Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity

K2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ(9)-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R).JWH-018, five potential monohydroxylated metabolites (M1-M5), and one carboxy metabolite (M6) were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [(3)H]CP-55,940, and then for CB1R intrinsic efficacy using an [(35)S]GTPγS binding assay. JWH-018 and M1-M5 bound CB1Rs with high affinity, exhibiting K(i) values that were lower than or equivalent to Δ(9)-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ(9)-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ(9)-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251.Unlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations, combined with higher CB1R affinity and activity relative to Δ(9)-THC, may contribute to the greater prevalence of adverse effects observed with JWH-018-containing products relative to cannabis

A Small Molecule p75NTR Ligand, LM11A-31, Reverses Cholinergic Neurite Dystrophy in Alzheimer's Disease Mouse Models with Mid- to Late-Stage Disease Progression

Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6-8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12-13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages

Ecological Context, Concentrated Disadvantage, and Youth Reoffending: Identifying the Social Mechanisms in a Sample of Serious Adolescent Offenders

Serious youthful offenders are presented with a number of significant challenges when trying to make a successful transition from adolescence to adulthood. One of the biggest obstacles for these youth to overcome concerns their ability to desist from further antisocial behavior, and although an emerging body of research has documented important risk and protective factors associated with desistance, the importance of the neighborhoods within which these youth reside has been understudied. Guided by the larger neighborhood effects on crime literature, the current study examines the direct and indirect effects of concentrated disadvantage on youth reoffending among a sample of highly mobile, serious youthful offenders. We use data from Pathways to Desistance, a longitudinal study of serious youthful offenders (N = 1,354; 13.6 % female; 41.4 % African American, 33.5 % Hispanic, 20.2 % White), matched up with 2000 Census data on neighborhood conditions for youth’s main residence location during waves 7 and 8 of the study. These waves represent the time period in which youth are navigating the transition to adulthood (aged 18–22; average age = 20). We estimate structural equation models to determine direct effects of concentrated disadvantage on youth reoffending and also to examine the possible indirect effects working through individual-level mechanisms as specified by theoretical perspectives including social control (e.g., unsupervised peer activities), strain (e.g., exposure to violence), and learning (e.g., exposure to antisocial peers). Additionally, we estimate models that take into account the impact that a change in neighborhood conditions may have on the behavior of youth who move to new residences during the study period. Our results show that concentrated disadvantage is indirectly associated with youth reoffending primarily through its association with exposure to deviant peers. Taking into account youth mobility during the study period produced an additional indirect pathway by which concentrated disadvantage is associated with goal blockage (i.e., the gap between belief in conventional goals and perceived potential to reach those goals), which was then associated with exposure to deviant peers and indirectly, reoffending behavior. We conclude that the neighborhood effects literature offers a promising framework for continued research on understanding the successful transition to adulthood by serious youthful offenders.No Full Tex