Stimulants as Specific Inducers of Dopamine-Independent <i>σ</i> Agonist Self-Administration in Rats

Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi; Kopajtic, Theresa; Katz, Jonathan L.

doi:10.1124/jpet.113.207522

Cited by 27 publications

(22 citation statements)

References 47 publications

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“…The goal was to have the food-reinforcement comparator procedurally and functionally as similar as possible to the drug self administration procedure. As shown previously with this procedure, the rates of foodreinforced responding were an inverted U-shaped function of food amount (Hiranita et al, 2013b;Li et al, 2013).…”

Section: Methodssupporting

confidence: 75%

“…Although evidence supports the selectivity of (1)-pentazocine (Hellewell et al, 1994;Hiranita et al, 2013b), as well as PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride] (Garcés-Ramírez et al, 2011), for s 1 Rs, there are few identified s 2 R-selective ligands (Matsumoto, 2007). Moreover, identification of in vivo functional agonists and antagonists at either sR subtype has historically been problematic.…”

Section: Introductionmentioning

confidence: 99%

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

Katz

Hiranita

Kopajtic

et al. 2016

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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Section: Methodssupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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

Katz

Hiranita

Kopajtic

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Perhaps related, ketamine is a powerful mobilizer of midbrain catecholamines, particularly dopamine, and these properties could account for both the psychotomimetic and antidepressant properties (Tan et al, 2012). However, a recent rat study indicated that although self-administration of d-amphetamine reinforces sigma 1 receptor agonist use that can be blocked by dopamine antagonists, similar effects on sigma agonist use are not observed for ketamine (Hiranita et al, 2013). These data suggest that ketamine's antidepressant effects are independent of dopaminergic/sigma 1 interactions (Hiranita et al, 2013).…”

Section: Other Moa'smentioning

confidence: 99%

Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?

Sanacora

Schatzberg

2014

Neuropsychopharmacol

136

124

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Large 'real world' studies demonstrating the limited effectiveness and slow onset of clinical response associated with our existing antidepressant medications has highlighted the need for the development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing antidepressant treatments with fundamentally novel mechanisms of action over the past six decades, leaving the field wary and skeptical about any new developments. However, a series of relatively small proof-of-concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, antidepressant effects can be achieved with a single administration of ketamine. We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the antidepressant action. In this Circumspectives piece, Dr Sanacora and Dr Schatzberg share their opinions on these issues and discuss paths to move the field forward.

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confidence: 99%

“…respectively [1,4]. The discovery of the reinforcing effects of the σR agonists was unexpected because a number of the previous studies generally failed to observe substantial behavioral effects of the σR agonists [8].…”

mentioning

confidence: 99%

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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Stimulants as Specific Inducers of Dopamine-Independent σ Agonist Self-Administration in Rats

Cited by 27 publications

References 47 publications

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

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

Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?

Role of the σRs for Development of Medications

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