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Bruce E. Blough - One of the best experts on this subject based on the ideXlab platform.
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chronic Phenmetrazine treatment promotes d2 dopaminergic and α2 adrenergic receptor desensitization and alters phosphorylation of signaling proteins and local cerebral glucose metabolism in the rat brain
Brain Research, 2021Co-Authors: Bradley M Keegan, Bruce E. Blough, Thomas J R Beveridge, Annie L Dreitzler, Tammy Sexton, Hilary R Smith, Mack D Miller, Linda J Porrino, Steven R Childers, Allyn C HowlettAbstract:Abstract Phenmetrazine (PHEN) is a putative treatment for cocaine and psychostimulant recidivism; however, neurochemical changes underlying its activity have not been fully elucidated. We sought to characterize brain homeostatic adaptations to chronic PHEN, specifically on functional brain activity (local cerebral glucose utilization), G-Protein Coupled Receptor-stimulated G-protein activation, and phosphorylation of ERK1/2Thr202/Tyr204, GSK3βTyr216, and DARPP-32Thr34. Male Sprague-Dawley rats were implanted with sub-cutaneous minipumps delivering either saline (vehicle), acute (2-day) or chronic (14-day) low dose (25 mg/kg/day) or high dose (50 mg/kg/day) PHEN. Acute administration of high dose PHEN increased local cerebral glucose utilization measured by 2-[14C]-deoxyglucose uptake in basal ganglia and motor-related regions of the rat brain. However, chronically treated animals developed tolerance to these effects. To identify the neurochemical changes associated with PHEN’s activity, we performed [35S]GTPγS binding assays on unfixed and immunohistochemistry on fixed coronal brain sections. Chronic PHEN treatment dose-dependently attenuated D2 dopamine and α2-adrenergic, but not 5-HT1A, receptor-mediated G-protein activation. Two distinct patterns of effects on pERK1/2 and pDARPP-32 were observed: 1) chronic low dose PHEN decreased pERK1/2, and also significantly increased pDARPP-32 levels in some regions; 2) acute and chronic PHEN increased pERK1/2, but chronic high dose PHEN treatment tended to decrease pDARPP-32. Chronic low dose, but not high dose, PHEN significantly reduced pGSK3β levels in several regions. Our study provides definitive evidence that extended length PHEN dosage schedules elicit distinct modes of neuronal acclimatization in cellular signaling. These pharmacodynamic modifications should be considered in drug development for chronic use.
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skin delivery and irritation potential of Phenmetrazine as a candidate transdermal formulation for repurposed indications
Aaps Journal, 2019Co-Authors: Ying Jiang, Bruce E. Blough, Kevin S Murnane, Sonalika A Bhattaccharjee, Ajay K BangaAbstract:Phenmetrazine, a selective dopamine and norepinephrine releaser, previously available as an oral anorectic, is prone to be abused. This study aimed to assess the feasibility of delivering Phenmetrazine via the transdermal route for a new indication, while also minimizing its abuse potential. The passive permeation of Phenmetrazine through dermatomed human cadaver skin was evaluated using static Franz diffusion cells at 10 mg/mL for the fumarate salt, and at 20, 40, and 80 mg/mL for the free base in propylene glycol for 24 h. Further, oleic acid (5% w/w), oleyl alcohol (5% and 10% w/w), and lauric acid (10% w/w) were investigated as chemical permeation enhancers to enhance the delivery. Skin irritation potential was assessed using EpiDerm™ in vitro reconstructed human epidermal model. The free base showed superior 24-h delivery (8.13 ± 4.07%, 10.6 ± 2.5%, and 10.4 ± 1.4% for groups with 20, 40, and 80 mg/mL of the free base, respectively) to Phenmetrazine fumarate salt (undetectable). The successful screening of effective chemical enhancers, oleyl alcohol (5% and 10% w/w), oleic acid (5% w/w), and lauric acid (10% w/w) resulted in significant enhancement of delivery. The calculated therapeutic relevant flux for the potential indication, attention deficit hyperactivity disorder, 20 μg/cm2/h was met, where a 24-mg daily dose from a 50-cm2 patch was projected to be delivered to a 60-kg individual. Irritation study results suggest that formulations with therapeutically relevant delivery are likely to be non-irritant. In conclusion, it is feasible to deliver therapeutically relevant amounts of Phenmetrazine via the transdermal route.
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Fluorinated Phenmetrazine "legal highs" act as substrates for high-affinity monoamine transporters of the SLC6 family.
Neuropharmacology, 2017Co-Authors: Felix P. Mayer, Bruce E. Blough, John S Partilla, Nadine V. Burchardt, Ann M. Decker, Gavin Mclaughlin, Pierce V. Kavanagh, Walter Sandtner, Simon D. BrandtAbstract:A variety of new psychoactive substances (NPS) are appearing in recreational drug markets worldwide. NPS are compounds that target various receptors and transporters in the central nervous system to achieve their psychoactive effects. Chemical modifications of existing drugs can generate NPS that are not controlled by current legislation, thereby providing legal alternatives to controlled substances such as cocaine or amphetamine. Recently, 3-fluoroPhenmetrazine (3-FPM), a derivative of the anorectic compound Phenmetrazine, appeared on the recreational drug market and adverse clinical effects have been reported. Phenmetrazine is known to elevate extracellular monoamine concentrations by an amphetamine-like mechanism. Here we tested 3-FPM and its positional isomers, 2-FPM and 4-FPM, for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We found that 2-, 3- and 4-FPM inhibit uptake mediated by DAT and NET in HEK293 cells with potencies comparable to cocaine (IC50 values 80 μM). Experiments directed at identifying transporter-mediated reverse transport revealed that FPM isomers induce efflux via DAT, NET and SERT in HEK293 cells, and this effect is augmented by the Na+/H+ ionophore monensin. Each FPM evoked concentration-dependent release of monoamines from rat brain synaptosomes. Hence, this study reports for the first time the mode of action for 2-, 3- and 4-FPM and identifies these NPS as monoamine releasers with marked potency at catecholamine transporters implicated in abuse and addiction. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
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the individual and combined effects of Phenmetrazine and mglur2 3 agonist ly379268 on the motivation to self administer cocaine
Drug and Alcohol Dependence, 2016Co-Authors: Anushree N Karkhanis, Bruce E. Blough, Thomas J R Beveridge, Sara R Jones, Mark J FerrisAbstract:Abstract Background The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly due in part to the fact that repeated cocaine use results in dysregulation of multiple neurotransmitter systems, including glutamate and dopamine, and an emergence of increased negative affective states and heightening motivation to take cocaine despite negative consequences. We used a combination therapy approach to assess whether modulation of both glutamate and dopamine transmission would reduce the motivation to self- administer cocaine compared to modulation of either system alone. Methods The metabotropic glutamate 2/3 receptor agonist, LY379268, and the monoamine releaser, Phenmetrazine, were used to assess their individual and combined ability to decrease the reinforcing efficacy of cocaine because they modulate glutamate and dopamine levels, respectively. Cocaine breakpoints and cocaine intake was assessed, using a progressive ratio schedule, at baseline in three groups based on dose of cocaine (0.19, 0.38, 0.75 mg/kg/infusion), and following LY379268 (0.03 or 0.30 mg/kg; i.p.), Phenmetrazine (25 mg/kg/day; osmotic minipump), and a combination of the two drugs. Results LY379268 and Phenmetrazine alone reduced breakpoints for all doses of cocaine. The combination of the two drugs showed a concerted effect in reducing breakpoints for all doses of cocaine, with the lowest dose of cocaine reduced by as much as 70%. Conclusions These data support combination therapy of dopamine and glutamate systems as an effective means to reduce the motivation to take cocaine since a combination of drugs can address neurobiological dysfunction in multiple neurotransmitter systems compared to therapies using single drugs.
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dissociable effects of the prodrug phendimetrazine and its metabolite Phenmetrazine at dopamine transporters
Scientific Reports, 2016Co-Authors: Ernesto Solis, Bruce E. Blough, Stevens S Negus, Julie A Suyama, Matthew F Lazenka, Louis J Defelice, Matthew L BanksAbstract:Phendimetrazine (PDM) is a clinically available anorectic and a candidate pharmacotherapy for cocaine addiction. PDM has been hypothesized to function as a prodrug that requires metabolism to the amphetamine-like monoamine transporter substrate Phenmetrazine (PM) to produce its pharmacological effects; however, whether PDM functions as an inactive prodrug or has pharmacological activity on its own remains unclear. The study aim was to determine PDM pharmacological mechanisms using electrophysiological, neurochemical, and behavioral procedures. PDM blocked the endogenous basal hDAT (human dopamine transporter) current in voltage-clamped (−60 mV) oocytes consistent with a DAT inhibitor profile, whereas its metabolite PM induced an inward hDAT current consistent with a DAT substrate profile. PDM also attenuated the PM-induced inward current during co-application, providing further evidence that PDM functions as a DAT inhibitor. PDM increased nucleus accumbens dopamine levels and facilitated electrical brain stimulation reinforcement within 10 min in rats, providing in vivo evidence supporting PDM pharmacological activity. These results demonstrate that PDM functions as a DAT inhibitor that may also interact with the pharmacological effects of its metabolite PM. Overall, these results suggest a novel mechanism for PDM therapeutic effects via initial PDM DAT inhibition followed by PM DAT substrate-induced dopamine release.
Michael H. Baumann - One of the best experts on this subject based on the ideXlab platform.
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chemical modifications to alter monoamine releasing activity of Phenmetrazine analogs as potential treatments of stimulant addiction
CPDD 76th Annual Meeting, 2014Co-Authors: Ojas A Namjoshi, Michael H. Baumann, Richard B. Rothman, John S Partilla, Ann M. Decker, Antonio Landavazo, Bruce E. BloughAbstract:and gender, a multiple regression analysis revealed that ACOA status significantly predicted alcohol-related problems (p< .01, R2 = .425). Further, ACOA status moderated the effect between affect lability and problems, B=626, p< .01. Conclusions: Higher affect lability predicted more alcoholrelated problems and this effect was strengthened for those classified as an ACOA, making them more vulnerable to alcoholrelated problems. These results have practical implications on the prevention of risky alcohol use among young adults. Further research is needed to determine the causal mechanisms involved. Financial support: This work was supported by a fellowship from the Society of Public Health Education.
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selective suppression of cocaine versus food maintained responding by monoamine releasers in rhesus monkeys benzylpiperazine Phenmetrazine and 4 benzylpiperidine
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: S. Stevens Negus, Michael H. Baumann, Richard B. Rothman, Nancy K. Mello, Bruce E. BloughAbstract:Monoamine releasers constitute one class of drugs currently under investigation as potential agonist medications for the treatment of cocaine dependence. The efficacy and safety of monoamine releasers as candidate medications may be influenced in part by their relative potency to release dopamine and serotonin, and we reported previously that releasers with approximately 30-fold selectivity for dopamine versus serotonin release may be especially promising. The present study examined the effects of the releasers benzylpiperazine, (+)Phenmetrazine, and 4-benzylpiperidine, which have 20- to 48-fold selectivity in vitro for releasing dopamine versus serotonin. In an assay of cocaine discrimination, rhesus monkeys were trained to discriminate 0.4 mg/kg i.m. cocaine from saline in a two-key, food-reinforced procedure. Each of the releasers produced a dose- and time-dependent substitution for cocaine. 4-Benzylpiperidine had the most rapid onset and shortest duration of action. Phenmetrazine and benzylpiperazine had slower onsets and longer durations of action. In an assay of cocaine self-administration, rhesus monkeys were trained to respond for cocaine injections and food pellets under a second order schedule. Treatment for 7 days with each of the releasers produced a dose-dependent and selective reduction in self-administration of cocaine (0.01 mg/kg/injection). The most selective effects were produced by Phenmetrazine. Phenmetrazine also produced a downward shift in the cocaine self-administration dose effect curve, virtually eliminating responding maintained by a 30-fold range of cocaine doses (0.0032–0.1 mg/kg/injection) while having only small and transient effects on food-maintained responding. These findings support the potential utility of dopamine-selective releasers as candidate treatments for cocaine dependence.
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Selective Suppression of Cocaine- versus Food-Maintained Responding by Monoamine Releasers in Rhesus Monkeys: Benzylpiperazine, (+)Phenmetrazine, and 4-Benzylpiperidine
The Journal of pharmacology and experimental therapeutics, 2009Co-Authors: S. Stevens Negus, Michael H. Baumann, Richard B. Rothman, Nancy K. Mello, Bruce E. BloughAbstract:Monoamine releasers constitute one class of drugs currently under investigation as potential agonist medications for the treatment of cocaine dependence. The efficacy and safety of monoamine releasers as candidate medications may be influenced in part by their relative potency to release dopamine and serotonin, and we reported previously that releasers with approximately 30-fold selectivity for dopamine versus serotonin release may be especially promising. The present study examined the effects of the releasers benzylpiperazine, (+)Phenmetrazine, and 4-benzylpiperidine, which have 20- to 48-fold selectivity in vitro for releasing dopamine versus serotonin. In an assay of cocaine discrimination, rhesus monkeys were trained to discriminate 0.4 mg/kg i.m. cocaine from saline in a two-key, food-reinforced procedure. Each of the releasers produced a dose- and time-dependent substitution for cocaine. 4-Benzylpiperidine had the most rapid onset and shortest duration of action. Phenmetrazine and benzylpiperazine had slower onsets and longer durations of action. In an assay of cocaine self-administration, rhesus monkeys were trained to respond for cocaine injections and food pellets under a second order schedule. Treatment for 7 days with each of the releasers produced a dose-dependent and selective reduction in self-administration of cocaine (0.01 mg/kg/injection). The most selective effects were produced by Phenmetrazine. Phenmetrazine also produced a downward shift in the cocaine self-administration dose effect curve, virtually eliminating responding maintained by a 30-fold range of cocaine doses (0.0032–0.1 mg/kg/injection) while having only small and transient effects on food-maintained responding. These findings support the potential utility of dopamine-selective releasers as candidate treatments for cocaine dependence.
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interaction of the anorectic medication phendimetrazine and its metabolites with monoamine transporters in rat brain
European Journal of Pharmacology, 2002Co-Authors: Richard B. Rothman, Bruce E. Blough, Marina Katsnelson, John S Partilla, Christina M Dersch, Michael H. BaumannAbstract:Abstract Phendimetrazine is an effective and widely prescribed appetite suppressant. Preclinical findings show that phendimetrazine displays stimulant properties similar to amphetamine, but few studies have examined the neurochemical mechanism of the drug. In the present work, we characterize the activity of phendimetrazine and its putative metabolites [Phenmetrazine, pseudoPhenmetrazine, and associated stereoisomers] at biogenic amine transporters. All drugs were tested in vitro using assays to measure uptake and release of [ 3 H]dopamine, [ 3 H]norepinephrine, and [ 3 H]serotonin ([ 3 H]5-HT) in rat brain synaptosomes. Selected drugs were tested in vivo using microdialysis to measure extracellular dopamine and serotonin (5-HT) in rat nucleus accumbens. Phendimetrazine itself had no effect on uptake or release of any transmitter. In contrast, the trans -configured N -demethylated metabolite, Phenmetrazine, was a potent releaser of [ 3 H]norepinephrine (EC 50 =50 nM) and [ 3 H]dopamine (EC 50 =131 nM). The cis N -demethylated metabolite, pseudoPhenmetrazine, displayed modest potency at releasing [ 3 H]norepinephrine (EC 50 =514 nM) and blocking [ 3 H]dopamine re-uptake (IC 50 =2630 nM). All drugs tested were inactive or weak in the [ 3 H]5-HT assays. When injected intravenously, phendimetrazine had minimal effects on extracellular transmitter levels, whereas Phenmetrazine produced dose-related elevations in extracellular dopamine. The collective findings suggest that phendimetrazine is a “prodrug” that is converted to the active metabolite Phenmetrazine, a potent substrate for norepinephrine and dopamine transporters.
Richard B. Rothman - One of the best experts on this subject based on the ideXlab platform.
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chemical modifications to alter monoamine releasing activity of Phenmetrazine analogs as potential treatments of stimulant addiction
CPDD 76th Annual Meeting, 2014Co-Authors: Ojas A Namjoshi, Michael H. Baumann, Richard B. Rothman, John S Partilla, Ann M. Decker, Antonio Landavazo, Bruce E. BloughAbstract:and gender, a multiple regression analysis revealed that ACOA status significantly predicted alcohol-related problems (p< .01, R2 = .425). Further, ACOA status moderated the effect between affect lability and problems, B=626, p< .01. Conclusions: Higher affect lability predicted more alcoholrelated problems and this effect was strengthened for those classified as an ACOA, making them more vulnerable to alcoholrelated problems. These results have practical implications on the prevention of risky alcohol use among young adults. Further research is needed to determine the causal mechanisms involved. Financial support: This work was supported by a fellowship from the Society of Public Health Education.
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selective suppression of cocaine versus food maintained responding by monoamine releasers in rhesus monkeys benzylpiperazine Phenmetrazine and 4 benzylpiperidine
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: S. Stevens Negus, Michael H. Baumann, Richard B. Rothman, Nancy K. Mello, Bruce E. BloughAbstract:Monoamine releasers constitute one class of drugs currently under investigation as potential agonist medications for the treatment of cocaine dependence. The efficacy and safety of monoamine releasers as candidate medications may be influenced in part by their relative potency to release dopamine and serotonin, and we reported previously that releasers with approximately 30-fold selectivity for dopamine versus serotonin release may be especially promising. The present study examined the effects of the releasers benzylpiperazine, (+)Phenmetrazine, and 4-benzylpiperidine, which have 20- to 48-fold selectivity in vitro for releasing dopamine versus serotonin. In an assay of cocaine discrimination, rhesus monkeys were trained to discriminate 0.4 mg/kg i.m. cocaine from saline in a two-key, food-reinforced procedure. Each of the releasers produced a dose- and time-dependent substitution for cocaine. 4-Benzylpiperidine had the most rapid onset and shortest duration of action. Phenmetrazine and benzylpiperazine had slower onsets and longer durations of action. In an assay of cocaine self-administration, rhesus monkeys were trained to respond for cocaine injections and food pellets under a second order schedule. Treatment for 7 days with each of the releasers produced a dose-dependent and selective reduction in self-administration of cocaine (0.01 mg/kg/injection). The most selective effects were produced by Phenmetrazine. Phenmetrazine also produced a downward shift in the cocaine self-administration dose effect curve, virtually eliminating responding maintained by a 30-fold range of cocaine doses (0.0032–0.1 mg/kg/injection) while having only small and transient effects on food-maintained responding. These findings support the potential utility of dopamine-selective releasers as candidate treatments for cocaine dependence.
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Selective Suppression of Cocaine- versus Food-Maintained Responding by Monoamine Releasers in Rhesus Monkeys: Benzylpiperazine, (+)Phenmetrazine, and 4-Benzylpiperidine
The Journal of pharmacology and experimental therapeutics, 2009Co-Authors: S. Stevens Negus, Michael H. Baumann, Richard B. Rothman, Nancy K. Mello, Bruce E. BloughAbstract:Monoamine releasers constitute one class of drugs currently under investigation as potential agonist medications for the treatment of cocaine dependence. The efficacy and safety of monoamine releasers as candidate medications may be influenced in part by their relative potency to release dopamine and serotonin, and we reported previously that releasers with approximately 30-fold selectivity for dopamine versus serotonin release may be especially promising. The present study examined the effects of the releasers benzylpiperazine, (+)Phenmetrazine, and 4-benzylpiperidine, which have 20- to 48-fold selectivity in vitro for releasing dopamine versus serotonin. In an assay of cocaine discrimination, rhesus monkeys were trained to discriminate 0.4 mg/kg i.m. cocaine from saline in a two-key, food-reinforced procedure. Each of the releasers produced a dose- and time-dependent substitution for cocaine. 4-Benzylpiperidine had the most rapid onset and shortest duration of action. Phenmetrazine and benzylpiperazine had slower onsets and longer durations of action. In an assay of cocaine self-administration, rhesus monkeys were trained to respond for cocaine injections and food pellets under a second order schedule. Treatment for 7 days with each of the releasers produced a dose-dependent and selective reduction in self-administration of cocaine (0.01 mg/kg/injection). The most selective effects were produced by Phenmetrazine. Phenmetrazine also produced a downward shift in the cocaine self-administration dose effect curve, virtually eliminating responding maintained by a 30-fold range of cocaine doses (0.0032–0.1 mg/kg/injection) while having only small and transient effects on food-maintained responding. These findings support the potential utility of dopamine-selective releasers as candidate treatments for cocaine dependence.
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interaction of the anorectic medication phendimetrazine and its metabolites with monoamine transporters in rat brain
European Journal of Pharmacology, 2002Co-Authors: Richard B. Rothman, Bruce E. Blough, Marina Katsnelson, John S Partilla, Christina M Dersch, Michael H. BaumannAbstract:Abstract Phendimetrazine is an effective and widely prescribed appetite suppressant. Preclinical findings show that phendimetrazine displays stimulant properties similar to amphetamine, but few studies have examined the neurochemical mechanism of the drug. In the present work, we characterize the activity of phendimetrazine and its putative metabolites [Phenmetrazine, pseudoPhenmetrazine, and associated stereoisomers] at biogenic amine transporters. All drugs were tested in vitro using assays to measure uptake and release of [ 3 H]dopamine, [ 3 H]norepinephrine, and [ 3 H]serotonin ([ 3 H]5-HT) in rat brain synaptosomes. Selected drugs were tested in vivo using microdialysis to measure extracellular dopamine and serotonin (5-HT) in rat nucleus accumbens. Phendimetrazine itself had no effect on uptake or release of any transmitter. In contrast, the trans -configured N -demethylated metabolite, Phenmetrazine, was a potent releaser of [ 3 H]norepinephrine (EC 50 =50 nM) and [ 3 H]dopamine (EC 50 =131 nM). The cis N -demethylated metabolite, pseudoPhenmetrazine, displayed modest potency at releasing [ 3 H]norepinephrine (EC 50 =514 nM) and blocking [ 3 H]dopamine re-uptake (IC 50 =2630 nM). All drugs tested were inactive or weak in the [ 3 H]5-HT assays. When injected intravenously, phendimetrazine had minimal effects on extracellular transmitter levels, whereas Phenmetrazine produced dose-related elevations in extracellular dopamine. The collective findings suggest that phendimetrazine is a “prodrug” that is converted to the active metabolite Phenmetrazine, a potent substrate for norepinephrine and dopamine transporters.
S. Stevens Negus - One of the best experts on this subject based on the ideXlab platform.
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selective suppression of cocaine versus food maintained responding by monoamine releasers in rhesus monkeys benzylpiperazine Phenmetrazine and 4 benzylpiperidine
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: S. Stevens Negus, Michael H. Baumann, Richard B. Rothman, Nancy K. Mello, Bruce E. BloughAbstract:Monoamine releasers constitute one class of drugs currently under investigation as potential agonist medications for the treatment of cocaine dependence. The efficacy and safety of monoamine releasers as candidate medications may be influenced in part by their relative potency to release dopamine and serotonin, and we reported previously that releasers with approximately 30-fold selectivity for dopamine versus serotonin release may be especially promising. The present study examined the effects of the releasers benzylpiperazine, (+)Phenmetrazine, and 4-benzylpiperidine, which have 20- to 48-fold selectivity in vitro for releasing dopamine versus serotonin. In an assay of cocaine discrimination, rhesus monkeys were trained to discriminate 0.4 mg/kg i.m. cocaine from saline in a two-key, food-reinforced procedure. Each of the releasers produced a dose- and time-dependent substitution for cocaine. 4-Benzylpiperidine had the most rapid onset and shortest duration of action. Phenmetrazine and benzylpiperazine had slower onsets and longer durations of action. In an assay of cocaine self-administration, rhesus monkeys were trained to respond for cocaine injections and food pellets under a second order schedule. Treatment for 7 days with each of the releasers produced a dose-dependent and selective reduction in self-administration of cocaine (0.01 mg/kg/injection). The most selective effects were produced by Phenmetrazine. Phenmetrazine also produced a downward shift in the cocaine self-administration dose effect curve, virtually eliminating responding maintained by a 30-fold range of cocaine doses (0.0032–0.1 mg/kg/injection) while having only small and transient effects on food-maintained responding. These findings support the potential utility of dopamine-selective releasers as candidate treatments for cocaine dependence.
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Selective Suppression of Cocaine- versus Food-Maintained Responding by Monoamine Releasers in Rhesus Monkeys: Benzylpiperazine, (+)Phenmetrazine, and 4-Benzylpiperidine
The Journal of pharmacology and experimental therapeutics, 2009Co-Authors: S. Stevens Negus, Michael H. Baumann, Richard B. Rothman, Nancy K. Mello, Bruce E. BloughAbstract:Monoamine releasers constitute one class of drugs currently under investigation as potential agonist medications for the treatment of cocaine dependence. The efficacy and safety of monoamine releasers as candidate medications may be influenced in part by their relative potency to release dopamine and serotonin, and we reported previously that releasers with approximately 30-fold selectivity for dopamine versus serotonin release may be especially promising. The present study examined the effects of the releasers benzylpiperazine, (+)Phenmetrazine, and 4-benzylpiperidine, which have 20- to 48-fold selectivity in vitro for releasing dopamine versus serotonin. In an assay of cocaine discrimination, rhesus monkeys were trained to discriminate 0.4 mg/kg i.m. cocaine from saline in a two-key, food-reinforced procedure. Each of the releasers produced a dose- and time-dependent substitution for cocaine. 4-Benzylpiperidine had the most rapid onset and shortest duration of action. Phenmetrazine and benzylpiperazine had slower onsets and longer durations of action. In an assay of cocaine self-administration, rhesus monkeys were trained to respond for cocaine injections and food pellets under a second order schedule. Treatment for 7 days with each of the releasers produced a dose-dependent and selective reduction in self-administration of cocaine (0.01 mg/kg/injection). The most selective effects were produced by Phenmetrazine. Phenmetrazine also produced a downward shift in the cocaine self-administration dose effect curve, virtually eliminating responding maintained by a 30-fold range of cocaine doses (0.0032–0.1 mg/kg/injection) while having only small and transient effects on food-maintained responding. These findings support the potential utility of dopamine-selective releasers as candidate treatments for cocaine dependence.
Thomas J R Beveridge - One of the best experts on this subject based on the ideXlab platform.
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chronic Phenmetrazine treatment promotes d2 dopaminergic and α2 adrenergic receptor desensitization and alters phosphorylation of signaling proteins and local cerebral glucose metabolism in the rat brain
Brain Research, 2021Co-Authors: Bradley M Keegan, Bruce E. Blough, Thomas J R Beveridge, Annie L Dreitzler, Tammy Sexton, Hilary R Smith, Mack D Miller, Linda J Porrino, Steven R Childers, Allyn C HowlettAbstract:Abstract Phenmetrazine (PHEN) is a putative treatment for cocaine and psychostimulant recidivism; however, neurochemical changes underlying its activity have not been fully elucidated. We sought to characterize brain homeostatic adaptations to chronic PHEN, specifically on functional brain activity (local cerebral glucose utilization), G-Protein Coupled Receptor-stimulated G-protein activation, and phosphorylation of ERK1/2Thr202/Tyr204, GSK3βTyr216, and DARPP-32Thr34. Male Sprague-Dawley rats were implanted with sub-cutaneous minipumps delivering either saline (vehicle), acute (2-day) or chronic (14-day) low dose (25 mg/kg/day) or high dose (50 mg/kg/day) PHEN. Acute administration of high dose PHEN increased local cerebral glucose utilization measured by 2-[14C]-deoxyglucose uptake in basal ganglia and motor-related regions of the rat brain. However, chronically treated animals developed tolerance to these effects. To identify the neurochemical changes associated with PHEN’s activity, we performed [35S]GTPγS binding assays on unfixed and immunohistochemistry on fixed coronal brain sections. Chronic PHEN treatment dose-dependently attenuated D2 dopamine and α2-adrenergic, but not 5-HT1A, receptor-mediated G-protein activation. Two distinct patterns of effects on pERK1/2 and pDARPP-32 were observed: 1) chronic low dose PHEN decreased pERK1/2, and also significantly increased pDARPP-32 levels in some regions; 2) acute and chronic PHEN increased pERK1/2, but chronic high dose PHEN treatment tended to decrease pDARPP-32. Chronic low dose, but not high dose, PHEN significantly reduced pGSK3β levels in several regions. Our study provides definitive evidence that extended length PHEN dosage schedules elicit distinct modes of neuronal acclimatization in cellular signaling. These pharmacodynamic modifications should be considered in drug development for chronic use.
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the individual and combined effects of Phenmetrazine and mglur2 3 agonist ly379268 on the motivation to self administer cocaine
Drug and Alcohol Dependence, 2016Co-Authors: Anushree N Karkhanis, Bruce E. Blough, Thomas J R Beveridge, Sara R Jones, Mark J FerrisAbstract:Abstract Background The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly due in part to the fact that repeated cocaine use results in dysregulation of multiple neurotransmitter systems, including glutamate and dopamine, and an emergence of increased negative affective states and heightening motivation to take cocaine despite negative consequences. We used a combination therapy approach to assess whether modulation of both glutamate and dopamine transmission would reduce the motivation to self- administer cocaine compared to modulation of either system alone. Methods The metabotropic glutamate 2/3 receptor agonist, LY379268, and the monoamine releaser, Phenmetrazine, were used to assess their individual and combined ability to decrease the reinforcing efficacy of cocaine because they modulate glutamate and dopamine levels, respectively. Cocaine breakpoints and cocaine intake was assessed, using a progressive ratio schedule, at baseline in three groups based on dose of cocaine (0.19, 0.38, 0.75 mg/kg/infusion), and following LY379268 (0.03 or 0.30 mg/kg; i.p.), Phenmetrazine (25 mg/kg/day; osmotic minipump), and a combination of the two drugs. Results LY379268 and Phenmetrazine alone reduced breakpoints for all doses of cocaine. The combination of the two drugs showed a concerted effect in reducing breakpoints for all doses of cocaine, with the lowest dose of cocaine reduced by as much as 70%. Conclusions These data support combination therapy of dopamine and glutamate systems as an effective means to reduce the motivation to take cocaine since a combination of drugs can address neurobiological dysfunction in multiple neurotransmitter systems compared to therapies using single drugs.
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effects of the dopamine norepinephrine releaser Phenmetrazine on cocaine self administration and cocaine primed reinstatement in rats
Psychopharmacology, 2015Co-Authors: Paul W Czoty, Bruce E. Blough, Phuong Tran, Leanne N Thomas, T J Martin, Amanda Grigg, Thomas J R BeveridgeAbstract:Rationale Like other monoamine releasers such as D-amphetamine, chronic treatment with Phenmetrazine can attenuate cocaine self-administration in monkeys.