholidine did not significantly affect locomotor activity.

Conclusions: (-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine reward, suggesting that it may be useful in treating relapse in cocaine addiction.

Citing Articles

Natural Product-Inspired Dopamine Receptor Ligands.

Dorogan M, Namballa H, Harding W J Med Chem. 2024; 67(15):12463-12484.

PMID: 39038276 PMC: 11320586. DOI: 10.1021/acs.jmedchem.4c00537.

First synthesis of thiazepino[3,4-a]isoquinolines, a facile new synthetic route to diazepino[3,4-a]isoquinolines and assessment of their dopamine and σ receptor affinities.

Cordone P, Namballa H, Harding W J Heterocycl Chem. 2021; 57(10):3709-3713.

PMID: 34565832 PMC: 8460126. DOI: 10.1002/jhet.4086.

Low-dose polypharmacology targeting dopamine D1 and D3 receptors reduces cue-induced relapse to heroin seeking in rats.

Ewing S, Dorcely C, Maidi R, Paker G, Schelbaum E, Ranaldi R Addict Biol. 2021; 26(4):e12988.

PMID: 33496050 PMC: 8225548. DOI: 10.1111/adb.12988.

(-)-Stepholidine blocks expression, but not development, of cocaine conditioned place preference in rats.

Bennett A, Barrera E, Namballa H, Harding W, Ranaldi R Neurosci Lett. 2020; 734:135151.

PMID: 32531529 PMC: 7368993. DOI: 10.1016/j.neulet.2020.135151.

A critical review: traditional uses, phytochemistry, pharmacology and toxicology of S. Moore (Fen Fang Ji).

Jiang Y, Liu M, Liu H, Liu S Phytochem Rev. 2020; 19(2):449-489.

PMID: 32336965 PMC: 7180683. DOI: 10.1007/s11101-020-09673-w.

References

Galaj E, Ananthan S, Saliba M, Ranaldi R . The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats. Psychopharmacology (Berl). 2013; 231(3):501-10. DOI: 10.1007/s00213-013-3254-y. View

Fiorentini C, Busi C, Gorruso E, Gotti C, Spano P, Missale C . Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization. Mol Pharmacol. 2008; 74(1):59-69. DOI: 10.1124/mol.107.043885. View

Gadhiya S, Hu C, Harding W . An alternative synthesis and x-ray crystallographic confirmation of (-)-stepholidine. Tetrahedron Lett. 2016; 57(19):2090-2092. PMC: 4852479. DOI: 10.1016/j.tetlet.2016.03.108. View

Tiffany S . A cognitive model of drug urges and drug-use behavior: role of automatic and nonautomatic processes. Psychol Rev. 1990; 97(2):147-68. DOI: 10.1037/0033-295x.97.2.147. View

Wang J, Mantsch J . l-tetrahydropalamatine: a potential new medication for the treatment of cocaine addiction. Future Med Chem. 2012; 4(2):177-86. PMC: 3878639. DOI: 10.4155/fmc.11.166. View

Galaj E, Harding W, Ranaldi R . Dopamine D1 and D3 receptor interactions in cocaine reward and seeking in rats. Psychopharmacology (Berl). 2016; 233(23-24):3881-3890. DOI: 10.1007/s00213-016-4420-9. View

Nichols A, Ruffolo Jr R, Brooks D . The pharmacology of fenoldopam. Am J Hypertens. 1990; 3(6 Pt 2):116S-119S. DOI: 10.1093/ajh/3.6.116s. View

Xu W, Wang Y, Ma Z, Chiu Y, Huang P, Rasakham K . L-isocorypalmine reduces behavioral sensitization and rewarding effects of cocaine in mice by acting on dopamine receptors. Drug Alcohol Depend. 2013; 133(2):693-703. PMC: 3954112. DOI: 10.1016/j.drugalcdep.2013.08.021. View

Xi Z, Yang Z, Li S, Li X, Dillon C, Peng X . Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats. Neuropharmacology. 2007; 53(6):771-82. PMC: 2965413. DOI: 10.1016/j.neuropharm.2007.08.004. View

10.

Mantsch J, Li S, Risinger R, Awad S, Katz E, Baker D . Levo-tetrahydropalmatine attenuates cocaine self-administration and cocaine-induced reinstatement in rats. Psychopharmacology (Berl). 2007; 192(4):581-91. DOI: 10.1007/s00213-007-0754-7. View

11.

Kiyatkin E . Cocaine enhances the changes in extracellular dopamine in nucleus accumbens associated with reinforcing stimuli: a high-speed chronoamperometric study in freely moving rats. Eur J Neurosci. 1993; 5(3):284-91. DOI: 10.1111/j.1460-9568.1993.tb00495.x. View

12.

Marcellino D, Ferre S, Casado V, Cortes A, Le Foll B, Mazzola C . Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum. J Biol Chem. 2008; 283(38):26016-25. PMC: 2533781. DOI: 10.1074/jbc.M710349200. View

13.

Haney M, Ward A, Foltin R, FISCHMAN M . Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans. Psychopharmacology (Berl). 2001; 155(4):330-7. DOI: 10.1007/s002130100725. View

14.

Asico L, Ladines C, Fuchs S, Accili D, Carey R, Semeraro C . Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension. J Clin Invest. 1998; 102(3):493-8. PMC: 508909. DOI: 10.1172/JCI3685. View

15.

Yue K, Ma B, Chen L, Tian X, Ru Q, Gan Y . L-Stepholidine, a naturally occurring dopamine D1 receptor agonist and D2 receptor antagonist, attenuates heroin self-administration and cue-induced reinstatement in rats. Neuroreport. 2013; 25(1):7-11. DOI: 10.1097/WNR.0000000000000012. View

16.

Crombag H, Grimm J, Shaham Y . Effect of dopamine receptor antagonists on renewal of cocaine seeking by reexposure to drug-associated contextual cues. Neuropsychopharmacology. 2002; 27(6):1006-15. DOI: 10.1016/S0893-133X(02)00356-1. View

17.

Luippold G, Zimmermann C, Mai M, Kloor D, Starck D, Gross G . Dopamine D(3) receptors and salt-dependent hypertension. J Am Soc Nephrol. 2001; 12(11):2272-2279. DOI: 10.1681/ASN.V12112272. View

18.

Meade J, Free R, Miller N, Chun L, Doyle T, Moritz A . (-)-Stepholidine is a potent pan-dopamine receptor antagonist of both G protein- and β-arrestin-mediated signaling. Psychopharmacology (Berl). 2014; 232(5):917-30. PMC: 5234683. DOI: 10.1007/s00213-014-3726-8. View

19.

Le Moine C, Bloch B . Expression of the D3 dopamine receptor in peptidergic neurons of the nucleus accumbens: comparison with the D1 and D2 dopamine receptors. Neuroscience. 1996; 73(1):131-43. DOI: 10.1016/0306-4522(96)00029-2. View

20.

Mo J, Guo Y, Yang Y, Shen J, Jin G, Zhen X . Recent developments in studies of l-stepholidine and its analogs: chemistry, pharmacology and clinical implications. Curr Med Chem. 2008; 14(28):2996-3002. DOI: 10.2174/092986707782794050. View