Decreases in Cocaine Self-Administration with Dual Inhibition of the Dopamine Transporter and σ Receptors

Hiranita, Takato; Soto, Paul L.; Kohut, Stephen J.; Kopajtic, Theresa; Cao, Jianjin; Newman, Amy Hauck; Tanda, Gianluigi; Katz, Jonathan L.

doi:10.1124/jpet.111.185025

Cited by 72 publications

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“…In addition, the sigma receptor (σR) antagonist rimcazole and its analogs (SH 3-24 and SH 3-28) dose-dependently decrease Coc SA [3]. The antagonist actions of the BZT and rimcazole analogs were quite distinct from the effects of the standard DA uptake inhibitors and other σR antagonists.…”

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confidence: 87%

“…The antagonist actions of the BZT and rimcazole analogs were quite distinct from the effects of the standard DA uptake inhibitors and other σR antagonists. For example, standard DA uptake inhibitors (WIN 35,428, methylphenidate and nomifensine) dose-dependently shifted the dose-effect curve of Coc SA to the left, suggesting a potentiation of the reinforcing effects of Coc whereas standard σR antagonists (BD 1008, BD 1047, BD 1063, AC 927 and NE 100) were without effects on Coc SA [2][3][4]. Importantly, the BZT and rimcazole analogs both are more potent in decreasing Coc SA than in decreasing food-maintained behavior [2,3], suggesting selectivity of their effects on Coc SA.…”

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confidence: 99%

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Role of the σRs for Development of Medications

Hiranita¹

2014

J Alcohol Drug Depend

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I found that several N-substituted benztropine (BZT) analogs (JHW 007 and AHN 2-005) can dose-dependently decrease self-administration (SA) of stimulants cocaine (Coc) or dmethamphetamine (MA) despite their high affinity and high selectivity for the dopamine transporter (DAT) [1,2]. In addition, the sigma receptor (σR) antagonist rimcazole and its analogs (SH 3-24 and SH 3-28) dose-dependently decrease Coc SA [3]. The antagonist actions of the BZT and rimcazole analogs were quite distinct from the effects of the standard DA uptake inhibitors and other σR antagonists. For example, standard DA uptake inhibitors (WIN 35,428, methylphenidate and nomifensine) dose-dependently shifted the dose-effect curve of Coc SA to the left, suggesting a potentiation of the reinforcing effects of Coc whereas standard σR antagonists (BD 1008, BD 1047, BD 1063, AC 927 and NE 100) were without effects on Coc SA [2][3][4]. Importantly, the BZT and rimcazole analogs both are more potent in decreasing Coc SA than in decreasing food-maintained behavior [2,3], suggesting selectivity of their effects on Coc SA. Further, a wide range of doses of the BZT and rimcazole analogs failed to maintain responding above vehicle levels when substituted for Coc [2,3,5,6], suggesting little if any abuse liability of their own. The lack of the reinforcing effects of the BZT analogs was also quite distinct from a substantial capacity of the typical DA uptake inhibitors to maintain responding when substituted for Coc [2][3][4] indicating that these compounds have abuse liability of their own. Finally, studies with in vitro radioligand binding assays demonstrated relatively high affinities of the BZT and rimcazole analogs for the DAT as well as to σRs [3,7]. A Subsequent study demonstrated that combinations with typical DA uptake inhibitors and the selective σR antagonists can decrease Coc SA, suggesting dual inhibition at the DAT and σRs as a potential combined target approach for medical treatments for Coc abuse [3]. The published study [3] was chosen as the March 2012 Featured Article on the NIDA-IRP website (http://irp.drugabuse.gov/ hotpaperArchive.php), indicative of a substantial interest in this field of research. Thus one of my current research interest is to further explore this "dual inhibition" hypothesis as a target for Coc abuse medications.The second research interest of mine is an unexpected by-product of the study on "dual σR/DAT inhibitions." In the middle of a previous study, I found a capacity of the σR agonists (DTG and PRE-084) to 1) dose-dependently shift to the left a dose-effect curve for Coc SA and 2) substitute for Coc or d-MA in rats trained to self-administer Coc or d-MA,This is an open

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confidence: 87%

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Role of the σRs for Development of Medications

Hiranita¹

2014

J Alcohol Drug Depend

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“…It binds to presynaptic DAT and NET, but not to SERT, blocking DA and NE re-uptake and increasing synaptic DA and NE (Leonard et al, 2004). Methylphenidate is self-administered in rodents, and pretreatment with methylphenidate significantly shifts the cocaine self-administration dose-response curve to the left (Hiranita et al, 2009(Hiranita et al, , 2011, suggesting that methylphenidate has cocaine-like abuse potential and produces additive effects in combination with cocaine.…”

Section: Methylphenidatementioning

confidence: 99%

Medication Development for the Treatment of Cocaine Addiction – Progress at Preclinical and Clinical Levels

Xi¹

2012

Addictions - From Pathophysiology to Treatment

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“…Thus, the TLR4 hypothesis is less viable to develop medications for drug abuse; 2) It is important to assess pharmacological specificity using food-reinforced responding as successfully employed in previous studies [5][6][7][8][9].…”

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Lack of Effects of Toll-Like Receptor 4 Antagonists on the Reinforcing Effects of Cocaine and Remifentanil

Hiranita¹

2016

J Alcohol Drug Depend

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EditorialThe toll like receptor 4 (TLR4) is expressed in glial cells and reacts to potential toxic entities. This activation triggers various inflammatory reactions. (+)-Naloxone and (+)-naltrexone, dextrorotatory enantiomers of opioid receptor antagonists [respectively, (-)-naloxone and (-)-naltrexone], have been demonstrated to dock to TLR4 using "in-silico" models, and function as an antagonist at this site in vivo [1,2]. Recently, (+)-naloxone have been reported to antagonize selfadministration of a µ-opioid agonist remifentanil [3]. Further, (+)-naltrexone blocked self-administration of a dopamine uptake inhibitor cocaine [4]. These findings suggested a "novel" TLR4-mediated mechanism underlying the reinforcing effects of drugs of abuse across pharmacological classes. A more recent study [5] has, however, indicated that the TLR4 hypothesis is less viable.Tanda and his colleagues further assessed specificity of the blocking effects of the TLR4 antagonists on self-administration of remifentanil or cocaine [5]. Consistent with the results from the two earlier studies [3,4], both (+)-naloxone and (+)-naltrexone dose-dependently produced an insurmountable antagonism against self-administration of remifentanil or cocaine. However, the antagonism was accompanied with a dose-dependent decrease in food-reinforced responding. For example, (+)-naloxone and (+)-naltrexone were equipotent in decreasing responding maintained by injections of remifentanil or cocaine or presentations of food pellets. Thus, the apparent antagonism of the TLR4 antagonists against drug self-administration is likely due to a non-specific disruption of overall behavioral performance rather than an interaction with the reinforcing effects of cocaine or remifentanil. On the other hand, cocaine was not reinforcing under a fixed-and progressive-ratio schedule of reinforcement in TLR4 mutant mice whereas sucrose was reinforcing [4]. Thus, TLR4 signaling appears to mediate somehow cocaine reinforcement.The more recent results by Tanda et al. [5] indicate the following message: 1) There is no specific preclinical efficacy of TLR4 antagonists (+)-naloxone and (+)-naltrexone for self-administration of cocaine and remifentanil. Thus, the TLR4 hypothesis is less viable to develop medications for drug abuse; 2) It is important to assess pharmacological specificity using food-reinforced responding as successfully employed in previous studies [5][6][7][8][9].

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Decreases in Cocaine Self-Administration with Dual Inhibition of the Dopamine Transporter and σ Receptors

Cited by 72 publications

References 37 publications

Role of the σRs for Development of Medications

Role of the σRs for Development of Medications

Medication Development for the Treatment of Cocaine Addiction – Progress at Preclinical and Clinical Levels

Lack of Effects of Toll-Like Receptor 4 Antagonists on the Reinforcing Effects of Cocaine and Remifentanil

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