Self-Administration of Cocaine Induces Dopamine-Independent Self-Administration of Sigma Agonists

Hiranita, Takato; Mereu, Maddalena; Soto, Paul L.; Katz, Jonathan L.

doi:10.1038/npp.2012.224

Cited by 36 publications

(54 citation statements)

References 48 publications

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“…In addition, the reinforcing effects of the σR agonists did not occur in naïve subjects and were distinct from those of Coc. For example, Coc SA was dosedependently antagonized by the selective DA receptor antagonists (SCH 39166 and L-741,626) as expected [9]. In contrast, neither SCH 39166 nor L-741,626 alone or in combinations affected the SA of the σR agonists (DTG and PRE-084, [9], unpublished data).…”

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confidence: 57%

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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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supporting

confidence: 57%

“…For example, Coc SA was dosedependently antagonized by the selective DA receptor antagonists (SCH 39166 and L-741,626) as expected [9]. In contrast, neither SCH 39166 nor L-741,626 alone or in combinations affected the SA of the σR agonists (DTG and PRE-084, [9], unpublished data). These results suggest a unique reinforcement mechanism that is DA-independent.…”

supporting

confidence: 57%

Role of the σRs for Development of Medications

Hiranita¹

2014

J Alcohol Drug Depend

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“…A two-way, repeated-measures ANOVA indicated a significant effect of (1)-pentazocine dose, presession treatment dose of BD 1063, and interaction of the two (Table 5). In a previous study BD 1063 produced similar effects on the self administration of DTG and PRE-084 (Hiranita et al, 2010(Hiranita et al, , 2013a.…”

Section: Subtype-selective S Antagonists and Self Administrationmentioning

confidence: 59%

“…Subjects with cocaine self administration experience, as in previous studies (Hiranita et al, 2010(Hiranita et al, , 2013a, self administered the sR agonists, PRE-084, (1)-pentazocine, and DTG, and that effect was used to characterize in vivo antagonist effects of several novel sR ligands. As discussed above, in vitro assay of s 1 R agonist or antagonist activity has advanced with the identification of the intracellular chaperone function of s 1 Rs Su, 2001, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Rates of responding maintained by cocaine were most frequently similar with and without pretreatment; however, statistical analyses occasionally identified points after pretreatments that differed from those after cocaine with saline pretreatment (Table 4). Those significant differences were typically increases in response rates less than 0.055 responses per second [CM 398,(6) At doses that had no effect on cocaine self administration (Hiranita et al, 2010(Hiranita et al, , 2013a, BD 1063 produced dose-related decreases in maximal self administration of (1)-pentazocine.…”

Section: Subtype-selective S Antagonists and Self Administrationmentioning

confidence: 99%

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Blockade of Cocaine or σ Receptor Agonist Self Administration by Subtype-Selective σ Receptor Antagonists

Katz

Hiranita

Kopajtic

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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The identification of sigma receptor (sR) subtypes has been based on radioligand binding and, despite progress with s 1 R cellular function, less is known about sR subtype functions in vivo. Recent findings that cocaine self administration experience will trigger sR agonist self administration was used in this study to assess the in vivo receptor subtype specificity of the agonists (1)-pentazocine, PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], and 1,3-di-o-tolylguanidine (DTG) and several novel putative sR antagonists. Radioligand binding studies determined in vitro sR selectivity of the novel compounds, which were subsequently studied for self administration and antagonism of cocaine, (1)-pentazocine, PRE-084, or DTG self administration. Across the dose ranges studied, none of the novel compounds were self administered, nor did they alter cocaine self administration. All compounds blocked DTG self administration, with a subset also blocking (1)-pentazocine and PRE-084 self administration. The most selective of the compounds in binding s 1 Rs blocked cocaine self administration when combined with a dopamine transport inhibitor, either methylphenidate or nomifensine. These drug combinations did not decrease rates of responding maintained by food reinforcement. In contrast, the most selective of the compounds in binding s 2 Rs had no effect on cocaine self administration in combination with either dopamine transport inhibitor. Thus, these results identify subtype-specific in vivo antagonists, and the utility of sR agonist substitution for cocaine self administration as an assay capable of distinguishing sR subtype selectivity in vivo. These results further suggest that effectiveness of dual sR antagonism and dopamine transport inhibition in blocking cocaine self administration is specific for s 1 Rs and further support this dual targeting approach to development of cocaine antagonists.

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A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

Lever

Miller

Green

et al. 2013

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Cocaine functions, in part, through agonist actions at sigma-1 (σ1 ) receptors, while roles played by sigma-2 (σ2 ) receptors are less established. Attempts to discriminate σ2 receptor-mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5-bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide, 1, a ligand shown by others to bind preferentially to σ2 over σ1 receptors, as well as dopamine D2 and D3 sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57-fold selectivity for σ2 receptors over the serotonin transporter, and >800-fold selectivity for σ2 receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD-1® mice, and saw no alteration of basal activity at doses up to 31.6 µmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with 1 at 31.6 µmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ1 receptors or the dopamine transporter by 1, or its possible metabolites, at the 31.6 µmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ2 receptor-selective antagonist that is able to counteract cocaine's motor stimulatory effects.

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Self-Administration of Cocaine Induces Dopamine-Independent Self-Administration of Sigma Agonists

Cited by 36 publications

References 48 publications

Role of the σRs for Development of Medications

Role of the σRs for Development of Medications

Blockade of Cocaine or σ Receptor Agonist Self Administration by Subtype-Selective σ Receptor Antagonists

A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

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