2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors

Rationale: Over the last decade many new psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs. Another aminoindan derivative, 5-methoxy-2-aminoindan (5-MeO-AI or MEAI), is the active ingredient in a product marketed online as an alcohol substitute. Methods: Here we tested 2-AI and its ring-substituted derivatives 5-MeO-AI, 5-methoxy-6-methyl-2-aminoindan (MMAI), and 5,6-methylenedioxy-2-aminoindan (MDAI) for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We also compared the binding affinities of the aminoindans at 29 receptor and transporter binding sites. Results: 2-AI was a selective substrate for NET and DAT. Ring substitution increased potency at SERT while reducing potency at DAT and NET. MDAI was moderately selective for SERT and NET, with 10-fold weaker effects on DAT. 5-MeO-AI exhibited some selectivity for SERT, having 6-fold lower potency at NET and 20-fold lower potency at DAT. MMAI was highly selective for SERT, with 100-fold lower potency at NET and DAT. The aminoindans had relatively high affinity for α2-adrenoceptor subtypes. 2-AI had particularly high affinity for α2C receptors (Ki = 41 nM) and slightly lower affinity for the α2A (Ki = 134 nM) and α2B (Ki = 211 nM) subtypes. 5-MeO-AI and MMAI also had moderate affinity for the 5-HT2B receptor. Conclusions: 2-AI is predicted to have (+)-amphetamine-like effects and abuse potential whereas the ring-substituted derivatives may produce 3,4-methylenedioxymethamphetamine (MDMA)-like effects but with less abuse liability

Impact of novel psychoactive substances on clinical and forensic toxicology and global public health

Novel psychoactive substances (NPS) have been a part of the landscape of clinical and forensic toxicology for over a century, beginning with the introduction of a few new drugs like heroin, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA) and gammahydroxybutyric acid (GHB). However, after the appearance of synthetic cannabinoids in the early 2000’s there was a rapid emergence of hundreds of synthetic cathinones, benzodiazepines and opioids. Toxicology laboratories previously focused on a rather narrow range of compounds including amphetamines, cannabinoids, cocaine, opioids, antidepressants, salicylate and acetaminophen. Now potent fentanyl derivatives are mixed with heroin or substituted entirely, killing unsuspecting drug users at an alarming rate. Toxicology laboratories are challenged with detecting potent drug analogs that are only present in blood for a short period of time, urinary metabolites whose chemical formula and structures are initially unknown, and no available reference standards. Here four international experts discuss what fueled the global NPS market, how toxicology laboratories can best address this challenge, and how public health and law enforcement agencies can help reduce the morbidity and mortality associated with NPS

Reinforcing and neurochemical effects of the "bath salts" constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats.

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

Pneumothorax, pneumomediastinum and subcutaneous emphysema following closed percutaneous pleural biopsy: a case report

Minimally invasive investigations, such as pleural fluid cytological assessment and closed percutaneous pleural biopsy, are often performed first in the investigation of suspected malignant pleural effusions. Malignant pleural effusions can be diagnosed with pleural fluid cytology alone in most cases; however, closed pleural biopsy is performed to increase the diagnostic yield when pleural fluid cytology is negative. This additional yield is at the expense of increased complication rates. We report a 64-year old man with a negative pleural fluid cytology but suspected malignant pleural effusion who underwent a closed pleural biopsy, which was complicated by pneumothorax, pneumomediastinum and severe subcutaneous emphysema. Pulmonary laceration by the pleural biopsy needle is the most likely aetiology of these complications. Our case report highlights an infrequent but significant complication of closed percutaneous pleural biopsy

Is there a no-go theorem for superradiant quantum phase transitions in cavity and circuit QED ?

In cavity quantum electrodynamics (QED), the interaction between an atomic transition and the cavity field is measured by the vacuum Rabi frequency $\Omega_0$. The analogous term "circuit QED" has been introduced for Josephson junctions, because superconducting circuits behave as artificial atoms coupled to the bosonic field of a resonator. In the regime with $\Omega_0$ comparable to the two-level transition frequency, "superradiant" quantum phase transitions for the cavity vacuum have been predicted, e.g. within the Dicke model. Here, we prove that if the time-independent light-matter Hamiltonian is considered, a superradiant quantum critical point is forbidden for electric dipole atomic transitions due to the oscillator strength sum rule. In circuit QED, the capacitive coupling is analogous to the electric dipole one: yet, such no-go property can be circumvented by Cooper pair boxes capacitively coupled to a resonator, due to their peculiar Hilbert space topology and a violation of the corresponding sum rule

Atypical dopamine efflux caused by3,4-methylenedioxypyrovalerone (MDPV) via the human dopamine transporter

Synthetic cathinones are similar in chemical structure to amphetamines, and their behavioral effects are associated with enhanced dopaminergic signaling. The past ten years of research on the common constituent of bath salts, MDPV (the synthetic cathinone 3,4-methylenedioxypyrovalerone), has aided the understanding of how synthetic cathinones act at the dopamine (DA) transporter (DAT). Several groups have described the ability of MDPV to block the DAT with high-affinity. In this study, we demonstrate for the first time, a new mode of action of MDPV, namely its ability to promote DAT-mediated DA efflux. Using single cell amperometric assays, we determined that low concentrations of MDPV (1 nM) can cause reverse transport of DA via DAT. Notably, administration of MDPV leads to hyperlocomotion in Drosophila melanogaster. These data describe further how MDPV acts at the DAT possibly paving the way for novel treatment strategies for individuals who abuse bath salts

Analytical characterization and pharmacological evaluation of the new psychoactive substance 4-fluoromethylphenidate (4F-MPH) and differentiation between the (±)-threo- and (±)-erythro- diastereomers

Misuse of (±)-threo-methylphenidate (methyl-2-phenyl-2-(piperidin-2-yl)acetate; Ritalin®, MPH) has long been acknowledged, but the appearance of MPH analogs in the form of ‘research chemicals’ has only emerged in more recent years. 4-Fluoromethylphenidate (4F-MPH) is one of these recent examples and this study presents the identification and analytical characterization of two powdered 4F-MPH products that were obtained from an online vendor in 2015. Interestingly, the products appeared to have originated from two distinct batches given that one product consisted of (±)-threo-4F-MPH isomers whereas the second sample consisted of a mixture of (±)-threo and (±)-erythro 4F-MPH. Monoamine transporter studies using rat brain synaptosomes revealed that the biological activity of the 4F-MPH mixture resided with the (±)-threo- and not the (±)-erythro isomers based on higher potencies determined for blockage of dopamine uptake (IC50 4F-MPHmixture = 66 nM vs. IC50 (±)-threo = 61 nM vs. IC50 (±)-erythro = 8,528 nM) and norepinephrine uptake (IC50 4F-MPHmixture = 45 nM vs. (±)-threo = 31 nM vs. IC50 (±)-erythro = 3,779 nM). In comparison, MPH was three times less potent than (±)-threo-4F-MPH at the dopamine transporter (IC50 = 131 nM) and around 2.5-times less potent at the norepinephrine transporter (IC50 = 83 nM). Both substances were catecholamine selective with IC50 values of 8,805 nM and >10,000 nM for (±)-threo-4F-MPH and MPH at the serotonin transporter. These findings suggest that the psychostimulant properties of (±)-threo-4F-MPH might be more potent in humans than MPH

Fast cavity-enhanced atom detection with low noise and high fidelity

Cavity quantum electrodynamics describes the fundamental interactions between light and matter, and how they can be controlled by shaping the local environment. For example, optical microcavities allow high-efficiency detection and manipulation of single atoms. In this regime fluctuations of atom number are on the order of the mean number, which can lead to signal fluctuations in excess of the noise on the incident probe field. Conversely, we demonstrate that nonlinearities and multi-atom statistics can together serve to suppress the effects of atomic fluctuations when making local density measurements on clouds of cold atoms. We measure atom densities below 1 per cavity mode volume near the photon shot-noise limit. This is in direct contrast to previous experiments where fluctuations in atom number contribute significantly to the noise. Atom detection is shown to be fast and efficient, reaching fidelities in excess of 97% after 10 us and 99.9% after 30 us.Comment: 7 pages, 4 figures, 1 table; extensive changes to format and discussion according to referee comments; published in Nature Communications with open acces

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Fe d'errates disponible a: http://​dx.​doi.​org/​10.​1007/​s00213-013-3283-6Rationale Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine. Objective The major aims were to investigate the pharmacokineticsa and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. Methods Mephedrone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min. Results Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α=10.23 h−1, β=1.86 h−1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59±3.67%. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85±0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic-pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. Conclusions We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude,and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity