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.
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Pyrazoloquinolinones (PQs) have been extensively studied as modulators of GABAA receptors with different subunit composition, exerting modulatory effects by binding at α+/β- ...interfaces of GABAA receptors. PQs with a substituent in position R7 have been reported to preferentially modulate α6- subunit containing GABAA receptors which are mostly expressed in the cerebellum but were also found in the olfactory bulb, in the cochlear nucleus, in the hippocampus and in the trigeminal sensory pathway. They are considered potentially interesting in the context of sensori-motor gating deficits, depressive-like behavior, migraine and orofacial pain. Here we explored the option to modify the lead ligands’ R7 position. In the compound series we observed two different patterns of allosteric modulation in recombinantly expressed α6β3γ2 receptors, namely monophasic and biphasic positive modulation. In the latter case the additional phase occurred in the nanomolar range, while all compounds displayed robust modulation in the micromolar range. Nanomolar, near silent binding has been reported to occur at benzodiazepine binding sites, but was not investigated at the diazepam insensitive α6+/γ2- interface. To clarify the mechanism underlying the biphasic effect we tested one of the compounds in concatenated receptors. In these constructs the subunits are covalently linked, allowing to form either the α6+/γ2- interface, or the α6+/β3- interface, to study the resulting modulation. With this approach we were able to ascribe the nanomolar modulation to the α6+/γ2- interface. While not all compounds display the nanomolar phase, the strong modulation at the α6+/β3 interface proved to be tolerant for all tested R7 groups. This provides the future option to introduce e.g. isotope labelled or fluorescent moieties or substituents that enhance solubility and bioavailability.
The internal structure of nucleons (protons and neutrons) remains one of the greatest outstanding problems in modern nuclear physics. By scattering high-energy electrons off a proton we are able to ...resolve its fundamental constituents and probe their momenta and positions. Here we investigate the dynamics of quarks and gluons inside nucleons using deeply virtual Compton scattering (DVCS)-a highly virtual photon scatters off the proton, which subsequently radiates a photon. DVCS interferes with the Bethe-Heitler (BH) process, where the photon is emitted by the electron rather than the proton. We report herein the full determination of the BH-DVCS interference by exploiting the distinct energy dependences of the DVCS and BH amplitudes. In the regime where the scattering is expected to occur off a single quark, measurements show an intriguing sensitivity to gluons, the carriers of the strong interaction.
The three-dimensional structure of nucleons (protons and neutrons) is embedded in so-called generalized parton distributions, which are accessible from deeply virtual Compton scattering. In this ...process, a high-energy electron is scattered off a nucleon by exchanging a virtual photon. Then, a highly energetic real photon is emitted from one of the quarks inside the nucleon, which carries information on the quark’s transverse position and longitudinal momentum. By measuring the cross-section of deeply virtual Compton scattering, Compton form factors related to the generalized parton distributions can be extracted. Here, we report the observation of unpolarized deeply virtual Compton scattering off a deuterium target. From the measured photon-electroproduction cross-sections, we have extracted the cross-section of a quasifree neutron and a coherent deuteron. Due to the approximate isospin symmetry of quantum chromodynamics, we can determine the contributions from the different quark flavours to the helicity-conserved Compton form factors by combining our measurements with previous ones probing the proton’s internal structure. These results advance our understanding of the description of the nucleon structure, which is important to solve the proton spin puzzle.The internal structure of the neutron has now been probed by highly energetic photons scattering off it. Combined with previous results for protons, these measurements reveal the contributions of quark flavours to the nucleon structure.
The electromagnetic form factors of the proton and neutron encode information on the spatial structure of their charge and magnetization distributions. While measurements of the proton are relatively ...straightforward, the lack of a free neutron target makes measurements of the neutron's electromagnetic structure more challenging and more sensitive to experimental or model-dependent uncertainties. Various experiments have attempted to extract the neutron form factors from scattering from the neutron in deuterium, with different techniques providing different, and sometimes large, systematic uncertainties. We present results from a novel measurement of the neutron magnetic form factor using quasielastic scattering from the mirror nuclei ^{3}H and ^{3}He, where the nuclear effects are larger than for deuterium but expected to largely cancel in the cross-section ratios. We extracted values of the neutron magnetic form factor for low-to-modest momentum transfer, 0.6<Q^{2}<2.9 GeV^{2}, where existing measurements give inconsistent results. The precision and Q^{2} range of these data allow for a better understanding of the current world's data and suggest a path toward further improvement of our overall understanding of the neutron's magnetic form factor.
The strong interaction is not well understood at low energies or for interactions with low momentum transfer. Chiral perturbation theory gives testable predictions for the nucleonic generalized ...polarizabilities, which are fundamental quantities describing the nucleon’s response to an external field. We report a measurement of the proton’s generalized spin polarizabilities extracted with a polarized electron beam and a polarized solid ammonia target in the region where chiral perturbation theory is expected to be valid. The investigated structure function g2 characterizes the internal spin structure of the proton. From its moments, we extract the longitudinal–transverse spin polarizability δLT and twist-3 matrix element and polarizability d2¯. Our results provide discriminating power between existing chiral perturbation theory calculations and will help provide a better understanding of this strong quantum chromodynamics regime.Measurements of the proton’s generalized spin polarizabilities provide discriminating power between effective descriptions of the strong interaction at low energy.
Valerenic acid (VA)-a β2/3-selective GABA type A (GABAA) receptor modulator-displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we ...analyzed β-subunit-dependent enhancement of GABA-induced chloride currents (IGABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced IGABA enhancement was determined in oocytes expressing α1β1γ2S, α1β2γ2S, or α1β3γ2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. β2/3-selective VA derivatives such as VA-amide (VA-A) modulating α1β3γ2S (VA-A: Emax = 972 ± 69%, n = 6, P < 0.05) and α1β2γ2S receptors (Emax = 1119 ± 72%, n = 6, P < 0.05) more efficaciously than VA (α1β3γ2S: VA: Emax = 632 ± 88%, n = 9 versus α1β2γ2S: VA: Emax = 721 ± 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 ± 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 ± 1.9 mg/kg PTZ, P < 0.05). Similarly, VA's methylamide (VA-MA) enhancing IGABA through β3-containing receptors more efficaciously than VA (Emax = 1043 ± 57%, P < 0.01, n = 6) displayed stronger anticonvulsive effects. Increased potency of IGABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole (α1β3γ2S: VA-TET: EC50 = 6.0 ± 1.0 μM, P < 0.05; VA-TET: 0.3 mg/kg: 47.3 ± 0.5 mg/kg PTZ versus VA: 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ, P < 0.05). At higher doses (≥10 mg/kg), VA-A, VA-MA, and VA-TET reduced locomotion. In contrast, unselective VA derivatives induced anticonvulsive effects only at high doses (30 mg/kg) or did not display any behavioral effects. Our data indicate that the β2/3-selective compounds VA-A, VA-MA, and VA-TET induce anticonvulsive effects at low doses (≤10 mg/kg), whereas impairment of locomotion was observed at doses ≥10 mg/kg.
The parity-violating cross-section asymmetry in the elastic scattering of polarized electrons from unpolarized protons has been measured at a four-momentum transfer squared Q2 = 0.624 GeV2 and beam ...energy E(b) = 3.48 GeV to be A(PV) = -23.80 ± 0.78(stat) ± 0.36(syst) parts per million. This result is consistent with zero contribution of strange quarks to the combination of electric and magnetic form factors G(E)(s) + 0.517G(M)(s) = 0.003 ± 0.010(stat) ± 0.004(syst) ± 0.009(ff), where the third error is due to the limits of precision on the electromagnetic form factors and radiative corrections. With this measurement, the world data on strange contributions to nucleon form factors are seen to be consistent with zero and not more than a few percent of the proton form factors.
We present deeply virtual π^{0} electroproduction cross-section measurements at x_{B}=0.36 and three different Q^{2} values ranging from 1.5 to 2 GeV^{2}, obtained from Jefferson Lab Hall A ...experiment E07-007. The Rosenbluth technique is used to separate the longitudinal and transverse responses. Results demonstrate that the cross section is dominated by its transverse component and, thus, is far from the asymptotic limit predicted by perturbative quantum chromodynamics. Nonetheless, an indication of a nonzero longitudinal contribution is provided by the measured interference term σ_{LT}. Results are compared with several models based on the leading-twist approach of generalized parton distributions (GPDs). In particular, a fair agreement is obtained with models in which the scattering amplitude includes convolution terms of chiral-odd (transversity) GPDs of the nucleon with the twist-3 pion distribution amplitude. This experiment, together with previous extensive unseparated measurements, provides strong support to the exciting idea that transversity GPDs can be accessed via neutral pion electroproduction in the high-Q^{2} regime.
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