Publications by authors named "Brenda M Gannon"

21 Publications

  • Page 1 of 1

Effects of Laboratory Housing Conditions on Core Temperature and Locomotor Activity in Mice.

J Am Assoc Lab Anim Sci 2021 Apr 22. Epub 2021 Apr 22.

Drug developers worldwide assess compound safety and efficacy using measures that include mouse core temperature andlocomotor activity. Subtle differences in animal housing conditions between institutions can alter these values, impacting scientific rigor and reproducibility. In these studies, adult male NIH Swiss mice were surgically implanted with radiotelemetry probes that simultaneously monitored core temperature and locomotor activity across various housing conditions. In the first study, ambient temperature was varied between 20 °C and 28 °C in groups of singly housed mice. Additional studies held the mice at a constant ambient temperature and examined the effects of cage density (housing animals singly or in groups of 3 or 6), bedding change and provision of nesting material, and the availability of a running wheel on core temperature and locomotor activity. Mice overwhelmingly maintained species-typical core temperatures across all ambient temperatures,across all housing conditions, when bedding was fresh or old, and with or without the provision of cotton squares as nesting material. However, engaging in wheel running and the combination of fresh bedding and cotton squares transiently increased core temperatures beyond the species-typical range. Similarly, the circadian distribution of locomotor activity was significantly disrupted by placing animals in cages with fresh bedding or nesting material, or by performing both of these manipulations concurrently during the light period. These findings suggest that standard husbandry practices and common housing conditions may transiently affect core temperature in adult mice. Furthermore, these practices may have profound and relatively long-lasting effects on motor activity and the regulation of circadian rhythms.
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http://dx.doi.org/10.30802/AALAS-JAALAS-20-000093DOI Listing
April 2021

α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and uptake1 and uptake2 monoamine transporters.

Neuropharmacology 2021 Apr 20;190:108570. Epub 2021 Apr 20.

Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria; AddRess Centre for Addiction Research and Science, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria. Electronic address:

While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC values in the low micromolar range). Furthermore, uptake inhibition assays at low-affinity monoamine transporters, i.e., the human organic cation transporters (hOCT) 1-3 and human plasma membrane monoamine transporter (hPMAT), bring to light that all compounds inhibit hOCT1 and 2 (IC values in the low micromolar range) while less potently interacting with hPMAT and hOCT3. In conclusion, this study describes (i) three new hybrid compounds that efficaciously block hDAT while being partial releasers at hNET, and (ii) highlights the interactions of α-PPP-derivatives with low-affinity monoamine transporters, giving impetus to further studies investigating the interaction of drugs of abuse with OCT1-3 and PMAT.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108570DOI Listing
April 2021

MDPV "high-responder" rats also self-administer more oxycodone than their "low-responder" counterparts under a fixed ratio schedule of reinforcement.

Psychopharmacology (Berl) 2021 Apr 23;238(4):1183-1192. Epub 2021 Jan 23.

Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Atlanta, GA, 30341, USA.

Rationale: Oxycodone is one of the most commonly prescribed and most frequently abused opioid analgesics, yet little is known regarding individual vulnerabilities to oxycodone abuse. The synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) has been shown to produce a "high-responder" phenotype characterized by increased drug intake and responding during periods of signaled drug unavailability (e.g., during post-infusion timeouts) in ~ 40% of male Sprague-Dawley rats. This phenotype also transfers to other psychostimulants (e.g., cocaine and methamphetamine), but it is unknown whether this phenotype transfers to other (non-stimulant) drugs of abuse.

Objectives: The present study aimed to (1) reestablish the "high-responder" phenotype in male Sprague-Dawley rats (n = 11) that acquired self-administration of MDPV (0.032 mg/kg/inf) on a fixed ratio 1 (FR1) schedule of reinforcement and (2) compare full dose-response curves for MDPV and oxycodone self-administration under an FR5 schedule of reinforcement.

Results: MDPV was ~ 3-fold more potent at maintaining peak levels of behavior and resulted in greater overall drug intake than oxycodone. High levels of timeout responding were noted in a subset of rats that acquired MDPV self-administration ("high-responders", n = 5), and the FR5 dose-response curve for MDPV was shifted upward for these rats relative to their "low-responder" (n = 6) counterparts. "High-responders" also self-administered more infusions of oxycodone under an FR5 schedule of reinforcement than "low-responders"; however, this was not coupled with increased levels of timeout responding.

Conclusions: The present data suggest that a subset of individuals with a history of using synthetic cathinones may be particularly vulnerable to the abuse of oxycodone.
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http://dx.doi.org/10.1007/s00213-021-05764-4DOI Listing
April 2021

The abuse-related effects of pyrrolidine-containing cathinones are related to their potency and selectivity to inhibit the dopamine transporter.

Neuropsychopharmacology 2018 11 10;43(12):2399-2407. Epub 2018 Sep 10.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Synthetic cathinones are common constituents of abused "bath salts" preparations and represent a large family of structurally related compounds that function as cocaine-like inhibitors or amphetamine-like substrates of dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters. Preclinical evidence suggests that some cathinones (e.g., MDPV and α-PVP) are more effective reinforcers than prototypical stimulant drugs of abuse, such as cocaine or methamphetamine. Although the reinforcing potency of these cathinones is related to their potency to inhibit DAT, less is known about the pharmacological determinants of their unusually high reinforcing effectiveness. To this end, we tested the hypothesis that reinforcing effectiveness of cathinone stimulants is positively correlated with their selectivity for DAT relative to SERT. Uptake inhibition assays in rat brain synaptosomes were used to directly compare the potency of MDPV, MDPBP, MDPPP, α-PVP, α-PPP, and cocaine at DAT, NET, and SERT, whereas intravenous self-administration in rats was used to quantify relative reinforcing effectiveness of the drugs using progressive ratio (PR) and behavioral economic procedures. All cathinones were more potent at DAT than NET or SERT, with a rank order for selectivity at DAT over SERT of α-PVP > α-PPP > MDPV > MDPBP > MDPPP > cocaine. These synthetic cathinones were more effective reinforcers than cocaine, and the measures of reinforcing effectiveness determined by PR and demand curve analyses were highly correlated with selectivity for DAT over SERT. Together, these studies provide strong and convergent evidence that the abuse potential of stimulant drugs is mediated by uptake inhibition at DAT, with activity at SERT serving as a negative modulator of reinforcing effectiveness.
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http://dx.doi.org/10.1038/s41386-018-0209-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180085PMC
November 2018

Behavioral economic analysis of the reinforcing effects of "bath salts" mixtures: studies with MDPV, methylone, and caffeine in male Sprague-Dawley rats.

Psychopharmacology (Berl) 2019 Mar 29;236(3):1031-1041. Epub 2018 Sep 29.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr - MC# 7764, San Antonio, TX, 78229, USA.

Rationale: "Bath salts" preparations often contain combinations of synthetic cathinones (e.g., 3,4-methylenedioxymethcathinone [methylone], 3,4-methylenedioxypyrovalerone [MDPV]), and caffeine, and evidence suggests that mixtures of synthetic cathinones and caffeine (e.g., MDPV + caffeine or methylone + caffeine) can be more potent and/or effective reinforcers than predicted for an additive interaction.

Objective: To use demand curve analyses to compare the reinforcing effectiveness of MDPV and methylone to mixtures of MDPV + caffeine and methylone + caffeine.

Methods: Male Sprague-Dawley rats acquired methylone self-administration (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement and generated full dose-response curves for methylone (0.01-1 mg/kg/inf) under an FR5 schedule of reinforcement. Demand curves were then obtained for methylone, MDPV, caffeine, and methylone + caffeine and MDPV + caffeine mixtures by increasing the FR across sessions according to the following series: 3, 10, 18, 32, 56, 100, 178, etc. RESULTS: Self-administration of methylone was rapidly acquired by 87.5% of rats and was maintained across a range of doses, producing an inverted U-shaped dose-response curve. Rank order demand for the individual constituents was MDPV > methylone > caffeine. Demand for the 3:1 (but not 10:1) methylone + caffeine mixture was greater than that for methylone alone, and demand for MDPV alone was similar to both MDPV + caffeine mixtures evaluated.

Conclusions: These studies provide additional evidence that although methylone is an effective reinforcer, combining methylone with caffeine results in an enhanced reinforcing effectiveness compared to methylone alone. Thus, abused "bath salts" preparations containing synthetic cathinones and caffeine may have higher abuse liability than preparations containing only synthetic cathinones.
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http://dx.doi.org/10.1007/s00213-018-5046-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440875PMC
March 2019

Evaluation of morphine-like effects of the mixed mu/delta agonist morphine-6--sulfate in rats: Drug discrimination and physical dependence.

Pharmacol Res Perspect 2018 07 19;6(4):e00403. Epub 2018 Jun 19.

Department of Pharmacology and Toxicology University of Arkansas for Medical Sciences Little Rock Arkansas 72205.

Morphine-6-O-sulfate (M6S) is as a mixed-action mu/delta (μ/δ) opioid receptor agonist with high potency and analgesic efficacy. These studies used assays of drug discrimination and schedule-controlled responding to assess abuse-liability, tolerance, and physical dependence as compared to morphine in rats. Attempts to train 0.3 mg/kg (IP) M6S from saline failed, but all rats rapidly acquired the discrimination when the training dose was changed to 3.0 mg/kg morphine, and substitution tests showed that morphine and fentanyl both fully substituted for the training dose, M6S and M3A6S (3-O-acetyl ester of M6S) only partially substituted, and salvinorin A did not elicit morphine-like effects. Tolerance to response rate-decreasing effects was studied in rats administered either 1.0 or 3.0 mg/kg morphine or M6S before food-reinforced operant sessions. At both unit doses, tolerance to M6S-elicited rate suppression developed more slowly than tolerance to morphine-induced reductions in response rates. To assess dependence, rats were maintained on 1.0 mg/kg morphine or 1.0 mg/kg M6S until food-reinforced response rates were stable for at least 5 days. Rats were then administered saline or increasing doses of the opioid antagonist naltrexone (NTX) (0.3, 1.0, 3.0, or 10.0 mg/kg) in order to determine antagonist-precipitated withdrawal. NTX precipitated withdrawal was similar in both morphine-maintained and M6S-maintained rats. In conclusion, the mixed μ/δ agonist activity of M6S failed to completely protect against the development of physical dependence, but delayed tolerance development to behavioral effects and resulted in decreased morphine-like subjective effects, perhaps implying a decreased abuse liability over μ agonists.
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http://dx.doi.org/10.1002/prp2.403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009770PMC
July 2018

Inhibition of Cocaine and 3,4-Methylenedioxypyrovalerone (MDPV) Self-Administration by Lorcaserin Is Mediated by 5-HT2C Receptors in Rats.

J Pharmacol Exp Ther 2018 03 7;364(2):359-366. Epub 2017 Dec 7.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (B.M.G., G.T.C.); South Texas Veterans Health Care System, San Antonio, Texas (G.T.C.); and Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (A.S., K.C.R.)

Lorcaserin is a serotonin (5-HT) receptor-preferring agonist approved by the US Food and Drug Administration to treat obesity. Lorcaserin decreases cocaine self-administration in rats and monkeys. Although this effect is partially inhibited by a 5-HT receptor antagonist (SB242084), lorcaserin also has effects at 5-HT and 5-HT receptors, and the relative contribution of these receptors to its anti-cocaine effects has not been investigated. The goals of this study were to determine 1) the potency and effectiveness of lorcaserin to decrease self-administration of cocaine and 3,4-methylenedioxypyrovalerone (MDPV), a common "bath salts" constituent; and 2) the receptor(s) mediating the effects of lorcaserin on cocaine and MDPV self-administration. Male Sprague-Dawley rats ( = 6) were trained to self-administer MDPV under a progressive ratio schedule of reinforcement and maintained under this schedule with daily access to 0.32 mg/kg per infusion of cocaine or 0.032 mg/kg per infusion of MDPV. Dose-response curves for the effects of lorcaserin on cocaine and MDPV self-administration were generated by administering lorcaserin (0.1-5.6 mg/kg) 25 minutes before the start of the session. To assess the effects of 5-HT (SB242084, 0.1 mg/kg), 5-HT (MDL100907, 0.1 mg/kg), and 5-HT (WAY100635, 0.178 mg/kg) receptor antagonists, they were administered 15 minutes before lorcaserin. Lorcaserin decreased cocaine and MDPV self-administration with equal potency. Antagonism of 5-HT (but not 5-HT or 5-HT) receptors blocked the effects of lorcaserin on cocaine and MDPV self-administration. Taken together, these data provide additional support for further development of 5-HT receptor agonists, such as lorcaserin, for the treatment of stimulant abuse.
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http://dx.doi.org/10.1124/jpet.117.246082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787931PMC
March 2018

Role of monoaminergic systems and ambient temperature in bath salts constituent 3,4-methylenedioxypyrovalerone (MDPV)-elicited hyperthermia and locomotor stimulation in mice.

Neuropharmacology 2018 05 5;134(Pt A):13-21. Epub 2017 Sep 5.

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. Electronic address:

3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of illicit bath salts products, and in vitro studies implicate monoamine transporters as mediators of its pharmacological effects. Locomotor and thermoregulatory effects of MDPV depend on ambient temperature, so the current studies aimed to gauge the involvement of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in MDPV-induced locomotor stimulation and hyperthermia in the mouse at different ambient temperatures. Mice were pretreated with the selective 5-HT-reuptake inhibitor fluoxetine (3 mg/kg), the NE-reuptake inhibitor desipramine (3 mg/kg), the DA-reuptake inhibitor bupropion (10 mg/kg), or saline, followed by 10 mg/kg MDPV while thermoregulation and locomotor activity were monitored via radiotelemetry. In other studies, mice were pretreated for three days with saline, 100 mg/kg of the tryptophan hydroxylase inhibitor para-chlorophenylalanine (p-CPA), or 100 mg/kg of the tyrosine hydroxylase inhibitor α-methyl-para-tyrosine (α-MPT) before receiving 10 mg/kg MDPV on the fourth day. All manipulations were conducted at both 20 °C and 28 °C ambient temperatures. MDPV increased locomotor activity under both ambient conditions and modestly increased core body temperature at 20 °C; however, neither pretreatment with monoamine reuptake inhibitors nor monoamine synthesis inhibitors significantly altered these effects. At 28 °C, MDPV induced a more pronounced hyperthermic effect which was attenuated by bupropion, desipramine, or fluoxetine pretreatment, but not by the monoamine synthesis inhibitors. These results suggest that MDPV may have a more complex pharmacological profile than suggested by in vitro studies, perhaps extending beyond interactions with monoamine transporters. A more thorough binding profile of MDPV at various brain recognition sites should be developed. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
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http://dx.doi.org/10.1016/j.neuropharm.2017.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837893PMC
May 2018

Effects of orally self-administered bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice.

Drug Alcohol Depend 2017 10 4;179:408-415. Epub 2017 Aug 4.

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States. Electronic address:

Synthetic cathinones in bath salts products are psychostimulant drugs of abuse, and 3,4-methylenedioxypyrovalerone (MDPV) is a common constituent of these products. Oral MDPV has been show to stimulate locomotor activity but reinforcing, locomotor and appetitive stimulus effects of oral MDPV are unknown. Choice procedures evaluated preference for 0.03, 0.10, 0.30, and 1.00mg/mL MDPV solutions versus 0.10mg/mL quinine solution or water. To verify that oral MDPV produced pharmacological effects, locomotor activity was monitored during and after consumption of water, quinine, or MDPV solutions. Conditioned place preference (CPP) tested the apparent appetitive effects of a preferred concentration of oral MDPV with locomotor stimulant effects (0.30mg/mL), using water as a control, and compared with results from intraperitoneally-administered MDPV. Consumption of MDPV solutions (0.03-1.00mg/mL) was low when the alternative fluid was water, but a history of MDPV consumption increased MDPV choice. When paired with a quinine control solution, MDPV solutions (0.03-0.30mg/mL) were almost exclusively preferred, and treatment with the catecholamine synthesis inhibitor αMPT decreased MDPV choice. Consumption of MDPV concentrations (0.1-1.0mg/mL) stimulated locomotor activity. Chronic (10day) access to 0.30mg/mL MDPV resulted in escalated consumption, but locomotor effects did not systematically change across the access period. Finally, consumption of 0.30mg/mL MDPV elicited CPP with a magnitude similar to the preference observed following intraperitoneal administration of MDPV. Consistent with human abuse patterns, oral MDPV has reinforcing effects in the mouse which are most likely related to its psychostimulant-like pharmacological profile.
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http://dx.doi.org/10.1016/j.drugalcdep.2017.06.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708564PMC
October 2017

Phencyclidine-like in vivo effects of methoxetamine in mice and rats.

Neuropharmacology 2018 05 19;134(Pt A):158-166. Epub 2017 Aug 19.

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Interdisciplinary Biomedical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address:

Methoxetamine (MXE) is a novel drug of abuse that is structurally similar to phencyclidine (PCP). In the present study, rats were trained to discriminate PCP from saline and substitution tests were performed with arylcyclohexylamines PCP, eticyclidine (PCE), tenocyclidine (TCP), and MXE. PCP and PCE engendered PCP-lever selection in all subjects, whereas MXE and TCP produced PCP-lever selection in animals that did not display behavioral disruption. Last, the substituted tryptamine dipropyltryptamine (DPT) produced moderate PCP-lever selection and elicited behavioral disruption in all subjects at the highest dose tested. Immediately following the final substitution test in the drug discrimination experiment, the same rats and a separate group of experimentally-naïve rats were implanted with osmotic mini-pumps delivering continuous PCP infusions for 11 days. Consistent with PCP withdrawal, disruption of food-maintained operant responding was observed when the pumps were removed, but cumulative MXE administration dose-dependently reversed this effect. A third group of rats self-administered several unit doses of PCP and MXE. Results of the self-administration tests revealed that MXE was a less effective reinforcer than PCP. Lastly, mice were implanted with radiotelemetry probes to simultaneously monitor thermoregulatory and locomotor responses following injections of PCP, PCE, or MXE. All three arylcyclohexylamines elicited dose-dependent hypothermic effects, but only PCP produced increases in locomotor activity. Together, these findings indicate that MXE elicits PCP-like interoceptive effects, but reduced reinforcing and locomotor stimulant effects in vivo. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
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http://dx.doi.org/10.1016/j.neuropharm.2017.08.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818319PMC
May 2018

Relative reinforcing effects of second-generation synthetic cathinones: Acquisition of self-administration and fixed ratio dose-response curves in rats.

Neuropharmacology 2018 05 12;134(Pt A):28-35. Epub 2017 Aug 12.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; South Texas Veterans Health Care System, San Antonio, TX 78229, USA. Electronic address:

"Bath salts" preparations contain synthetic cathinones which interact with monoamine transporters and function as either monoamine uptake inhibitors or releasers. 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), and 4-methylmethcathinone (mephedrone) were three of the most common cathinones (i.e., "first-generation" cathinones); however, after the US Drug Enforcement Administration placed them under Schedule I regulations, they were replaced with structurally related cathinones that were not subject to regulations (i.e., "second-generation" cathinones). Although the reinforcing effects of some second-generation cathinones have been described (e.g., α-pyrrolidinopentiophenone [α-PVP]), little is known about how structural modifications, particularly those involving the methylenedioxy moiety and α-alkyl side chain, impact the abuse liability of other second-generation cathinones (e.g., α-pyrrolidinopropiophenone [α-PPP], 3,4-methylenedioxy-α-pyrrolidinobutiophenone [MDPBP], and 3,4-methylenedioxy-α-pyrrolidinopropiophenone [MDPPP]). The present study used male Sprague-Dawley rats (n = 12 per drug) to directly compare: (1) the acquisition of responding for α-PVP (0.032 mg/kg/inf), α-PPP (0.32 mg/kg/inf), MDPBP (0.1 mg/kg/inf), and MDPPP (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement; and (2) full dose-response curves for each drug to maintain responding under an FR5 schedule of reinforcement. The average number of days (∼4 days) and percentage (100%) of rats that acquired self-administration was similar for each drug. The observed rank order potency to maintain responding under an FR5 schedule of reinforcement (α-PVP ≈ MDPBP>α-PPP > MDPPP) is consistent with their potencies to inhibit dopamine uptake. These are the first studies to report on the reinforcing effects of the unregulated second-generation cathinones MDPBP, MDPPP, and α-PPP and indicate all three compounds are readily self-administered, suggesting each possesses high potential for abuse. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
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http://dx.doi.org/10.1016/j.neuropharm.2017.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809320PMC
May 2018

Reinforcing Effects of Binary Mixtures of Common Bath Salt Constituents: Studies with 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-Methylenedioxymethcathinone (methylone), and Caffeine in Rats.

Neuropsychopharmacology 2018 03 5;43(4):761-769. Epub 2017 Jul 5.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Bath salts use is associated with high rates of abuse, toxicity, and death. Bath salt preparations often contain mixtures of drugs including multiple synthetic cathinones (eg, 3,4-methylenedioxypyrovalerone (MDPV) or 3,4-methylenedioxymethcathinone (methylone)) or synthetic cathinones and caffeine; however, little is known about whether interactions among bath salt constituents contribute to the abuse-related effects of bath salts preparations. This study used male Sprague-Dawley rats responding under a progressive ratio schedule to quantify the reinforcing effectiveness of MDPV, methylone, and caffeine, administered alone and as binary mixtures (n=12 per mixture). Each mixture was evaluated at four ratios (10 : 1, 3 : 1, 1 : 1, and 1 : 3) relative to the mean ED for each drug alone. Dose-addition analyses were used to determine the predicted, additive effect for each dose pair within each drug mixture. MDPV, methylone, and caffeine maintained responding in a dose-dependent manner, with MDPV being the most potent and effective, and caffeine being the least potent and effective of the three bath salts constituents. High levels of responding were also maintained by each of the bath salts mixtures. Although the nature of the interactions tended toward additivity for most bath salts mixtures, supra-additive (3 : 1 MDPV : caffeine, and 3 : 1 and 1 : 1 methylone : caffeine) and sub-additive (3 : 1, 1 : 1, and 1 : 3 MDPV : methylone) interactions were also observed. Together, these findings demonstrate that the composition of bath salts preparations can have an impact on both their reinforcing potency and effectiveness, and suggest that such interactions among constituent drugs could contribute to the patterns of use and effects reported by human bath salts users.
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http://dx.doi.org/10.1038/npp.2017.141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809783PMC
March 2018

Reinforcing effects of abused 'bath salts' constituents 3,4-methylenedioxypyrovalerone and α-pyrrolidinopentiophenone and their enantiomers.

Behav Pharmacol 2017 10;28(7):578-581

aDepartment of Pharmacology, University of Texas Health Science Center at San Antonio bSouth Texas Veterans Health Care System, San Antonio, Texas cMolecular Targets and Medications Discovery Branch, NIDA and NIAAA, Bethesda, Maryland, USA.

Synthetic cathinones found in abused 'bath salts' preparations are chiral molecules. Racemic 3,4-methylenedioxypyrovalerone (MDPV) and α-pyrrolidinopentiophenone (α-PVP) are two common constituents of these preparations that have been reported to be highly effective reinforcers; however, the relative contribution of each enantiomer toward these effects has not been determined. Thus, male Sprague-Dawley rats were trained to respond for racemic MDPV or α-PVP (n=9/drug), with full dose-response curves for the racemate and the S and R enantiomers of MDPV and α-PVP generated under a progressive ratio schedule of reinforcement. Racemic mixtures of both MDPV and α-PVP as well as each enantiomer maintained responding in a dose-dependent manner, with racemic MDPV and α-PVP being equipotent. The rank order of potency within each drug was S enantiomer>racemate ≫ R enantiomer. Although both enantiomers of α-PVP were as effective as racemic α-PVP, R-MDPV was a slightly less effective reinforcer than both S and racemic MDPV. The results of these studies provide clear evidence that both enantiomers of MDPV and α-PVP function as highly effective reinforcers and likely contribute toward the abuse-related effects of 'bath salts' preparations containing racemic MDPV and/or α-PVP.
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http://dx.doi.org/10.1097/FBP.0000000000000315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599337PMC
October 2017

Individual Differences in the Relative Reinforcing Effects of 3,4-Methylenedioxypyrovalerone under Fixed and Progressive Ratio Schedules of Reinforcement in Rats.

J Pharmacol Exp Ther 2017 04 8;361(1):181-189. Epub 2017 Feb 8.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (B.M.G., K.I.G., G.T.C.); South Texas Veterans Health Care System, San Antonio, Texas (G.T.C.); and Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R.)

The recreational use of designer drugs, including synthetic cathinones (bath salts), is associated with high levels of abuse and toxicity, and represents a growing threat to public health. 3,4-Methylenedioxypyrovalerone (MDPV) is a cocaine-like monoamine uptake inhibitor, and one of the most widely available and abused synthetic cathinones. The present study used male Sprague-Dawley rats to directly compare: (1) the acquisition of responding for MDPV and cocaine under a fixed ratio (FR) 1 schedule of reinforcement; (2) full dose-response curves for MDPV and cocaine under a FR5 schedule; and (3) progressive ratio (PR) schedules of reinforcement. Self-administration of MDPV and cocaine was acquired at comparable rates, and by a similar percentage of rats. Compared with cocaine, MDPV was ∼10-fold more potent and ∼3-fold more effective at maintaining responding (PR; final ratio completed). Unlike cocaine, for which little variability was observed among rats, the FR5 dose-response curve for MDPV was shifted ∼3-fold upward for a subset of rats (high-responders) relative to other rats with identical histories (low-responders). Compared with low-responding rats, high responders also self-administered more cocaine under the FR5 schedule, and earned significantly more MDPV, cocaine, and methamphetamine under a PR schedule of reinforcement. In addition to functioning as a significantly more effective reinforcer than either cocaine or methamphetamine, MDPV also appears to be unique in its capacity to establish an enduring phenotype in rats, characterized by unusually high levels of drug intake. Although the factors underlying this high-responder phenotype are unclear, they might be related to individual differences in human drug-taking behavior.
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http://dx.doi.org/10.1124/jpet.116.239376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363773PMC
April 2017

Methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxypyrovalerone (MDPV) induce differential cytotoxic effects in bovine brain microvessel endothelial cells.

Neurosci Lett 2016 08 16;629:125-130. Epub 2016 Jun 16.

Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, USA. Electronic address:

Designer drugs such as synthetic psychostimulants are indicative of a worldwide problem of drug abuse and addiction. In addition to methamphetamine (METH), these drugs include 3,4-methylenedioxy-methamphetamine (MDMA) and commercial preparations of synthetic cathinones including 3,4-methylenedioxypyrovalerone (MDPV), typically referred to as "bath salts." These psychostimulants exert neurotoxic effects by altering monoamine systems in the brain. Additionally, METH and MDMA adversely affect the integrity of the blood-brain barrier (BBB): there are no current reports on the effects of MDPV on the BBB. The aim of this study was to compare the effects of METH, MDMA and MDPV on bovine brain microvessel endothelial cells (bBMVECs), an accepted in vitro model of the BBB. Confluent bBMVEC monolayers were treated with METH, MDMA and MDPV (0.5mM-2.5mM) for 24h. METH and MDMA increased lactate dehydrogenase release only at the highest concentration (2.5mM), whereas MDPV induced cytotoxicity at all concentrations. MDMA and METH decreased cellular proliferation only at 2.5mM, with similar effects observed after MDPV exposures starting at 1mM. Only MDPV increased reactive oxygen species production at all concentrations tested whereas all 3 drugs increased nitric oxide production. Morphological analysis revealed different patterns of compound-induced cell damage. METH induced vacuole formation at 1mM and disruption of the monolayer at 2.5mM. MDMA induced disruption of the endothelial monolayer from 1mM without vacuolization. On the other hand, MDPV induced monolayer disruption at doses ≥0.5mM without vacuole formation; at 2.5mM, the few remaining cells lacked endothelial morphology. These data suggest that even though these synthetic psychostimulants alter monoaminergic systems, they each induce BBB toxicity by different mechanisms with MDPV being the most toxic.
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http://dx.doi.org/10.1016/j.neulet.2016.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983252PMC
August 2016

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine.

PLoS One 2016 10;11(3):e0150602. Epub 2016 Mar 10.

Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.

Rationale: The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays.

Methods: Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms.

Results: Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy.

Conclusions: The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150602PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786259PMC
August 2016

Stereoselective Effects of Abused "Bath Salt" Constituent 3,4-Methylenedioxypyrovalerone in Mice: Drug Discrimination, Locomotor Activity, and Thermoregulation.

J Pharmacol Exp Ther 2016 Mar 14;356(3):615-23. Epub 2016 Jan 14.

Department of Pharmacology and Toxicology (B.M.G., W.E.F.), College of Medicine (A.W.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institutes of Health National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (M.S., K.C.R.)

3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of illicit "bath salts" products. MDPV is a chiral molecule, but the contribution of each enantiomer to in vivo effects in mice has not been determined. To address this, mice were trained to discriminate 10 mg/kg cocaine from saline, and substitutions with racemic MDPV, S(+)-MDPV, and R(-)-MDPV were performed. Other mice were implanted with telemetry probes to monitor core temperature and locomotor responses elicited by racemic MDPV, S(+)-MDPV, and R(-)-MDPV under a warm (28°C) or cool (20°C) ambient temperature. Mice reliably discriminated the cocaine training dose from saline, and each form of MDPV fully substituted for cocaine, although marked potency differences were observed such that S(+)-MDPV was most potent, racemic MDPV was less potent than the S(+) enantiomer, and R(-)-MDPV was least potent. At both ambient temperatures, locomotor stimulant effects were observed after doses of S(+)-MDPV and racemic MDPV, but R(-)-MDPV did not elicit locomotor stimulant effects at any tested dose. Interestingly, significant increases in maximum core body temperature were only observed after administration of racemic MDPV in the warm ambient environment; neither MDPV enantiomer altered core temperature at any dose tested, at either ambient temperature. These studies suggest that all three forms of MDPV induce biologic effects, but R(-)-MDPV is less potent than S(+)-MDPV and racemic MDPV. Taken together, these data suggest that the S(+)-MDPV enantiomer is likely responsible for the majority of the biologic effects of the racemate and should be targeted in therapeutic efforts against MDPV overdose and abuse.
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http://dx.doi.org/10.1124/jpet.115.229500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767395PMC
March 2016

Cocaine-Like Discriminative Stimulus Effects of Mephedrone and Naphyrone in Mice.

J Drug Alcohol Res 2016 31;5. Epub 2016 Dec 31.

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Background: In recent years, commercial products containing synthetic cathinone analogues have emerged as illicit drugs of abuse. These cathinones are structurally similar to the psychostimulants 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH), and produce their effects via interactions with monoamine transporters, where smaller compounds (e.g., mephedrone) are amphetamine-like monoamine releasers, while the structurally larger compounds (e.g., naphyrone) are cocaine-like monoamine reuptake inhibitors. Individual cathinones also differ from one another with respect to selectivity among the three monoamine transporters.

Statement Of Purpose Of Study: This study was designed to assess the cocaine-like interoceptive effects of synthetic cathinone analogues functioning as passive monoamine reuptake inhibitors (naphyrone) or as releasers (mephedrone) in mice in order to compare effectiveness (degree of substitution) and potency with positive control psychostimulants cocaine, METH, and MDMA.

Procedures: In the present study, mice were trained to discriminate 10 mg/kg cocaine from saline, and substitutions with METH, MDMA, mephedrone, naphyrone, and morphine were performed.

Main Findings: Mice reliably discriminated the cocaine training dose from saline, and METH, MDMA, mephedrone, and naphyrone all elicited full cocaine-like responding, while morphine did not. Potency differences were observed such that METH was most potent, while mephedrone, cocaine, MDMA, and naphyrone exhibited roughly equivalent potency.

Principal Conclusions: These data confirm that interaction with DAT is an important component of cocaine-like discriminative stimulus effects, and suggest that synthetic cathinones likely elicit psychostimulant-like abuse-related effects.
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http://dx.doi.org/10.4303/jdar/236009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393345PMC
December 2016

Psychostimulant Abuse and HIV Infection: cocaine, methamphetamine, and "bath salts" cathinone analogues.

Curr Addict Rep 2014 Sep;1(3):237-242

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR.

Psychostimulants are among the most widely-abused substances worldwide, and typically exert their abuse-related effects via interactions with monoamine reuptake transporters within the CNS. Over the last decade, a symbiotic relationship between psychostimulant abuse and HIV infection has been demonstrated, where psychostimulants potentiate the effects of HIV infection, and HIV infection increases sensitivity to psychostimulant drugs. Most recently, a new class of designer psychostimulants has emerged in abuse-ready "bath salt" preparations. These commercial products typically contain ring-substituted and/or side-chain-substituted analogues of cathinone, which is itself a psychostimulant drug of abuse in its natural plant form. The cathinone analogues exhibit a range of interactions with monoamine transporters, from cocaine-like reuptake inhibition to methamphetamine-like release. Since the primary mechanism of action of these novel drugs overlaps with those of traditional psychostimulants, it may be the case that the cathinone analogues also interact with HIV infection. As use of these emerging cathinone-derived drugs continues to rise, there is an urgent need to better understand the pharmacology and toxicology of these novel compounds, both in terms of their abuse-related effects, and in terms of their capacity to interact with HIV infection.
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http://dx.doi.org/10.1007/s40429-014-0025-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582446PMC
September 2014

Hippocampal administration of chondroitinase ABC increases plaque-adjacent synaptic marker and diminishes amyloid burden in aged APPswe/PS1dE9 mice.

Acta Neuropathol Commun 2015 Sep 4;3:54. Epub 2015 Sep 4.

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 611, Little Rock, AR, 72205, USA.

Introduction: Substantial data has shown that the lectican group of chondroitin sulfate proteoglycans are involved in inhibition of axonal plasticity in response to injury in the central nervous system. Increasing evidence indicates that lecticans may also play a role in synaptic plasticity related to memory, especially associated with aging. A recent study has shown that lectican expression is elevated at a young age in the APPswe/PS1dE9 mouse model and Alzheimer's disease (AD) and hippocampal treatment with chondroitinase ABC reversed a loss of contextual fear memory and restored long-term potentiation. The purpose of this study was to examine the presence of a synaptic lectican in AD tissue, determine if amyloid-β (Aβ) binds to lecticans purified from brain tissue, and examine how treatment of the same AD model with chondroitinase ABC would influence plaque burden and the density of the synaptic marker synaptophysin around plaques.

Results: In human superior frontal gyrus, levels of the brain-specific lectican, brevican, were significantly elevated in AD compared to non-cognitively impaired subjects, with a trend toward an increase in tissue from subjects with mild cognitive impairment. In vitro immunoprecipitation studies showed that brevican binds to oligomeric and fibrillar Aβ1-42, and less so to monomeric Aβ1-42. Intrahippocampal injection of 15 months APPswe/PS1dE9 mice with chondroitinase ABC resulted in a reduction of Aβ burden in the stratum lacunosum moleculare and a reversal of the loss of synaptic density surrounding plaques in the same region.

Conclusions: It is possible that lecticans, particularly brevican, inhibit synaptic plasticity in this model of AD. Since the hippocampus undergoes changes in synaptic plasticity early in the disease process, it could be possible that removal of lecticans or inhibition of their signaling pathways could prolong plasticity in patients early in the disease process, and delay cognitive decline of AD progression.
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http://dx.doi.org/10.1186/s40478-015-0233-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559967PMC
September 2015

In vivo effects of abused 'bath salt' constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice: drug discrimination, thermoregulation, and locomotor activity.

Neuropsychopharmacology 2013 Mar 8;38(4):563-73. Epub 2012 Nov 8.

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

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.
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http://dx.doi.org/10.1038/npp.2012.233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572465PMC
March 2013