SUMMARY1. In dogs anaesthetized with chloralose, small latex balloons were positioned at the left pulmonary vein-atrial junctions so as to stretch this region. By recording action potentials from slips of the cervical vagi it was established that distension of these balloons stimulated receptor endings in the atrial endocardium which discharged into the myelinated branches of the vagi i.e. Paintal type A, type B and Intermediate type receptors.2. In other dogs, cooling the cervical vagus in steps of 2 'C reduced this response in vagal myelinated fibres. With twelve receptors the response to distension was reduced by 30 % when the vagus was cooled to 16 'C , by 70 % when cooled to 12 'C and abolished at 8-12 'C.3. In a third group of dogs, distension of balloons at the pulmonary vein-atrial junctions resulted in a reflex increase in heart rate. Cooling the cervical vagi in these dogs in stages to 8 'C reduced this increase in heart rate. In nine dogs the response was reduced by 20 % when the vagi was cooled to 16 'C, by 70 % when cooled to 12 'C and abolished between 12 and 8 TC.4. In a fourth group of dogs, distension of balloons at the pulmonary vein-atrial junctions was shown also to activate receptor endings in the atria which discharged into non-myelinated branches of the Vagi. In twelve receptors, cooling the cervical vagus in steps of 2 'C reduced this evoked increase in activity in non-myelinated fibres. These responses were abolished over a wide range of temperature unlike the responses observed above.5. It is concluded that the increase in heart rate which follows distension of balloons at the pulmonary vein-atrial junctions is mediated solely by the Paintaltype receptors which discharge into the myelinated fibres in the vagi.

N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signalling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 can be restored to wild type by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive functions, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.

SUMMARYIn dogs anaesthetized with a-chloralose the effects of distension of a large balloon in the lumen of the left atrium on the discharge of action potentials in vagal fibres and on urine flow were studied with the cervical vagi cooled at 18 and 12 IC. Distension of the balloon in seven dogs resulted in an increase in urine flow. Cooling the cervical vagi to 18 'C reduced the response to 70% of that obtained at 37 IC, and at 12 IC the response was reduced to 28%. In a second group of dogs, the effect of distension of the balloon on atrial receptors which discharged into myelinated nerve fibres of the vagi, i.e. Paintal type A and type B receptors, was examined. The increase in the activity of these receptors was reduced to 68% when the vagus nerve was cooled to 18 'C and was reduced further to 25% at 12 IC. In a third group of dogs, the effect of distension of the balloon on receptors which discharged into non-myelinated nerve fibres in the vagi was examined. Cooling of the cervical vagi also reduced the evoked increase in activity in these fibres; this reduction in activity occurred over a wider range of temperature, unlike the effect of cooling on the response in myelinated vagal fibres. It is concluded that the increase in urine flow caused by distension of a balloon in the left atrium is mediated solely by the Paintal-type atrial receptors which discharge into the myelinated fibres in the vagi.

Unequivocal evidence suggests an increased prevalence of cardiovascular disease (CVD) amongst South Asian Canadians (SACs) compared to other ethnic cohorts, due to a combination of their unique cardiometabolic profile and environmental factors. This unfavorable CVD profile is characterized by an elevated risk of dyslipidemia, high apolipoprotein B/apolipoprotein A1 ratio, hypertension, glucose intolerance, type 2 diabetes mellitus, as well as increased BMI, body fat percentage, abdominal and visceral adiposity. Despite the overwhelming evidence for the effectiveness of physical activity (PA) in circumventing the onset of CVD and in the reduction of CVD risk factors, SACs are among the most physically inactive cohorts in Canada. This relates to a set of common and unique socio-cultural barriers, such as gender, beliefs and perceptions about illness, immigration, unfavorable PA environments, and their high prevalence of debilitating chronic diseases. Several strategies to improve PA participation rates in this high-risk population have been suggested, and include the implementation of culturally sensitive PA interventions, as well as clinician training in PA prescription through workshops that emphasize knowledge translation into clinical practice. Therefore, the purpose of this mini-review is to highlight and discuss: (1) the burden of heart disease in SACs (2) the cardiovascular benefits of PA for SACs; (3) factors affecting PA participation among SACs and how they can be addressed; (4) the impact of culturally sensitive PA prescription on CVD prevention; (5) barriers to culture-specific PA prescription by clinicians, and strategies to improve its use and impact.

The endocannabinoid system (eCBs) encompasses the endocannabinoids, their synthetic and degradative enzymes, and cannabinoid (CB) receptors. The eCBs mediates inhibition of neurotransmitter release and acts as a major homeostatic system. Many aspects of the eCBs are altered in a number of psychiatric disorders including schizophrenia, which is characterized by dysregulation of dopaminergic signaling. The GluN1-Knockdown (GluN1KD) and Dopamine Transporter Knockout (DATKO) mice are models of hyperdopaminergia, which display abnormal psychosis-related behaviors, including hyperlocomotion and changes in pre-pulse inhibition (PPI). Here, we investigate the ability of a novel CB1 receptor (CB1R) allosteric modulator, ABM300, to ameliorate these dysregulated behaviors. ABM300 was characterized in vitro (receptor binding, β-arrestin2 recruitment, ERK1/2 phosphorylation, cAMP inhibition) and in vivo (anxiety-like behaviors, cannabimimetic effects, novel environment exploratory behavior, pre-pulse inhibition, conditioned avoidance response) to assess the effects of the compound in dysregulated behaviors within the transgenic models. In vitro, ABM300 increased CB1R agonist binding but acted as an inhibitor of CB1R agonist induced signaling, including β-arrestin2 translocation, ERK phosphorylation and cAMP inhibition. In vivo, ABM300 did not elicit anxiogenic-like or cannabimimetic effects, but it decreased novelty-induced hyperactivity, exaggerated stereotypy, and vertical exploration in both transgenic models of hyperdopaminergia, as well as normalizing PPI in DATKO mice. The data demonstrate for the first time that a CB1R allosteric modulator ameliorates the behavioral deficits in two models of increased dopamine, warranting further investigation as a potential therapeutic target in psychiatry.