Sex-dependent long-term effects of adolescent exposure to THC and/or MDMA on neuroinflammation and serotoninergic and cannabinoid systems in rats

Background and PurposeMany young people consume ecstasy as a recreational drug and often in combination with cannabis. In this study, we aimed to mimic human consumption patterns and investigated, in male and female animals, the long-term effects of Δ⁹-tetrahydrocannabinol (THC) and 3,4-methylenedioxymethamphetamine (MDMA) on diverse neuroinflammation and neurotoxic markers.Experimental ApproachMale and female Wistar rats were chronically treated with increasing doses of THC and/or MDMA during adolescence. The effects of THC and/or MDMA on glial reactivity and on serotoninergic and cannabinoid systems were assessed by immunohistochemistry in the hippocampus and parietal cortex.Key ResultsTHC increased the area staining for glial fibrilar acidic protein in both sexes. In males, both drugs, either separately or in combination, increased the proportion of reactive microglia cells [ionized calcium binding adaptor molecule 1 (Iba-1)]. In contrast, in females, each drug, administered alone, decreased of this proportion, whereas the combination of both drugs resulted in a ‘normalization’ to control values. In males, MDMA reduced the number of SERT positive fibres, THC induced the opposite effect and the group receiving both drugs did not significantly differ from the controls. In females, MDMA reduced the number of SERT positive fibres and the combination of both drugs counteracted this effect. THC also reduced immunostaining for CB₁ receptors in females and this effect was aggravated by the combination with MDMA.Conclusions and ImplicationsAdolescent exposure of rats to THC and/or MDMA induced long-term, sex-dependent neurochemical and glial alterations, and revealed interactions between the two drugs.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6     

Effects of MDMA and Intranasal Oxytocin on Social and Emotional Processing

MDMA (±3,4-methylenedioxymethamphetamine, ‘ecstasy'') is used recreationally, reportedly because it increases feelings of empathy, sociability, and interpersonal closeness. One line of evidence suggests that MDMA produces these effects by releasing oxytocin, a peptide involved in social bonding. In the current study, we investigated the acute effects of MDMA and oxytocin on social and emotional processing in healthy human volunteers. MDMA users (N=65) participated in a 4-session, within-between-subjects study in which they received oral MDMA (0.75, 1.5 mg/kg), intranasal oxytocin (20 or 40 IU), or placebo under double-blind conditions. The primary outcomes included measures of emotion recognition and sociability (desire to be with others). Cardiovascular and subjective effects were also assessed. As expected, MDMA dose-dependently increased heart rate and blood pressure and feelings of euphoria (eg, ‘High'' and ‘Like Drug''). On measures of social function, MDMA impaired recognition of angry and fearful facial expressions, and the larger dose (1.5 mg/kg) increased desire to be with others, compared with placebo. Oxytocin produced small but significant increases in feelings of sociability and enhanced recognition of sad facial expressions. Additionally, responses to oxytocin were related to responses to MDMA with subjects on two subjective measures of sociability. Thus, MDMA increased euphoria and feelings of sociability, perhaps by reducing sensitivity to subtle signs of negative emotions in others. The present findings provide only limited support for the idea that oxytocin produces the prosocial effects of MDMA.     

Increased cortisol levels in hair of recent Ecstasy/MDMA users

Previous research has revealed an acute 8-fold increase in salivary cortisol following self-administrated Ecstasy/MDMA in dance clubbers. It is currently not known to what extent repeated usage impacts upon activity of the hypothalamic–pituitary–adrenal axis over a more prolonged period of time. This study investigated the integrated cortisol levels in 3-month hair samples from recent Ecstasy/MDMA users and non-user controls. One hundred and one unpaid participants (53 males, 48 females; mean age 21.75 years) completed the University of East London recreational drug use questionnaire, modified to cover the past 3-months of usage. They comprised 32 light recent Ecstasy/MDMA users (1–4 times in last 3 months), 23 recent heavy MDMA users (+5 times in last 3 months), and 54 non-user controls. Volunteers provided 3 cm hair samples for cortisol analysis. Hair cortisol levels were observed to be significantly higher in recent heavy MDMA users (mean= 55.0±80.1 pg/mg), compared to recent light MDMA users (19.4±16.0 pg/mg; p=0.015), and to non-users (13.8±6.1 pg/mg; p<0.001). Hence the regular use of Ecstasy/MDMA was associated with almost 4-fold raised hair cortisol levels, in comparison with non-user controls. The present results are consistent with the bio-energetic stress model for Ecstasy/MDMA, which predicts that repeated stimulant drug use may increase cortisol production acutely, and result in greater deposits of the hormone in hair. These data may also help explain the neurocognitive, psychiatric, and other psychobiological problems of some abstinent users. Future study design and directions for research concerning the psychoneuroendocrinological impact of MDMA are also discussed.     

The clinical efficacy of cosmeceutical application of liquid crystalline nanostructured dispersions of alpha lipoic acid as anti-wrinkle

Topical 5% alpha lipoic acid (ALA) has shown efficacy in treatment of photo-damaged skin. The aim of this work was to evaluate the potential of poloxamer (P407) gel as a vehicle for the novel lipid base particulate system (cubosome dispersions) of ALA. Cubosome dispersions were formulated by two different approaches, emulsification of glyceryl monoolein (GMO) and poloxamer (P407) in water followed by ultrasonication, and the dilution method using a hydrotrope. Three different concentrations of GMO were used to formulate the cubosome dispersions using the first method, 5% (D1), 10% (D2) and 15% w/w (D3). In the second technique an isotropic liquid was produced by combining GMO with ethanol, and this isotropic liquid was then diluted with a P407 solution (D4). The dispersions were characterized by zeta potential, light scattering techniques, optical and transmission electron microscopy, encapsulation efficiency and in vitro drug release. Results showed that D4 was not a uniform dispersion and that D1, D2 and D3 were uniform dispersions, in which by increasing the GMO content in the dispersion, the size of the cubosomes decreased, zeta potential became more negative, encapsulation efficiency increased up to 86.48% and the drug release rate was slower. P407 gels were prepared using the cold method. Two concentrations of P407 gel were fabricated, 20 and 30% w/w. P407 gels were loaded with either ALA or dispersions containing ALA cubosomes. P407 gels were characterized by critical gelation temperature, rheological measurements and in vitro drug release studies. Results suggested that by increasing P407 concentration, the gelation temperature decreases and viscosity increases. Drug release in both cases was found to follow the Higuchi square root model. Gel loaded with ALA cubosomes provided a significantly lower release rate than the gel loaded with the un-encapsulated ALA. A double blinded placebo controlled clinical study was conducted, aiming to evaluate the efficacy as an anti-wrinkle agent and volunteer’s satisfaction upon application of topical 30% P407 gel loaded with ALA cubosomes. Results indicated reduction in facial lines, almost complete resolution of fine lines in the periorbital region and upper lip area and overall improvement in skin color and texture in most volunteers. There were no instances of irritation, peeling or other apparent adverse side effects.     

The Effect of the Reaction pH on Properties of Lead(II) Azide

Lead(II) azide is an initiating explosive; even a small amount can trigger an explosion caused by simple external stimuli, such as sparks, flames, friction or pinpricks, and is able to initiate the explosive reaction of rock-crushing explosives. Due to the fact that this initiating explosive triggers further reactions, the effect of priming detonators depends on the properties of its material. Its sensitivity is associated with the size of its crystals. For instance, it is used for mining detonators in the form of fine crystals. The quality of the crystals is also correlated to the safety of the production process, i.e., the crystals should be round-shaped rather than needle-like since breaking it would inevitably trigger an explosion. The process of lead(II) azide production on an industrial scale is based on the reaction of lead(II) nitrate with sodium azide with the presence of dextrin, which determines the desired shape of the crystals. The reaction pH affects the number of sediment particles formed in a periodical reactor. Changing the pH from 6.5 to 7.5 leads to the rapid growth of crystal particles.     

Uniformity of Thermoluminescence and Optically Stimulated Luminescence Signals Over the Length of Doped LiMgPO4 Crystal Rods Grown by Micro-Pulling-Down Method

The purpose of this work was to systematically assess the distribution of thermoluminescence (TL) and optically stimulated luminescence (OSL) properties along the length of crystals grown by the micro-pulling-down method, in relation to the microstructure and distribution of activators. We analyzed lithium magnesium phosphate (LiMgPO₄; LMP) crystals doped with terbium (Tb; 0.8 mol%) or with a combination of thulium (Tm; 0.8 mol% or 1.2 mol%) and boron (B; 10 mol%). Crystals of several centimeters in length and 3 mm in diameter were cut into 20–40 slices, depending on length. For each sample, TL glow curves and OSL decay curves were examined. Optical microscopy and scanning electron microscopy were used to assess the microstructure and elemental composition of several selected samples. Two-dimensional TL readouts were performed to identify the areas with higher and lower signal emission. Our study showed that there may be significant differences not only in LMP sensitivity along the crystal’s axis but also on the surface of the slice. The distribution of activators varies depending on the type of crystals and strongly affects luminescence properties.     

Particle Characteristics’ Influence on FLASH Sintering of Potassium Sodium Niobate: A Relationship with Conduction Mechanisms

The considerable decrease in temperature and time makes FLASH sintering a more sustainable alternative for materials processing. FLASH also becomes relevant if volatile elements are part of the material to be processed, as in alkali-based piezoelectrics like the promising lead-free K_0.5Na_0.5NbO₃ (KNN). Due to the volatile nature of K and Na, KNN is difficult to process by conventional sintering. Although some studies have been undertaken, much remains to be understood to properly engineer the FLASH sintering process of KNN. In this work, the effect of FLASH temperature, T_F, is studied as a function of the particle size and impurity content of KNN powders. Differences are demonstrated: while the particle size and impurity degree markedly influence T_F, they do not significantly affect the densification and grain growth processes. The conductivity of KNN FLASH-sintered ceramics and KNN single crystals (SCs) is compared to elucidate the role of particles’ surface conduction. When particles’ surfaces are not present, as in the case of SCs, the FLASH process requires higher temperatures and conductivity values. These results have implications in understanding FLASH sintering towards a more sustainable processing of lead-free piezoelectrics.