Microbiome-derived metabolites in substance use disorders: Mechanisms and implications.

Substance use disorders (SUDs) are a public health crisis with high mortality rates and significant societal costs. Current brain-targeted pharmacotherapies are often ineffective or poorly tolerated. Emerging evidence highlights the gut microbiome's role in influencing neurobiological and behavioral responses to drugs of abuse.

Brief exposure to oral antibiotics has age-dependent effects on morphine reward and gene expression in the medial prefrontal cortex of adolescent and adult mice.

Adolescence is a critical period for the initiation of problematic drug use, which significantly increases the risk of developing substance use disorders later in life. This heightened vulnerability is partly attributed to the immaturity of the prefrontal cortex, a brain region both essential for decision-making and implicated in drug reward. During adolescence, peripheral systems, such as the gut microbiome, also undergo substantial changes.

Gut microbiome depletion modulates cocaine-induced behavioral and transcriptional responses in female mice.

Cocaine use disorder is a chronic relapsing condition with no FDA-approved biological treatments. The gut microbiome has emerged as a key modulator of neurobehavioral responses to drugs of abuse, yet its role in female animals has been under studied. Here, we investigated the effects of gut microbiome depletion on cocaine-induced behavioral and transcriptional responses in female mice.

Synchrony between midbrain gene transcription and dopamine terminal regulation is modulated by chronic alcohol drinking.

Alcohol use disorder is marked by disrupted behavioral and emotional states which persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. Here, 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods.

Synaptogyrin-3 Prevents Cocaine Addiction and Dopamine Deficits.

Synaptogyrin-3, a functionally obscure synaptic vesicle protein, interacts with vesicular monoamine and dopamine transporters, bringing together dopamine release and reuptake sites. Synaptogyrin-3 was reduced by chronic cocaine exposure in both humans and rats, and synaptogyrin-3 levels inversely correlated with motivation to take cocaine in rats. Synaptogyrin-3 overexpression in dopamine neurons reduced cocaine self-administration, decreased anxiety-like behavior, and enhanced cognitive flexibility.

Colony-stimulating factor 2 (CSF2) as a gut microbiome dependent immune factor that alters molecular and behavioral responses to cocaine in male mice.

Cocaine use disorder is a condition that leads to tremendous morbidity and mortality for which there are currently no FDA-approved pharmacotherapies. Previous research has demonstrated an important role for the resident population of bacteria of the large intestine, collectively dubbed the gut microbiome, in modulating brain and behavior in models of cocaine and other substance use disorders. Importantly, previous work has repeatedly shown that depletion of the gut microbiome leads to increased cocaine taking and seeking behaviors in multiple models.

A Cocaine-Activated Ensemble Exerts Increased Control Over Behavior While Decreasing in Size.

Background: Substance use disorder is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens. Previous work has shown that cocaine exposure induces plasticity in broad, genetically defined cell types in the nucleus accumbens; however, in response to a stimulus, only a small percentage of neurons are transcriptionally active-termed an ensemble. Here, we identify an Arc-expressing neuronal ensemble that has a unique trajectory of recruitment and causally controls drug self-administration after repeated, but not acute, cocaine exposure.

Synchrony between midbrain gene transcription and dopamine terminal regulation is modulated by chronic alcohol drinking.

Alcohol use disorder is marked by disrupted behavioral and emotional states which persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. Here, 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods.

Microbiome Depletion Increases Fentanyl Self-Administration and Alters the Striatal Proteome Through Short-Chain Fatty Acids.

Opioid use disorder (OUD) is a public health crisis currently being exacerbated by increased rates of use and overdose of synthetic opioids, primarily fentanyl. Therefore, the identification of novel biomarkers and treatment strategies to reduce problematic fentanyl use and relapse to fentanyl taking is critical. In recent years, there has been a growing body of work demonstrating that the gut microbiome can serve as a potent modulator of the behavioral and transcriptional responses to both stimulants and opioids.

Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice.

Background: The pathophysiology of autism spectrum disorder (ASD) involves genetic and environmental factors. Mounting evidence demonstrates a role for the gut microbiome in ASD, with signaling via short-chain fatty acids (SCFA) as one mechanism. Here, we utilize mice carrying deletion to exons 4-22 of Shank3 (Shank3) to model gene by microbiome interactions in ASD.

Clinical and Preclinical Evidence for Gut Microbiome Mechanisms in Substance Use Disorders.

Substance use disorders are a set of recalcitrant neuropsychiatric conditions that cause tremendous morbidity and mortality and are among the leading causes of loss of disability-adjusted life years worldwide. While each specific substance use disorder is driven by problematic use of a different substance, they all share a similar pattern of escalating and out-of-control substance use, continued use despite negative consequences, and a remitting/relapsing pattern over time. Despite significant advances in our understanding of the neurobiology of these conditions, current treatment options remain few and are ineffective for too many individuals.

Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking.

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome, in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect.

Dietary polyphenols drive dose-dependent behavioral and molecular alterations to repeated morphine.

Opioid Use Disorder (OUD) is associated with tremendous morbidity and mortality. Despite this burden, current pharmacotherapies for OUD are ineffective or intolerable for many patients. As such, interventions aimed at promoting resilience against OUD are of immense clinical interest.

Effect of germ-free status on transcriptional profiles in the nucleus accumbens and transcriptomic response to chronic morphine.

Opioid use disorder is a public health crisis that causes tremendous suffering for patients as well as substantial social and economic costs for society. There are currently available treatments for patients with opioid use disorder, but they remain intolerable or ineffective for many. Thus the need to develop new avenues for therapeutics development in this space is great.

KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer's disease-related pathology.

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer's disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.

Granulocyte colony-stimulating factor (G-CSF) enhances cocaine effects in the nucleus accumbens via a dopamine release-based mechanism.

Cocaine use disorder is associated with alterations in immune function including altered expression of multiple peripheral cytokines in humans-several of which correlate with drug use. Individuals suffering from cocaine use disorder show altered immune system responses to drug-associated cues, highlighting the interaction between the brain and immune system as a critical factor in the development and expression of cocaine use disorder. We have previously demonstrated in animal models that cocaine use upregulates the expression of granulocyte colony-stimulating factor (G-CSF)-a pleiotropic cytokine-in the serum and the nucleus accumbens (NAc).

Cocaine self-administration induces sex-dependent protein expression in the nucleus accumbens.

Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by long-lasting alterations in the neural circuitry regulating reward and motivation. Substantial work has focused on characterizing the molecular substrates that underlie these persistent changes in neural function and behavior. However, this work has overwhelmingly focused on male subjects, despite mounting clinical and preclinical evidence that females demonstrate dissimilar progression to SUD and responsivity to stimulant drugs of abuse, such as cocaine.

Alterations in microbiome composition and metabolic byproducts drive behavioral and transcriptional responses to morphine.

Recent evidence has demonstrated that the gut microbiome has marked effects on neuronal function and behavior. Disturbances to microbial populations within the gut have been linked to myriad models of neuropsychiatric disorders. However, the role of the microbiome in substance use disorders remains understudied.

Contributions of neuroimmune and gut-brain signaling to vulnerability of developing substance use disorders.

Epidemiology and clinical research indicate that only a subset of people who are exposed to drugs of abuse will go on to develop a substance use disorder. Numerous factors impact individual susceptibility to developing a substance use disorder, including intrinsic biological factors, environmental factors, and interpersonal/social factors. Given the extensive morbidity and mortality that is wrought as a consequence of substance use disorders, a substantial body of research has focused on understanding the risk factors that mediate the shift from initial drug use to pathological drug use.

The role of gut-immune-brain signaling in substance use disorders.

Substance use disorders (SUDs) are debilitating neuropsychiatric conditions that exact enormous costs in terms of loss of life and individual suffering. While much progress has been made defining the neurocircuitry and intracellular signaling cascades that contribute to SUDs, these studies have yielded limited effective treatment options. This has prompted greater exploration of non-traditional targets in addiction.

Granulocyte-Colony Stimulating Factor Reduces Cocaine-Seeking and Downregulates Glutamatergic Synaptic Proteins in Medial Prefrontal Cortex.

Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no Food and Drug Administration (FDA)-approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility.

Chronic stress and antidepressant treatment alter purine metabolism and beta oxidation within mouse brain and serum.

Major depressive disorder (MDD) is a complex condition with unclear pathophysiology. Molecular disruptions within limbic brain regions and the periphery contribute to depression symptomatology and a more complete understanding the diversity of molecular changes that occur in these tissues may guide the development of more efficacious antidepressant treatments. Here, we utilized a mouse chronic social stress model for the study of MDD and performed metabolomic, lipidomic, and proteomic profiling on serum plus several brain regions (ventral hippocampus, nucleus accumbens, and medial prefrontal cortex) of susceptible, resilient, and unstressed control mice.

Granulocyte-Colony Stimulating Factor Alters the Pharmacodynamic Properties of Cocaine in Female Mice.

Addiction to psychostimulants is a major public health crisis that leads to significant morbidity and mortality, for which there are currently no FDA-approved pharmacotherapies. Female subjects have increased propensity to develop pathological substance use disorders after initial use, suggesting the possibility of different pathophysiological mechanisms between males and females. Recently, we identified the neuroactive cytokine granulocyte-colony stimulating factor (G-CSF) as a key mediator of neuronal and behavioral plasticity in response to cocaine in male mice.