SA 4503 attenuates cocaine-induced hyperactivity and enhances methamphetamine substitution for a cocaine discriminative stimulus

Miller

Fergason-Cantrell

et al. 2014

J Pharmacol Exp Ther

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Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 (s 1 ) receptors. Selective s 1 receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity s 1 antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity. To address this apparent paradox, we evaluated aspects of PD144418 binding in vitro, investigated s 1 receptor and dopamine transporter (DAT) occupancy in vivo, and re-examined effects on locomotor activity. PD144418 displayed high affinity for s 1 sites (K i 0.46 nM) and 3596-fold selectivity over s 2 sites (K i 1654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters (K i .100 mM), and the DAT interaction was weak (K i 9.0 mM). In vivo, PD144418 bound to central and peripheral s 1 sites in mouse, with an ED 50 of 0.22 mmol/kg in whole brain. No DAT occupancy by PD144418 (10.0 mmol/kg) or possible metabolites were observed. At doses that did not affect basal locomotor activity, PD144418 (1, 3.16, and 10 mmol/kg) attenuated cocaine-induced hyperactivity in a dosedependent manner in mice. There was good correlation (r 2 5 0.88) of hyperactivity reduction with increasing cerebral s 1 receptor occupancy. The behavioral ED 50 of 0.79 mmol/kg corresponded to 80% occupancy. Significant s 1 receptor occupancy and the ability to mitigate cocaine's motor stimulatory effects were observed for 16 hours after a single 10.0 mmol/kg dose of PD144418.

Section: Discussionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

Miller

Fergason-Cantrell

et al. 2014

J Pharmacol Exp Ther

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“…However, METH has previously been shown to substitute for cocaine in mice trained to discriminate cocaine from saline (eg, Rodvelt et al, 2011), and we have previously reported that cocaine produces full generalization in mice trained to discriminate S( þ )-MDMA or R( À )-MDMA from saline (Murnane et al, 2009). Similarly, Johanson et al (2006) reported that humans could be trained to discriminate among 20 mg d-amphetamine, 0.75 mg/kg mCPP and placebo, and that when tested with 1.0 and 1.5 mg/kg MDMA, half the participants reported MDMA to be amphetamine-like and half reported it to be mCPP-like.…”

Section: 4-methylenedioxypyrovalerone In Micementioning

confidence: 99%

In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity

Fantegrossi

Gannon

Zimmerman

et al. 2012

Neuropsychopharmacol

138

151

In recent years, synthetic analogues of naturally occurring cathinone have emerged as psychostimulant-like drugs of abuse in commercial 'bath salt' preparations. 3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of these illicit products, and its structural similarities to the more well-known drugs of abuse 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) suggest that it may have similar in vivo effects to these substances. In these studies, adult male NIH Swiss mice were trained to discriminate 0.3 mg/kg MDPV from saline, and the interoceptive effects of a range of substitution doses of MDPV, MDMA, and METH were then assessed. In separate groups of mice, surgically implanted radiotelemetry probes simultaneously monitored thermoregulatory and locomotor responses to various doses of MDPV and MDMA, as a function of ambient temperature. We found that mice reliably discriminated the MDPV training dose from saline and that cumulative doses of MDPV, MDMA, and METH fully substituted for the MDPV training stimulus. All three drugs had similar ED 50 values in this procedure. Stimulation of motor activity was observed following administration of a wide range of MDPV doses (1-30 mg/kg), and the warm ambient temperature potentiated motor activity and elicited profound stereotypy and self-injurious behavior at 30 mg/kg. In contrast, MDPV-induced hyperthermic effects were observed in only the warm ambient environment. This pattern of effects is in sharp contrast to MDMA, where ambient temperature interacts with thermoregulation, but not locomotor activity. These studies suggest that although the interoceptive effects of MDPV are similar to those of MDMA and METH, direct effects on thermoregulatory processes and locomotor activity are likely mediated by different mechanisms than those of MDMA.

“…Non-radioactive E -IA-DM-PE-PIPZE also partially attenuates (−)-cocaine induced locomotor hyperactivity, suggesting antagonist character [58]. At present, such behavioral studies are a principal way to assign the functional properties of σ 1 receptor ligands [38,64,179,180]. Dopamine transporter (DAT) inhibition is recognized as the main contributor to (−)-cocaine’s behavioral effects and abuse liability.…”

Section: Preclinical Imagingmentioning

confidence: 99%

Tactics for preclinical validation of receptor-binding radiotracers

Fan

Nuclear Medicine and Biology

2017

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Introduction Aspects of radiopharmaceutical development are illustrated through preclinical studies of [125I]-(E)-1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA- BF-PE-PIPZE), a radioligand for sigma-1 (σ1) receptors, coupled with examples from the recent literature. Findings are compared to those previously observed for [125I]-(E)-1-(2-(2,3-dimethoxy-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA-DM-PE-PIPZE). Methods Syntheses of E-IA-BF-PE-PIPZE and [125I]-E-IA-BF-PE-PIPZE were accomplished by standard methods. In vitro receptor binding studies and autoradiography were performed, and binding potential was predicted. Measurements of lipophilicity and protein binding were obtained. In vivo studies were conducted in mice to evaluate radioligand stability, as well as specific binding to σ1 sites in brain, brain regions and peripheral organs in the presence and absence of potential blockers. Results E-IA-BF-PE-PIPZE exhibited high affinity and selectivity for σ1 receptors (Ki = 0.43 ± 0.03 nM, σ2 / σ1 = 173). [125I]-E-IA-BF-PE-PIPZE was prepared in good yield and purity, with high specific activity. Radioligand binding provided dissociation (koff) and association (kon) rate constants, along with a measured Kd of 0.24 ± 0.01 nM and Bmax of 472 ± 13 fmol / mg protein. The radioligand proved suitable for quantitative autoradiography in vitro using brain sections. Moderate lipophilicity, Log D7.4 2.69 ± 0.28, was determined, and protein binding was 71 ± 0.3%. In vivo, high initial whole brain uptake, > 6% injected dose / g, cleared slowly over 24 h. Specific binding represented 75% to 93% of total binding from 15 min to 24 h. Findings were confirmed and extended by regional brain biodistribution. Radiometabolites were not observed in brain (1%). Conclusions Substitution of dihydrobenzofuranylethyl for dimethoxyphenethyl increased radioligand affinity for σ1 receptors by 16-fold. While high specific binding to σ1 receptors was observed for both radioligands in vivo, [125I]-E-IA-BF-PE-PIPZE displayed much slower clearance kinetics than [125I]-E-IA-DM-PE-PIPZE. Thus, minor structural modifications of σ1 receptor radioligands lead to major differences in binding properties in vitro and in vivo.