Ken Mackie

Ken Mackie
Indiana University Bloomington | IUB · Department of Psychological and Brain Sciences

MD

About

455
Publications
67,957
Reads
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45,768
Citations
Citations since 2016
139 Research Items
17849 Citations
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201620172018201920202021202205001,0001,5002,0002,5003,000
201620172018201920202021202205001,0001,5002,0002,5003,000
Additional affiliations
January 2011 - December 2012
Wayne State University
January 2011 - present
Indiana University East
January 2011 - present
University of Aberdeen

Publications

Publications (455)
Article
Full-text available
pioids are commonly used for treating chronic pain. However, with continued use, they may induce tolerance and/or hyperalgesia, which limits therapeutic efficacy. The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied, in part, because current models cannot fully recapitulate human pathology. Here, we engin...
Article
Painful peripheral neuropathy is a common neurological complication associated with human immunodeficiency virus (HIV) infection and anti-retroviral therapy. We characterized the impact of two CB2 cannabinoid agonists (AM1710 and LY2828360 – ligands differing in signaling bias and CNS penetration) on neuropathic nociception induced by the antiretro...
Article
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Blockade of cannabinoid type 1 (CB1)-receptor signaling decreases the rewarding properties of many drugs of abuse and has been proposed as an anti-addiction strategy. However, psychiatric side-effects limit the clinical potential of orthosteric CB1 antagonists. Negative allosteric modulators (NAMs) represent a novel and indirect approach to attenua...
Chapter
Measuring the functional behavior of G protein-coupled receptors (GPCRs) has been a major focus of academic and pharmaceutical research for many decades. These efforts have led to the development of many assays to measure the downstream effects of ligand binding on receptor activity. In this chapter, we describe an internalization/recycling assay t...
Chapter
Measuring protein levels of receptors and enzymes involved in endocannabinoid metabolism is an important step for understanding the distribution, function, and regulation of these components of the endocannabinoid system. A common approach for detecting proteins from complex biological systems is western blotting. In this chapter, we describe a gen...
Article
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In addition to phytocannabinoids, cannabis contains terpenoids that are claimed to have a myriad of effects on the body. We tested a panel of five common cannabis terpenoids, myrcene, linalool, limonene, α-pinene and nerolidol, in two neuronal models, autaptic hippocampal neurons and dorsal root ganglion (DRG) neurons. Autaptic neurons express a fo...
Article
Introduction: The antidepressant properties of ketamine have been extensively demonstrated in experimental and clinical settings. However, the psychotomimetic side effects still limit its wider use as an antidepressant. It was recently observed that endocannabinoids are inolved in ketamine induced reward properties. As an increase in endocannabinoi...
Article
Maternal cannabis use during lactation may expose developing infants to cannabinoids (CBs) such as ∆-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBs modulate lipid signaling molecules in the central nervous system in age- and cell-dependent ways, but their influence on the lipid composition of breast milk has yet to be established. This stu...
Article
Introduction: Adolescence is an important phase in brain maturation, specifically it is a time during which weak synapses are pruned and neural pathways are strengthened. Adolescence is also a time of experimentation with drugs, including cannabis, which may have detrimental effects on the developing nervous system. The cannabinoid type 1 receptor...
Preprint
Full-text available
Painful peripheral neuropathy is the most common neurological complication associated with human immune deficiency virus (HIV) infection. Currently available treatments fail to provide adequate symptom relief, indicating the need for novel treatment strategies. To address this gap in knowledge, we characterized the impact of cannabinoid CB2 agonist...
Article
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Cannabinoid receptor 1 (CB1R), a G protein-coupled receptor, plays a fundamental role in synaptic plasticity. Abnormal activity and deregulation of CB1R signaling result in a broad spectrum of pathological conditions. CB1R signaling is regulated by receptor desensitization including phosphorylation of residues within the intracellular C terminus by...
Preprint
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In humans and rodents, the protracted development of the prefrontal cortex (PFC) throughout adolescence represents a time for marked vulnerability towards environmental adversities, such as stress or drug exposure. We previously showed that the extracellular matrix protein reelin is an instrumental synaptic modulator that shapes medial PFC (mPFC) c...
Article
The use of opioids in pain management is hampered by the emergence of analgesic tolerance, which leads to increased dosing and side effects, both of which have contributed to the opioid epidemic. One promising potential approach to limit opioid analgesic tolerance is activating the CNS endocannabinoid system, via activation of CB1 receptors (CB1Rs)...
Preprint
Maternal cannabis use during lactation may expose developing infants to cannabinoids (CBs) such as tetrahydrocannabinol (THC) and cannabidiol (CBD). CBs modulate lipid signaling molecules in the central nervous system in age- and cell-dependent ways, but their influence on the lipid composition of breastmilk has yet to be established. This study in...
Article
Significance Cannabis is well known to regulate food intake, and cannabinoids increase the value of caloric and non-caloric rewards, while also regulating homeostatic feeding. Here, we show that tonic endogenous cannabinoid signaling regulates the melanocortin 4 receptor (MC4R) expressing paraventricular hypothalamic neurons through modulation of t...
Article
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Long-term cannabis use during adolescence has deleterious effects in brain that are largely ascribed to the activation of cannabinoid-1 receptors (CB1Rs) by delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive compound in marijuana. Systemic administration of ∆9-THC inhibits acetylcholine release in the prelimbic-prefrontal cortex (PL-PF...
Article
CB2 cannabinoid receptors (CB2) are a promising therapeutic target that lacks unwanted side effects of CB1 activation. However, the cell types expressing CB2 that mediate these effects remain poorly understood. We used transgenic mice with CB2 promoter-driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express C...
Article
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Cannabis contains more than 100 phytocannabinoids. Most of these remain poorly characterized, particularly in neurons. We tested a panel of five phytocannabinoids—cannabichromene (CBC), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), and Δ9-tetrahydrocannabivarin (THCV) in two neuronal models, autaptic hippocampal n...
Article
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Hermansky–Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS-1, leads to fatal adult-onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1R system and inducible nitric oxide synthase (iNOS) for dual-target therapeutic strategy using human bronchoalveo...
Article
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Introduction: There is widespread acceptance of cannabis for medical or recreational use across the society, including pregnant women. Concerningly, numerous studies find that the developing central nervous system (CNS) is vulnerable to the detrimental effects of Δ9-tetrahydrocannabinol (THC). In contrast, almost nothing on the consequences of peri...
Article
Background Cannabis use has been associated with abnormalities in cerebellar mediated motor and non-motor (i.e. cognition and personality) phenomena. Since the cerebellum is a region with high cannabinoid type 1 receptor density, these impairments may reflect alterations of signaling between the cerebellum and other brain regions. Aims We hypothes...
Article
Introduction: In mammals, sn-1-diacylglycerol lipases (DAGL) generate 2-arachidonoylglycerol (2-AG) that, as the major endocannabinoid, modulates synaptic neurotransmission by acting on CB1 cannabinoid receptors (CB1R). Even though the insect genome codes for inaE, which is a DAGL ortholog (dDAGL), its products and their functions remain unknown pa...
Article
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The endocannabinoid system (ECS) is involved in the modulation of several basic biological processes, having widespread roles in neurodevelopment, neuromodulation, immune response, energy homeostasis and reproduction. In the adult central nervous system (CNS) the ECS mainly modulates neurotransmitter release, however, a substantial body of evidence...
Article
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Human immunodeficiency virus type 1 (HIV-1) is known to provoke microglial immune responses which likely play a paramount role in the development of chronic neuroinflammatory conditions and neuronal damage related to HIV-1 associated neurocognitive disorders (HAND). In particular, HIV-1 Tat protein is a proinflammatory neurotoxin which predisposes...
Article
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Background and purpose Src homology 3‐domain growth factor receptor‐bound 2‐like endophilin interacting protein 1 (SGIP1) interacts with cannabinoid receptor 1 (CB1R). SGIP1 is abundantly and principally expressed within the nervous system. SGIP1 and CB1R co‐localize in axons and presynaptic boutons. SGIP1 interferes with the internalization of act...
Article
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Cannabinoid type 1 receptor (CB 1 R) is expressed and participates in several aspects of cerebral cortex embryonic development as demonstrated with whole-transcriptome mRNA sequencing and other contemporary methods. However, the cellular location of CB 1 R, which helps to specify molecular mechanisms, remains to be documented. Using three-dimension...
Article
Introduction: Overdose fatalities associated with the opioid epidemic are predictably attributable to drug-induced respiratory depression. In terms of illicit opioid abuse, fentanyl is the synthetic opioid responsible for the largest number of overdose deaths. There is, therefore, an urgent need to identify safe and effective therapeutics that can...
Article
Analgesic tolerance to opioids contributes to the opioid crisis by increasing the quantity of opioids prescribed and consumed. Thus, there is a need to develop non-opioid-based pain-relieving regimens as well as strategies to circumvent opioid tolerance. Previously, we revealed a non-opioid analgesic mechanism induced by median nerve electrostimula...
Article
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A specialized neurogenic niche along the ventricles accumulates millions of progenitor cells in the developing brain. After mitosis, fate-committed daughter cells delaminate from this germinative zone. Considering the high number of cell divisions and delaminations taking place during embryonic development, brain malformations caused by ectopic pro...
Article
RATIONALE The developments of new ionization technologies based on processes previously unknown to mass spectrometry (MS) have gained significant momentum. Herein we address the importance of understanding these unique ionization processes, demonstration of new capabilities currently unmet by other methods, and their considerable analytical potenti...
Article
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Emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling with studies on stress-induced endocannabinoid dysregulation focusing on cerebral changes that are temporally proximal to stressors. Little is known about temporally distal and sex-specific effects, especially in cerebellum, which is vul...
Article
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Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid Δ ⁹ -tetrahydrocannabinol (THC). Using a genetic knock-in...
Article
Functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPFC) has been implicated in the generation of negative affective states; however, the mechanisms by which stress increases amygdala-dmPFC synaptic strength and generates anxiety-like behaviors are not well understood. Here, we show that the mouse basolateral amygdala...
Article
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The evolution of human diets led to preferences toward polyunsaturated fatty acid (PUFA) content with ‘Western’ diets enriched in ω-6 PUFAs. Mounting evidence points to ω-6 PUFA excess limiting metabolic and cognitive processes that define longevity in humans. When chosen during pregnancy, ω-6 PUFA-enriched ‘Western’ diets can reprogram maternal bo...
Article
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The G protein-coupled cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), and their endocannabinoid (eCBs) ligands, have been implicated in several aspects of brain wiring during development. Here we aim to assess whether interfering with CB1R affects development, neuritogenesis and pathfinding of GnRH and AgRP neurons, forebrain neurons that co...
Article
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In the era of combined antiretroviral therapy, HIV-1 infected individuals are living longer lives; however, longevity is met with an increasing number of HIV-1 associated neurocognitive disorders (HAND) diagnoses. The transactivator of transcription (Tat) is known to mediate the neurotoxic effects in HAND by acting directly on neurons and also indi...
Article
Cannabinoid 1 receptor (CB1R) allosteric ligands hold far-reaching therapeutic promise. We report application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, arrestin2), me...
Preprint
Full-text available
Studies of early-life stress traditionally focus on glucocorticoid signaling as a modulator of neurodevelopmental risk, but emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling. Existing studies on stress-induced endocannabinoid dysregulation have focused on changes to cerebrum that are te...
Article
Tolerance to the antinociceptive effects of cannabinoids represents a significant limitation to their clinical use in managing chronic pain. Tolerance likely results from desensitization and down-regulation of the cannabinoid type 1 receptor (CB1R), with CB1R desensitization occurring via phosphorylation of CB1Rs by a G protein-coupled receptor kin...
Article
Background: Cannabis usage is increasing with its widespread legalization. Cannabis use by mothers during lactation transfers active cannabinoids to the developing offspring during this critical period and alters postnatal neurodevelopment. A key neurodevelopmental landmark is the excitatory to inhibitory gamma-aminobutyric acid (GABA) switch caus...
Article
Adolescence is a vulnerable period of development when limbic connection of the prefrontal cortex (PFC) involved in emotional processing may be rendered dysfunctional by chronic exposure to delta-9-tetrahydrocannabinol (∆9-THC), the major psychoactive compound in marijuana. Cannabinoid-1 receptors (CB1Rs) largely mediate the central neural effects...
Article
The endocannabinoid (eCB) signaling system has been functionally implicated in many brain regions. Our understanding of the role of cannabinoid receptor type 1 (CB 1 ) in olfactory processing remains limited. Cannabinoid signaling is involved in regulating glomerular activity in the main olfactory bulb (MOB). However, the cannabinoid-related circui...
Article
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Derived from arachidonic acid (AA), the endogenous cannabinoid (eCB) 2-arachidonoyl glycerol (2-AG) is a substrate for α/β hydrolase domain-12 (ABHD12). Loss-of-function mutations of ABHD12 are associated with the neurodegenerative disorder polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC). ABHD12 knockout (KO) mice s...
Article
Stimulation of the postsynaptic metabotropic glutamate receptor mGluR5 triggers retrograde signaling of endocannabinoids that activate presynaptic cannabinoid CB1 receptors on juxtaposing axon terminals. To better understand the synaptic structure that supports mGluR5 mediation of CB1 activation in the prefrontal cortex (PFC) and basolateral amygda...
Article
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Purpose: We previously showed that cannabinoid-related GPR18 receptors are present in the murine corneal epithelium, but their function remains unknown. The related CB1 receptors regulate corneal healing, possibly via chemotaxis. We therefore examined a potential role for GPR18 in corneal epithelial chemotaxis and wound healing. Methods: We examine...
Article
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OBJECTIVES/SPECIFIC AIMS: Early life stress is known to greatly impact neurodevelopment during critical periods, conferring risk for various psychopathologies, including the onset and exacerbation of schizophrenia and anxiety disorders. The endocannabinoid system is highly integrated into the stress response and may be one means by which early life...
Article
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GPR55, a lipid-sensing receptor, is implicated in cell cycle control, malignant cell mobilization, and tissue invasion in cancer. However, a physiological role for GPR55 is virtually unknown for any tissue type. Here, we localize GPR55 to self-renewing ductal epithelial cells and their terminally differentiated progeny in both human and mouse saliv...
Article
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Nestled within feeding circuits, the oval (ov) region of the Bed Nucleus of the Stria Terminalis (BNST) may be critical for monitoring energy balance through changes in synaptic strength. Here we report that bidirectional plasticity at ovBNST GABA synapses was tightly linked to the caloric state of male rats, seesawing between long-term potentiatio...
Article
AM1710 (3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c) chromen-6-one), a cannabilactone cannabinoid receptor 2 (CB2) agonist, suppresses chemotherapy-induced neuropathic pain in rodents without producing tolerance or unwanted side effects associated with CB1 receptors; however, the signaling profile of AM1710 remains incompletely characterize...
Poster
Neurocognitive deficits are well-established as characteristics common among individuals with HIV-1-associated neurocognitive disorder (HAND), a condition which often persists despite combined antiretroviral therapy (cART). HIV-1 transactivator of transcription (Tat) in particular has been found to disrupt synaptic function, but many of the specifi...
Article
Full-text available
Relative to Δ9-tetrahydrocannabinol (THC), the synthetic cannabinoid CP 55,940 (CP) is significantly more potent and efficacious at cannabinoid receptors, the primary targets for endogenous cannabinoids (eCBs). eCBs belong to a large, interconnected lipidome of bioactive signaling molecules with a myriad of effects in optimal and pathological funct...
Article
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Introduction: Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) are bioactive cannabinoids. We recently showed that acute THC administration drives region-dependent changes in the mouse brain lipidome. This study tested the hypothesis that cell lines representing cell types present in the central nervous system (CNS), neurons (N18 cells), astrocy...
Article
Significance Pain remains an unmet medical need due to the ineffectiveness or significant side effects of current pain therapies. Peripheral neurostimulation has been used to relieve pain for decades, but its mechanism(s) remain unsettled. Here, we established an animal model of median nerve stimulation by electrically stimulating the PC6 (Neiguan)...
Article
Full-text available
Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing reports of cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here we report sex-specific diffe...