Cannabis adulterated with the synthetic cannabinoid receptor agonist MDMB-4en-PINACA and the role of European drug checking services.

BACKGROUND: European drug checking services exchange information on drug trends within the Trans European Drug Information (TEDI) network, allowing monitoring and coordination of responses. Starting in Spring 2020, several services detected the synthetic cannabinoid receptor agonist MDMB-4en-PINACA in adulterated low-THC cannabis products. METHODS: Cannabis products suspected of adulteration were analyzed for the presence of MDMB-4en-PINACA by 9 services in 8 countries within the TEDI network. If available, phytocannabinoid analysis was also performed. RESULTS: 1142 samples sold as cannabis in herbal, resin and e-liquid form were analyzed, of which 270 were found to contain MDMB-4en-PINACA. All cannabis samples contained low THC (<1%), except the e-liquids which contained no phytocannabinoids. Three serious health incidents requiring hospitalization after use of an adulterated cannabis sample were reported. CONCLUSION: Adulteration of cannabis with synthetic cannabinoid receptor agonists is a new phenomenon that carries risk for people who use it. Given that cannabis consumers are not a usual target group for drug checking services, services and associated harm reduction interventions could be reconfigured to include them.

[Legislation of New Psychoactive Substances in the Netherlands]. / Nieuwe psychoactieve stoffen in Nederland.

Every year dozens of New Psychoactive Substances (NPS) appear for the first time on the drug market. Many of them will never find their way to a user group. If they do and a NPS is banned because of its harmfulness, a legal variant subsequently appears on the market. That is why more and more countries are opting for a so-called generic legislation, whereby entire groups of NPS are banned in advance. In this way, the Netherlands also wants to restrict the production, trade and availability of NPS and send out a signal that their use is not without risk. The question is what the effectiveness of such an approach will be and what unintended side effects it will have. In any case, it is essential to continue to monitor the market and the use of NPS by means of various indicators and to continue to focus on prevention and providing information about the risks.

Prenatal fluoxetine exposure induces life-long serotonin 5-HT3 receptor-dependent cortical abnormalities and anxiety-like behaviour.

Selective serotonin reuptake inhibitors (SSRIs) are the first choice of drugs to treat depression and anxiety during pregnancy. However, there is evidence that in utero exposure to SSRIs leads to adverse effects in offspring. Here we show that in mice, the adverse effects of the widely used antidepressant and SSRI fluoxetine are critically dependent on the 5-HT(3) receptor, the only ligand-gated ion channel in the family of serotonin receptors. In utero exposure to fluoxetine induces anxiety-like behavior in wildtype, but not in mice lacking the 5-HT(3) receptor. In addition to this behavioral phenotype, these mice show life-long abnormalities of cortical cytoarchitecture, which can be reversed in vitro by pharmacological block of 5-HT(3) receptors. Moreover, the effect of fluoxetine on the development of cortical neurons is absent in 5-HT(3) receptor knockout mice. These findings pinpoint the pivotal role of serotonergic signaling during development and provide a novel basis to investigate the adverse effects of the use of fluoxetine during pregnancy. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Alterations in Apical Dendrite Bundling in the Somatosensory Cortex of 5-HT(3A) Receptor Knockout Mice.

In various species and areas of the cerebral cortex, apical dendrites of pyramidal neurons form clusters which extend through several layers of the cortex also known as dendritic bundles. Previously, it has been shown that 5-HT(3A) receptor knockout mice show hypercomplex apical dendrites of cortical layer 2/3 pyramidal neurons, together with a reduction in reelin levels, a glycoprotein involved in cortical development. Other studies showed that in the mouse presubicular cortex, reelin is involved in the formation of modular structures. Here, we compare apical dendrite bundling in the somatosensory cortex of wildtype and 5-HT(3A) receptor knockout mice. Using a microtubule associated protein-2 immunostaining to visualize apical dendrites of pyramidal neurons, we compared dendritic bundle properties of wildtype and 5-HT(3A) receptor knockout mice in tangential sections of the somatosensory cortex. A Voronoi tessellation was performed on immunostained tangential sections to determine the spatial organization of dendrites and to define dendritic bundles. In 5-HT(3A) receptor knockout mice, dendritic bundle surface was larger compared to wildtype mice, while the number and distribution of reelin-secreting Cajal-Retzius cells was similar for both groups. Together with previously observed differences in dendritic complexity of cortical layer 2/3 pyramidal neurons and cortical reelin levels, these results suggest an important role for the 5-HT(3) receptor in determining the spatial organization of cortical connectivity in the mouse somatosensory cortex.

Impaired Social Behavior in 5-HT(3A) Receptor Knockout Mice.

The 5-HT(3) receptor is a ligand-gated ion channel expressed on interneurons throughout the brain. So far, analysis of the 5-HT(3A) knockout mouse revealed changes in nociceptive processing and a reduction in anxiety related behavior. Recently, it was shown that the 5-HT(3) receptor is also expressed on Cajal-Retzius cells which play a key role in cortical development and that knockout mice lacking this receptor showed aberrant growth of the dendritic tree of cortical layer II/III pyramidal neurons. Other mouse models in which serotonergic signaling was disrupted during development showed similar morphological changes in the cortex, and in addition, also deficits in social behavior. Here, we subjected male and female 5-HT(3A) knockout mice and their non-transgenic littermates to several tests of social behavior. We found that 5-HT(3A) knockout mice display impaired social communication in the social transmission of food preference task. Interestingly, we showed that in the social interaction test only female 5-HT(3A) knockout mice spent less time in reciprocal social interaction starting after 5 min of testing. Moreover, we observed differences in preference for social novelty for male and female 5-HT(3A) knockout mice during the social approach test. However, no changes in olfaction, exploratory activity and anxiety were detected. These results indicate that the 5-HT(3A) knockout mouse displays impaired social behavior with specific changes in males and females, reminiscent to other mouse models in which serotonergic signaling is disturbed in the developing brain.

Lifelong impact of variations in maternal care on dendritic structure and function of cortical layer 2/3 pyramidal neurons in rat offspring.

Maternal licking and grooming (LG) exerts profound influence on hippocampal development and function in the offspring. However, little information is available on the effects of variations in maternal care on other brain regions. Here we examined the effects of variation in the frequency of maternal LG on morphological and electrophysiological properties of layer 2/3 pyramidal neurons in the somatosensory cortex in adult offspring. Compared to low LG offspring, high LG offspring displayed decreased dendritic complexity, reduced spine density and decreased amplitude of spontaneous postsynaptic currents. These changes were accompanied by higher levels of reelin expression in offspring of high LG mothers. Taken together, these findings suggest that differential amount of naturally-occurring variations in maternal LG is associated with enduring changes in dendritic morphology and synaptic function in layer 2/3 pyramidal neurons of the somatosensory cortex.