2024 |
Sherwood, Alexander M; Burkhartzmeyer, Elise K; Williamson, Samuel E; Baumann, Michael H; Glatfelter, Grant C Psychedelic-like Activity of Norpsilocin Analogues Journal Article In: ACS Chem Neurosci, vol. 15, no. 2, pp. 315–327, 2024, ISSN: 1948-7193. @article{pmid38189238,Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT) but differ in their 5-HT-mediated effects . In particular, psilocin produces centrally mediated psychedelic effects , whereas norpsilocin, differing only by the loss of an -methyl group, is devoid of psychedelic-like effects. These observations suggest that the secondary methylamine group in norpsilocin impacts its central nervous system (CNS) bioavailability but not its receptor pharmacodynamics. To test this hypothesis, eight norpsilocin derivatives were synthesized with varied secondary alkyl-, allyl-, and benzylamine groups, primarily aiming to increase their lipophilicity and brain permeability. Structure-activity relationships for the norpsilocin analogues were evaluated using the mouse head-twitch response (HTR) as a proxy for CNS-mediated psychedelic-like effects. HTR studies revealed that extending the -methyl group of norpsilocin by a single methyl group, to give the corresponding secondary -ethyl analogue (4-HO-NET), was sufficient to produce psilocin-like activity (median effective dose or ED = 1.4 mg/kg). Notably, -allyl, -propyl, -isopropyl, and -benzyl derivatives also induced psilocin-like HTR activity (ED = 1.1-3.2 mg/kg), with variable maximum effects (26-77 total HTR events). By contrast, adding bulkier -butyl or cyclohexyl groups in the same position did not elicit psilocin-like HTRs. Pharmacological assessments of the tryptamine series demonstrated interactions with multiple serotonin receptor subtypes, including 5-HT, and other CNS signaling proteins (e.g., sigma receptors). Overall, our data highlight key structural requirements for CNS-mediated psychedelic-like effects of norpsilocin analogues. |
2023 |
Glatfelter, Grant C; Vandeputte, Marthe M; Chen, Li; Walther, Donna; Tsai, Meng-Hua M; Shi, Lei; Stove, Christophe P; Baumann, Michael H Alkoxy chain length governs the potency of 2-benzylbenzimidazole 'nitazene' opioids associated with human overdose Journal Article In: Psychopharmacology (Berl), vol. 240, no. 12, pp. 2573–2584, 2023, ISSN: 1432-2072. @article{pmid37658878,RATIONALE: Novel synthetic opioids (NSOs) are emerging in recreational drug markets worldwide. In particular, 2-benzylbenzimidazole 'nitazene' compounds are problematic NSOs associated with serious clinical consequences, including fatal respiratory depression. Evidence from in vitro studies shows that alkoxy chain length can influence the potency of nitazenes at the mu-opioid receptor (MOR). However, structure-activity relationships (SARs) of nitazenes for inducing opioid-like effects in animal models are not well understood compared to relevant opioids contributing to the ongoing opioid crisis (e.g., fentanyl).nnOBJECTIVES: Here, we examined the in vitro and in vivo effects of nitazene analogues with varying alkoxy chain lengths (i.e., metonitazene, etonitazene, isotonitazene, protonitazene, and butonitazene) as compared to reference opioids (i.e., morphine and fentanyl).nnMETHODS AND RESULTS: Nitazene analogues displayed nanomolar affinities for MOR in rat brain membranes and picomolar potencies to activate MOR in transfected cells. All compounds induced opioid-like effects on locomotor activity, hot plate latency, and body temperature in male mice, and alkoxy chain length markedly influenced potency. Etonitazene, with an ethoxy chain, was the most potent analogue in MOR functional assays (EC = 30 pM, E = 103%) and across all in vivo endpoints (ED = 3-12 μg/kg). In vivo SARs revealed that ethoxy, isopropoxy, and propoxy chains engendered higher potencies than fentanyl, whereas methoxy and butoxy analogues were less potent. MOR functional potencies, but not MOR affinities, were positively correlated with in vivo potencies to induce opioid effects.nnCONCLUSIONS: Overall, our data show that certain nitazene NSOs are more potent than fentanyl as MOR agonists in mice, highlighting concerns regarding the high potential for overdose in humans who are exposed to these compounds. |
Vandeputte, Marthe M; Tsai, Meng-Hua M; Chen, Li; Glatfelter, Grant C; Walther, Donna; Stove, Christophe P; Shi, Lei; Baumann, Michael H Comparative neuropharmacology of structurally distinct non-fentanyl opioids that are appearing on recreational drug markets worldwide Journal Article In: Drug Alcohol Depend, vol. 249, pp. 109939, 2023, ISSN: 1879-0046. @article{pmid37276825,BACKGROUND: The emergence of novel synthetic opioids (NSOs) is contributing to the opioid overdose crisis. While fentanyl analogs have historically dominated the NSO market, a shift towards non-fentanyl compounds is now occurring.nnMETHODS: Here, we examined the neuropharmacology of structurally distinct non-fentanyl NSOs, including U-47700, isotonitazene, brorphine, and N-desethyl isotonitazene, as compared to morphine and fentanyl. Compounds were tested in vitro using opioid receptor binding assays in rat brain tissue and by monitoring forskolin-stimulated cAMP accumulation in cells expressing the human mu-opioid receptor (MOR). Compounds were administered subcutaneously to male Sprague-Dawley rats, and hot plate antinociception, catalepsy score, and body temperature changes were measured.nnRESULTS: Receptor binding results revealed high MOR selectivity for all compounds, with MOR affinities comparable to those of morphine and fentanyl (i.e., nM). All drugs acted as full-efficacy MOR agonists in the cyclic AMP assay, but nitazene analogs had greater functional potencies (i.e., pM) compared to the other drugs (i.e., nM). When administered to rats, all compounds induced opioid-like antinociception, catalepsy, and body temperature changes, but nitazenes were the most potent. Similar to fentanyl, the nitazenes had faster onset and decline of in vivo effects when compared to morphine. In vivo potencies to induce antinociception and catalepsy (i.e., EDs) correlated with in vitro functional potencies (i.e., ECs) but not binding affinities (i.e., Ks) at MOR.nnCONCLUSIONS: Collectively, our findings indicate that non-fentanyl NSOs pose grave danger to those individuals who use opioids. Continued vigilance is needed to identify and characterize synthetic opioids as they emerge in clandestine drug markets. |
2018 |
Elmore, Joshua S; Decker, Ann M; Sulima, Agnieszka; Rice, Kenner C; Partilla, John S; Blough, Bruce E; Baumann, Michael H Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats. Journal Article In: Neuropharmacology, 2018, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking). @article{Elmore:2018ab,2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2A receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT2A receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3mg/kg), 25I-NBOMe (0.01-0.3mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1-3.0mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0mg/kg) and DOI (0.03-1.0mg/kg) were administered subcutaneously (sc) to male rats, and 5-HT2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT2A receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C-I. Pretreatment with the selective 5-HT2A antagonist (R)-(2,3-dimethoxyphenyl)1-[2-(4-fluorophenyl)ethyl]-4-piperidinylmethanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT2A agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users. |
Elmore, Joshua S; Baumann, Michael H Repeated Exposure to the "Spice" Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats. Journal Article In: Front Psychiatry, vol. 9, pp. 55, 2018, ISSN: 1664-0640 (Print); 1664-0640 (Linking). @article{Elmore:2018aa,Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) is a synthetic compound found in psychoactive "spice" products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc) temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc) or its vehicle for seven consecutive days. Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc) or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc), then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks), while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading, and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo. |
2017 |
Schindler, Charles W; Gramling, Benjamin R; Justinova, Zuzana; Thorndike, Eric B; Baumann, Michael H Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats. Journal Article In: Drug Alcohol Depend, vol. 179, pp. 387–394, 2017, ISSN: 1879-0046 (Electronic); 0376-8716 (Linking). @article{Schindler:2017aa,BACKGROUND: The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Delta(9)-tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. METHODS: Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. RESULTS: THC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH-018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the alpha1 adrenergic antagonist prazosin. CONCLUSIONS: Our results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow. |
Solis, Ernesto Jr; Partilla, John S; Sakloth, Farhana; Ruchala, Iwona; Schwienteck, Kathryn L; Felice, Louis J De; Eltit, Jose M; Glennon, Richard A; Negus, Stevens S; Baumann, Michael H N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability. Journal Article In: Neuropsychopharmacology, vol. 42, no. 10, pp. 1950–1961, 2017, ISSN: 1740-634X (Electronic); 0893-133X (Linking). @article{Solis:2017aa,Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability. All 4-MA analogs inhibited uptake at DAT, NET, and SERT, but lengthening the amine substituent from methyl to ethyl, propyl, and butyl produced a stepwise decrease in potency. N-methyl 4-MA was an efficacious substrate-type releaser at DAT that evoked an inward depolarizing current and calcium influx, whereas other analogs did not exhibit these effects. N-methyl and N-ethyl 4-MA were substrates at NET, whereas N-propyl and N-butyl 4-MA were not. All analogs acted as SERT substrates, though N-butyl 4-MA had very weak effects. Intracranial self-stimulation in rats showed that elongating the N-alkyl chain decreased abuse-related effects in vivo that appeared to parallel reductions in DAT activity. Overall, converging lines of evidence show that lengthening the N-alkyl substituent of 4-MA reduces potency to inhibit transporters, eliminates substrate activity at DAT and NET, and decreases abuse liability of the compounds. |
Prekupec, Matthew P; Mansky, Peter A; Baumann, Michael H Misuse of Novel Synthetic Opioids: A Deadly New Trend. Journal Article In: J Addict Med, vol. 11, no. 7, pp. 256–265, 2017. @article{Prekupec2017,Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non-fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone. |
Elmore, Joshua S; Dillon-Carter, Ora; Partilla, John S; Ellefsen, Kayla N; Concheiro, Marta; Suzuki, Masaki; Rice, Kenner C; Huestis, Marilyn A; Baumann, Michael H Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats. Journal Article In: Neuropsychopharmacology, vol. 42, no. 3, pp. 649–660, 2017, ISSN: 1740-634X (Electronic); 0893-133X (Linking). @article{Elmore:2017aa,3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the beta-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of methylone and its metabolites after subcutaneous (sc) methylone administration (3, 6, 12 mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that methylone and MDC peaked early (Tmax=15-45 min) and were short lived (t1/2=60-90 min), while HHMC and HMMC peaked later (Tmax=60-120 min) and persisted (t1/2=120-180 min). Area-under-the-curve values for methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only methylone and MDC (1, 3 mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo. |
2016 |
Schindler, Charles W; Thorndike, Eric B; Suzuki, Masaki; Rice, Kenner C; Baumann, Michael H Pharmacological mechanisms underlying the cardiovascular effects of the "bath salt" constituent 3,4-methylenedioxypyrovalerone (MDPV). Journal Article In: Br J Pharmacol, vol. 173, no. 24, pp. 3492–3501, 2016, ISSN: 1476-5381 (Electronic); 0007-1188 (Linking). @article{Schindler:2016ab,BACKGROUND AND PURPOSE: 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with stimulatory cardiovascular effects that can lead to serious medical complications. Here, we examined the pharmacological mechanisms underlying these cardiovascular actions of MDPV in conscious rats. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats had telemetry transmitters surgically implanted for the measurement of BP and heart rate (HR). On test days, rats were placed individually in standard isolation cubicles. Following drug treatment, cardiovascular parameters were monitored for 3 h sessions. KEY RESULTS: Racemic MDPV (0.3-3.0 mg.kg(-1) ) increased BP and HR in a dose-dependent manner. The S(+) enantiomer (0.3-3.0 mg.kg(-1) ) of MDPV produced similar effects, while the R(-) enantiomer (0.3-3.0 mg.kg(-1) ) had no effects. Neither of the hydroxylated phase I metabolites of MDPV altered cardiovascular parameters significantly from baseline. Pretreatment with the ganglionic blocker chlorisondamine (1 and 3 mg.kg(-1) ) antagonized the increases in BP and HR produced by 1 mg.kg(-1) MDPV. The alpha1 -adrenoceptor antagonist prazosin (0.3 mg.kg(-1) ) attenuated the increase in BP following MDPV, while the beta-adrenoceptor antagonists propranolol (1 mg.kg(-1) ) and atenolol (1 and 3 mg.kg(-1) ) attenuated the HR increases. CONCLUSIONS AND IMPLICATIONS: The S(+) enantiomer appeared to mediate the cardiovascular effects of MDPV, while the metabolites of MDPV did not alter BP or HR significantly; MDPV increased BP and HR through activation of central sympathetic outflow. Mixed-action alpha/beta-adrenoceptor antagonists may be useful as treatments in counteracting the adverse cardiovascular effects of MDPV. |
Mayer, F P; Wimmer, L; Dillon-Carter, O; Partilla, J S; Burchardt, N V; Mihovilovic, M D; Baumann, M H; Sitte, H H Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters. Journal Article In: Br J Pharmacol, vol. 173, no. 17, pp. 2657–2668, 2016, ISSN: 1476-5381 (Electronic); 0007-1188 (Linking). @article{Mayer:2016aa,BACKGROUND AND PURPOSE: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. EXPERIMENTAL APPROACH: We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3 mg.kg(-1) ) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. KEY RESULTS: In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood-brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone. |
Schindler, Charles W; Thorndike, Eric B; Goldberg, Steven R; Lehner, Kurt R; Cozzi, Nicholas V; Brandt, Simon D; Baumann, Michael H In: Psychopharmacology (Berl), vol. 233, no. 10, pp. 1981–1990, 2016, ISSN: 1432-2072 (Electronic); 0033-3158 (Linking). @article{Schindler:2016aa,RATIONALE: 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called "bath salts" products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT). OBJECTIVES: We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. METHODS: To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. RESULTS: MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. In contrast, methylone self-administration (0.3 and 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. CONCLUSIONS: Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats, suggesting these drugs possess significant abuse liability in humans. |
Marusich, Julie A; Antonazzo, Kateland R; Blough, Bruce E; Brandt, Simon D; Kavanagh, Pierce V; Partilla, John S; Baumann, Michael H In: Neuropharmacology, vol. 101, pp. 68–75, 2016, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking). @article{Marusich:2016aa,In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users. |
2024 |
Psychedelic-like Activity of Norpsilocin Analogues Journal Article In: ACS Chem Neurosci, vol. 15, no. 2, pp. 315–327, 2024, ISSN: 1948-7193. |
2023 |
Alkoxy chain length governs the potency of 2-benzylbenzimidazole 'nitazene' opioids associated with human overdose Journal Article In: Psychopharmacology (Berl), vol. 240, no. 12, pp. 2573–2584, 2023, ISSN: 1432-2072. |
Comparative neuropharmacology of structurally distinct non-fentanyl opioids that are appearing on recreational drug markets worldwide Journal Article In: Drug Alcohol Depend, vol. 249, pp. 109939, 2023, ISSN: 1879-0046. |
2018 |
Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats. Journal Article In: Neuropharmacology, 2018, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking). |
Repeated Exposure to the "Spice" Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats. Journal Article In: Front Psychiatry, vol. 9, pp. 55, 2018, ISSN: 1664-0640 (Print); 1664-0640 (Linking). |
2017 |
Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats. Journal Article In: Drug Alcohol Depend, vol. 179, pp. 387–394, 2017, ISSN: 1879-0046 (Electronic); 0376-8716 (Linking). |
N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability. Journal Article In: Neuropsychopharmacology, vol. 42, no. 10, pp. 1950–1961, 2017, ISSN: 1740-634X (Electronic); 0893-133X (Linking). |
Misuse of Novel Synthetic Opioids: A Deadly New Trend. Journal Article In: J Addict Med, vol. 11, no. 7, pp. 256–265, 2017. |
Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats. Journal Article In: Neuropsychopharmacology, vol. 42, no. 3, pp. 649–660, 2017, ISSN: 1740-634X (Electronic); 0893-133X (Linking). |
2016 |
Pharmacological mechanisms underlying the cardiovascular effects of the "bath salt" constituent 3,4-methylenedioxypyrovalerone (MDPV). Journal Article In: Br J Pharmacol, vol. 173, no. 24, pp. 3492–3501, 2016, ISSN: 1476-5381 (Electronic); 0007-1188 (Linking). |
Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters. Journal Article In: Br J Pharmacol, vol. 173, no. 17, pp. 2657–2668, 2016, ISSN: 1476-5381 (Electronic); 0007-1188 (Linking). |
In: Psychopharmacology (Berl), vol. 233, no. 10, pp. 1981–1990, 2016, ISSN: 1432-2072 (Electronic); 0033-3158 (Linking). |
In: Neuropharmacology, vol. 101, pp. 68–75, 2016, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking). |
