16 research outputs found
Effects of Endocannabinoid System Modulation on Cognitive and Emotional Behavior
Cannabis has long been known to produce cognitive and emotional effects. Research has shown that cannabinoid drugs produce these effects by driving the brain’s endogenous cannabinoid system and that this system plays a modulatory role in many cognitive and emotional processes. This review focuses on the effects of endocannabinoid system modulation in animal models of cognition (learning and memory) and emotion (anxiety and depression). We review studies in which natural or synthetic cannabinoid agonists were administered to directly stimulate cannabinoid receptors or, conversely, where cannabinoid antagonists were administered to inhibit the activity of cannabinoid receptors. In addition, studies are reviewed that involved genetic disruption of cannabinoid receptors or genetic or pharmacological manipulation of the endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH). Endocannabinoids affect the function of many neurotransmitter systems, some of which play opposing roles. The diversity of cannabinoid roles and the complexity of task-dependent activation of neuronal circuits may lead to the effects of endocannabinoid system modulation being strongly dependent on environmental conditions. Recent findings are reviewed that raise the possibility that endocannabinoid signaling may change the impact of environmental influences on emotional and cognitive behavior rather than selectively affecting any specific behavior
Unstable Maternal Environment, Separation Anxiety, and Heightened CO2 Sensitivity Induced by Gene-by-Environment Interplay
Background: In man, many different events implying childhood separation from caregivers/unstable parental environment
are associated with heightened risk for panic disorder in adulthood. Twin data show that the occurrence of such events in
childhood contributes to explaining the covariation between separation anxiety disorder, panic, and the related
psychobiological trait of CO2 hypersensitivity. We hypothesized that early interference with infant-mother interaction could
moderate the interspecific trait of response to CO2 through genetic control of sensitivity to the environment.
Methodology: Having spent the first 24 hours after birth with their biological mother, outbred NMRI mice were crossfostered
to adoptive mothers for the following 4 post-natal days. They were successively compared to normally-reared
individuals for: number of ultrasonic vocalizations during isolation, respiratory physiology responses to normal air (20%O2),
CO2-enriched air (6% CO2), hypoxic air (10%O2), and avoidance of CO2-enriched environments.
Results: Cross-fostered pups showed significantly more ultrasonic vocalizations, more pronounced hyperventilatory
responses (larger tidal volume and minute volume increments) to CO2-enriched air and heightened aversion towards CO2-
enriched environments, than normally-reared individuals. Enhanced tidal volume increment response to 6%CO2 was present
at 16–20, and 75–90 postnatal days, implying the trait’s stability. Quantitative genetic analyses of unrelated individuals, sibs
and half-sibs, showed that the genetic variance for tidal volume increment during 6%CO2 breathing was significantly higher
(Bartlett x = 8.3, p = 0.004) among the cross-fostered than the normally-reared individuals, yielding heritability of 0.37 and
0.21 respectively. These results support a stress-diathesis model whereby the genetic influences underlying the response to
6%CO2 increase their contribution in the presence of an environmental adversity. Maternal grooming/licking behaviour, and
corticosterone basal levels were similar among cross-fostered and normally-reared individuals.
Conclusions: A mechanism of gene-by-environment interplay connects this form of early perturbation of infant-mother
interaction, heightened CO2 sensitivity and anxiety. Some no
Influenza Vaccination and COVID-19 Mortality in the USA: An Ecological Study
The COVID-19 mortality rate is higher in the elderly and in those with pre-existing chronic medical conditions. The elderly also suffer from increased morbidity and mortality from seasonal influenza infections; thus, an annual influenza vaccination is recommended for them. In this study, we explore a possible county-level association between influenza vaccination coverage in people aged 65 years and older and the number of deaths from COVID-19. To this end, we used COVID-19 data up to 14 December 2020 and US population health data at the county level. We fit quasi-Poisson regression models using influenza vaccination coverage in the elderly population as the independent variable and the COVID-19 mortality rate as the outcome variable. We adjusted for an array of potential confounders using different propensity score regression methods. Results show that, on the county level, influenza vaccination coverage in the elderly population is negatively associated with mortality from COVID-19, using different methodologies for confounding adjustment. These findings point to the need for studying the relationship between influenza vaccination and COVID-19 mortality at the individual level to investigate any underlying biological mechanisms
Donor-derived acute myeloid leukemia in solid organ transplantation
We report the transmission of acute myeloid leukemia (AML) undetected at donation from a deceased organ donor to two kidneys and one liver recipients. We reviewed the medical records, and performed molecular analyses and whole exome sequencing (WES) to ascertain AML donor origin and its molecular evolution. The liver recipient was diagnosed 11 months after transplantation and died from complications 2 months later. The two kidney recipients (R1 and R2) were diagnosed 19 and 20 months after transplantation and both received treatment for leukemia. R1 died of complications 11 months after diagnosis, while R2 went into complete remission for 44months, before relapsing. R2 died 10 months later of complications from allogenic bone marrow transplantation. Microsatellite analysis demonstrated donor chimerism in circulating cells from both kidney recipients. Targeted molecular analyses and medical records revealed NPM1 mutation present in the donor and recipients, while FLT3 was mutated only in R1. These findings were confirmed by WES, which revealed additional founder and clonal mutations, and HLA genomic loss in R2. In conclusion, we report the first in--depth genomic analysis of AML transmission following solid organ transplantation, revealing distinct clonal evolution, and providing a potential molecular explanation for tumor escape
Structure–Activity Relationship Studies on a Series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders
The development of medications to
treat cocaine use disorders has
thus far defied success, leaving this patient population without pharmacotherapeutic
options. As the dopamine transporter (DAT) plays a prominent role
in the reinforcing effects of cocaine that can lead to addiction,
atypical DAT inhibitors have been developed that prevent cocaine from
binding to DAT, but they themselves are not cocaine-like. Herein,
a series of novel DAT inhibitors were synthesized, and based on its
pharmacological profile, the lead compound <b>10a</b> was evaluated
in phase I metabolic stability studies in mouse liver microsomes and
compared to cocaine in locomotor activity and drug discrimination
paradigms in mice. A molecular dynamic simulation study supported
the hypothesis that atypical DAT inhibitors have similar binding poses
at DAT in a conformation that differs from that of cocaine. Such differences
may ultimately contribute to their unique behavioral profiles and
potential for development as cocaine use disorder therapeutics
Structure–Activity Relationship Studies on a Series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders
The development of medications to
treat cocaine use disorders has
thus far defied success, leaving this patient population without pharmacotherapeutic
options. As the dopamine transporter (DAT) plays a prominent role
in the reinforcing effects of cocaine that can lead to addiction,
atypical DAT inhibitors have been developed that prevent cocaine from
binding to DAT, but they themselves are not cocaine-like. Herein,
a series of novel DAT inhibitors were synthesized, and based on its
pharmacological profile, the lead compound <b>10a</b> was evaluated
in phase I metabolic stability studies in mouse liver microsomes and
compared to cocaine in locomotor activity and drug discrimination
paradigms in mice. A molecular dynamic simulation study supported
the hypothesis that atypical DAT inhibitors have similar binding poses
at DAT in a conformation that differs from that of cocaine. Such differences
may ultimately contribute to their unique behavioral profiles and
potential for development as cocaine use disorder therapeutics