Ken Mackie

• MD
• Indiana University Bloomington

Mental disorders disturb the cognition, emotion, and behavior of a diverse patient population, and can reduce their quality of life and even cause death. Despite significant advances in the diagnosis and treatment of mental disorders, challenges remain in achieving objective understanding, accurate assessment, and timely intervention for personaliz...

Δ9-tetrahydrocannabinol (THC), the chief psychoactive ingredient of cannabis, acts in the brain primarily via cannabinoid CB1 receptors. These receptors are implicated in several forms of synaptic plasticity – depolarization-induced suppression of excitation (DSE), metabotropic suppression of excitation (MSE), long term depression (LTD) and activat...

Background Adolescent cannabinoid exposure can have long-lasting effects on the brain, particularly in the prefrontal cortex, where the reelin protein plays a crucial role in neural organization. Chronic cannabinoid exposure leads to reelin deficiency and behavioral abnormalities, but the underlying mechanisms remain unclear. With the increasing us...

The endocannabinoid (eCB) system regulates stress responsiveness and hypothalamic-pituitary-adrenal (HPA) axis activity. The enzyme N -acyl phosphatidylethanolamine phospholipase-D (NAPE-PLD) is primarily responsible for the synthesis of the endocannabinoid signaling molecule anandamide (AEA) and other structurally related lipid signaling molecules...

Organoids, three-dimensional in vitro organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites,...

Substance use disorders (SUDs) are complex mental health conditions involving a problematic pattern of substance use. Challenges remain in understanding its neural mechanisms, which are likely to lead to improved SUD treatments. Human brain organoids, brain-like 3D in vitro cultures derived from human stem cells, show unique potential in recapitula...

The Cannabis sativa plant has been used for centuries as a recreational drug and more recently in the treatment of patients with neurological or psychiatric disorders. In many instances, treatment goals include relief from posttraumatic disorders, anxiety, or to support treatment of chronic pain. Ligands acting on cannabinoid receptor 1 (CB1R) are...

While the opioid crisis has justifiably occupied news headlines, emergency rooms are seeing many thousands of visits for another cause: cannabinoid toxicity. This is partly due to the spread of cheap and extremely potent synthetic cannabinoids that can cause serious neurological and cardiovascular complications—and deaths—every year. While an opioi...

Recreational use of synthetic cannabinoid agonists (i.e., Spice compounds) that target the Cannabinoid Type 1 receptor (CB1) can cause acute respiratory failure in humans. However, Δ9-tetrahydrocannabinol (THC), the major psychoactive phytocannabinoid in cannabis, is not traditionally thought to interact with the brain respiratory system, based lar...

Cannabinoid CB2 agonists show therapeutic efficacy without the unwanted side effects commonly associated with direct activation of CB1 receptors. The G protein-biased CB2 receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks the development of morphine tolerance in this model....

The N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) catalyzes the production of N-acylethanolamines (NAEs), a family of endogenous bioactive lipids, which are involved in various biological processes ranging from neuronal functions to energy homeostasis and feeding behaviors. Reward-dependent behaviors depend on dopamine (DA) tr...

Brain-inspired computing hardware aims to emulate the structure and working principles of the brain and could be used to address current limitations in artificial intelligence technologies. However, brain-inspired silicon chips are still limited in their ability to fully mimic brain function as most examples are built on digital electronic principl...

In remembrance of Prof. Dr Przybylski, we are presenting a vision towards his beloved mass spectrometry (MS) and its far-reaching promises outside of the academic laboratory. Sub-atmospheric pressure (AP) ionization MS is well positioned to make a step-change in direct ionization, a concept that allows sublimation/evaporation ionization and mass an...

The N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) catalyzes the production of N-acylethanolamines (NAEs), a family of endogenous bioactive lipids, which are involved in various biological processes ranging from neuronal functions to energy homeostasis and feeding behaviors. Reward-dependent behaviors depend on dopamine (DA) tr...

The N -acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) catalyzes the production of N -acylethanolamines (NAEs), a family of endogenous bioactive lipids, which are involved in various biological processes ranging from neuronal functions to energy homeostasis and feeding behaviors. Reward-dependent behaviors depend on the dopamine (...

In the central nervous system (CNS), cannabinoid receptor 1 (CB1R) is preferentially expressed in axons where it has a unique property, namely resistance to agonist-driven endocytosis. This review aims to summarize what we know about molecular mechanisms of CB1R cell surface stability in axonal compartments, how these impact CB1R signaling, and to...

Autaptic hippocampal neurons are an architecturally simple model of neurotransmission that express several forms of cannabinoid signaling. Over the past twenty years this model has proven valuable for studies ranging from enzymatic control of endocannabinoid production and breakdown, to CB1 receptor structure/function, to CB2 signaling, understandi...

CB2 cannabinoid receptor activation suppresses pathological pain in animal models. CB2 agonists show promise as therapeutic agents because they lack unwanted side effects commonly associated with direct activation of CB1 receptors. However, the types of pain most responsive to CB2 agonists are incompletely understood and cell types which underlie C...

Cannabis use has become popular among athletes, many of whom are exposed to repetitive subconcussive head impacts. We aimed to test whether chronic cannabis use would be neuroprotective or exacerbating against acute subconcussive head impacts. This trial included 43 adult soccer players (Cannabis group using cannabis at least once a week for the pa...

Cannabinoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [119]) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at...

Introduction: How sex influences prefrontal cortexes (PFCs) synaptic development through adolescence remains unclear. Materials and Methods: In this study we describe sex-specific cellular and synaptic trajectories in the rat PFC from adolescence to adulthood. Results: The excitability of PFC layer 5 pyramidal neurons was lower in adult females com...

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...

Brain-inspired hardware emulates the structure and working principles of a biological brain and may address the hardware bottleneck for fast-growing artificial intelligence (AI). Current brain-inspired silicon chips are promising but still limit their power to fully mimic brain function for AI computing. Here, we develop Brainoware , living AI hard...

Transdermal drug delivery provides convenient and pain-free self-administration for personalized therapy. However, challenges remain in treating acute diseases mainly due to their inability to timely administrate therapeutics and precisely regulate pharmacokinetics within a short time window. Here we report the development of active acoustic metama...

Cannabinoids (CBs) have sex-dependent behavioral and physiological effects and modulate lipids across the body. To understand how some of these sex differences may be due to differences how both phyto- and endocannabinoids are regulated in the liver and plasma, male and female CD1 mice were administered 10 mg/kg i.p. of cannabidiol (CBD), ∆9-tetrah...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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 endocannabinoid system in the CNS, via activation of CB1 receptors...

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...

How sex influences PFC’s synaptic development through adolescence remains unclear. Here we describe sex-specific cellular and synaptic trajectories in the rat PFC from adolescence to adulthood. The excitability of PFC layer 5 pyramidal neurons was lower in adult females compared with other developmental stages. The developmental course of endocanna...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

Background and Purpose Src homology 3‐domain growth factor receptor‐bound 2‐like endophilin interacting protein 1 (SGIP1) interacts with cannabinoid CB1 receptors. SGIP1 is abundantly and principally expressed within the nervous system. SGIP1 and CB1 receptors co‐localize in axons and presynaptic boutons. SGIP1 interferes with the internalization o...

Cannabinoid type 1 receptor (CB1R) 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 CB1R, which helps to specify molecular mechanisms, remains to be documented. Using three-dimensional (...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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)...

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...