Dan L. McElroy

Bio: Dan L. McElroy is an academic researcher from University of Saskatchewan. The author has contributed to research in topics: Medicine & Cannabinoid receptor. The author has an hindex of 2, co-authored 5 publications receiving 11 citations.

Dissociable changes in spike and wave discharges following exposure to injected cannabinoids and smoked cannabis in Genetic Absence Epilepsy Rats from Strasbourg.

Abstract: There is significant interest in the use of cannabinoids for the treatment of many epilepsies including absence epilepsy (AE). Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model many aspects of AE including the presence of spike-and-wave discharges (SWDs) on electroencephalogram (EEG) and behavioral comorbidities, such as elevated anxiety. However, the effects of cannabis plant-based phytocannabinoids have not been tested in GAERS. Therefore, we investigated how SWDs in GAERS are altered by the two most common phytocannabinoids, Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), and exposure to smoke from two different chemovars of cannabis. Animals were implanted with bipolar electrodes in the somatosensory cortex and EEGs were recorded for 2 hr. Injected THC (1-10 mg/kg, i.p.) dose-dependently increased SWDs to over 200% of baseline. In contrast, CBD (30-100 mg/kg, i.p.) produced a ~50% reduction in SWDs. Exposure to smoke from a commercially available chemovar of high-THC cannabis (Mohawk, Aphria Inc.) increased SWDs whereas a low-THC/high-CBD chemovar of cannabis (Treasure Island, Aphria Inc.) did not significantly affect SWDs in GAERS. Pre-treatment with a CB1R antagonist (SR141716A) did not prevent the high-THC cannabis smoke from increasing SWDs, suggesting that the THC-mediated increase may not be CB1R-dependent. Plasma concentrations of THC and CBD were similar to previously reported values following injection and smoke exposure. Compared to injected CBD, it appears Treasure Island did not increase plasma levels sufficiently to observe an anti-epileptic effect. Together these experiments provide initial evidence that acute phytocannabinoid administration exerts the biphasic modulation of SWDs and may differentially impact patients with AE.

Effects of the cannabinoid receptor 1 positive allosteric modulator GAT211 and acute MK-801 on visual attention and impulsivity in rats assessed using the five-choice serial reaction time task

Abstract: Altered interactions between endocannabinoid and glutamate signaling may be involved in the pathophysiology of schizophrenia and acute psychosis. As cognitive disturbances are involved in schizophrenia, increased understanding of the roles of these neurotransmitter systems in cognition may lead to the development of novel therapeutics for disorder. In the present study, we examined the effects of a recently synthesized cannabinoid receptor 1 (CB1R) positive allosteric modulator GAT211 in a rodent model of acute psychosis induced by systemic treatment with MK-801. To assess cognitive function, we used the Five-Choice Serial Reaction Time (5CSRT) task, conducted in touchscreen-equipped operant conditioning chambers. Our measures of primary interest were accuracy – indicative of visual attentional capacity – and the number of premature responses – indicative of impulsivity. We also measured latencies, omissions, and perseverative responding during all test sessions. Thirteen adult male Long Evans rats were trained on the 5CSRT and were then tested using a repeated measures design with acute MK-801 (0 or 0.15 mg/kg, i.p.) and GAT211 (0, 3, or 10 mg/kg, i.p.) administration. Acute MK-801 severely impaired accuracy, increased omissions, and increased the number of premature responses. MK-801 also significantly increased correct response latencies, without significant effects on incorrect or reward correction latencies. GAT211 had no significant effects when administered alone, or in combination with acute MK-801. These data confirm the dramatic effects of acute MK-801 treatment on behavioral measures of attention and impulsivity. Continued investigation of CB1R positive allosteric modulators as potential treatments for the cognitive symptoms of schizophrenia and related disorders should be pursued in other rodent models.

Antipsychotic potential of the type 1 cannabinoid receptor positive allosteric modulator GAT211: preclinical in vitro and in vivo studies

Abstract: Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia. This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆9-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors. The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats. GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3–3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments. Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.

The type 1 cannabinoid receptor positive allosteric modulators GAT591 and GAT593 reduce spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg

Abstract: Childhood absence epilepsy (CAE) is a non-convulsive seizure disorder primarily in children characterized by absence seizures. Absence seizures consist of 2.5-5 Hz spike-and-wave discharges (SWDs) detectable using electroencephalography (EEG). Current drug treatments are only partially effective and adverse side effects have spurred research into alternative treatment approaches. Recent research shows that positive allosteric modulation of the type-1 cannabinoid receptor (CB1R) reduces the frequency and duration of SWDs in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model that recapitulates the SWDs in CAE. Here, we tested additional CB1R ago-PAMs, GAT591 and GAT593, for their potential in alleviating SWD activity in GAERS. In vitro experiments confirm that GAT591 and GAT593 exhibit increased potency and selectivity in cell cultures and behave as CB1R allosteric agonists and PAMs. To assess drug effects on SWDs, bilateral electrodes were surgically implanted in the somatosensory cortices of male GAERS and EEGs recorded for 4 h following systemic administration of GAT591 or GAT593 (1.0, 3.0 and 10.0 mg/kg). Both GAT591 and GAT593 dose-dependently reduced total SWD duration during the recording period. The greatest effect on SWD activity was observed at 10.0 mg/kg doses, with GAT591 and GAT593 reducing seizure duration by 36% and 34% respectively. Taken together, these results support the continued investigation of CB1R PAMs as a potential therapeutic to alleviate SWDs in absence epilepsy.

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

Abstract: The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems. In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development. The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development. The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases. This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.

Effect of Cannabidiol on Interictal Epileptiform Activity and Sleep Architecture in Children with Intractable Epilepsy: A Prospective Open-Label Study

Abstract: Background Cannabidiol has been shown to be effective in seizure reduction in patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis. However, very little is known about its potential to reduce interictal epileptiform activity and improve sleep architecture. Objective The objective of this prospective study was to evaluate the influence of cannabidiol therapy on the frequency of interictal epileptiform discharges (IEDs) and sleep microstructure in a cohort of children with drug-resistant epilepsy. Methods Children with drug-resistant epilepsy were prospectively followed from November 2019 to January 2021 during an open-label trial of cannabidiol at a dose of 20 mg/kg/day (to a maximum of 50 mg/kg/day) and stable concomitant medication. Electroencephalograms were recorded at baseline (T0) and after 3 months (T1). Two independent raters, blinded to clinical outcome, evaluated 5-min segments of sleep stage 2 or low-noise awake state. IEDs were visually identified and rates per minute calculated. Sleep microstructure was considered improved if sleep structures were seen at T1 that were not present at T0. IED rates at T0 and T1 were compared and correlated with seizure outcome, cannabidiol dose, initial IED rate, and disease duration. Results In total, 35 children (mean ± standard deviation age 10.1 ± 0.86) were included. The IED rate at T1 was significantly lower than at T0 (19.6 ± 19.5 vs. 36.8 ± 27.2, respectively; p Conclusion Our results strongly suggest the utility of cannabidiol in reducing IEDs and improving sleep microstructure in children with drug-resistant epilepsy. Larger controlled studies are needed to evaluate the clinical relevance of this effect in different epilepsy types. Trial registration DRKS00013177; 25 June 2019.