Dose- and Sex-Dependent Bidirectional Relationship between Intravenous Fentanyl Self-Administration and Gut Microbiota.

Gut bacteria influence neural circuits in addiction-related behaviors. Given the association between opioid use, gastrointestinal distress, and microbial dysbiosis in humans and mice, we test the hypothesis that interactions between gut bacteria and the brain mediate the rewarding and reinforcing properties of fentanyl. We implant rats with intravenous catheters in preparation for fentanyl intravenous self-administration (IVSA) on an escalating schedule of reinforcement to determine factors that influence fentanyl intake, including sex, dose, and gut microbiota. Our data show the impact of fentanyl IVSA on gut microbiota diversity, as well as the role of gut microbiota on fentanyl IVSA, in Sprague Dawley rats in a sex- and dose-dependent manner (n = 10-16/group). We found that the diversity of gut microbiota within females dose-dependently predicts progressive but not fixed ratio schedules of fentanyl IVSA. Depending on sex and fentanyl dose, alpha diversity (richness and evenness measured with Shannon index) is either increased or decreased following fentanyl IVSA and predicts progressive ratio breakpoint. Our findings collectively suggest a role of gut bacteria in drug-related behavior, including motivation and reinforcement. This work provides feasibility for an intravenous fentanyl self-administration model and uncovers potential factors mediating drug use, which may lead to the development of effective addiction interventions.

Unique effects of nicotine across the lifespan.

Smoking remains the leading cause of preventable death in the United States. Although combustible cigarettes are largely being replaced by tobacco-free products, nicotine use continues to increase in vulnerable populations, including youth, adolescents, and pregnant women. Nicotine exerts unique effects on specific brain regions during distinct developmental periods due to the dynamic expression of nicotinic acetylcholine receptors (nAChRs) throughout the lifespan. Nicotine exposure is a health concern not only for adults but also has neurotoxic effects on the fetus, newborn, child, and adolescent. In this review, we aim to highlight the dynamic roles of nAChRs throughout gestation, adolescence, and adulthood. We also provide clinical and preclinical evidence of the neurodevelopmental, cognitive, and behavioral consequences of nicotine exposure at different developmental periods. This comprehensive review highlights unique effects of nicotine throughout the lifespan to help elucidate interventions and public health measures to protect sensitive populations from nicotine exposure.

Antibiotic Knockdown of Gut Bacteria Sex-Dependently Enhances Intravenous Fentanyl Self-Administration in Adult Sprague Dawley Rats.

Communication between the brain and gut bacteria impacts drug- and addiction-related behaviors. To investigate the role of gut microbiota on fentanyl reinforcement and reward, we depleted gut bacteria in adult Sprague Dawley male and female rats using an oral, nonabsorbable antibiotic cocktail and allowed rats to intravenously self-administer fentanyl on an escalating schedule of reinforcement. We found that antibiotic treatment enhanced fentanyl self-administration in males, but not females, at the lowest schedule of reinforcement (i.e., fixed ratio 1). Both males and females treated with antibiotics self-administered greater amounts of fentanyl at higher schedules of reinforcement. We then replete microbial metabolites via short-chain fatty acid administration to evaluate a potential mechanism in gut-brain communication and found that restoring metabolites decreases fentanyl self-administration back to controls at higher fixed ratio schedules of reinforcement. Our findings highlight an important relationship between the knockdown and rescue of gut bacterial metabolites and fentanyl self-administration in adult rats, which provides support for a significant relationship between the gut microbiome and opioid use. Further work in this field may lead to effective, targeted treatment interventions in opioid-related disorders.

The role of the gut microbiome in opioid use.

Although the gut and brain are separate organs, they communicate with each other via trillions of intestinal bacteria that collectively make up one's gut microbiome. Findings from both humans and animals support a critical role of gut microbes in regulating brain function, mood, and behavior. Gut bacteria influence neural circuits that are notably affected in addiction-related behaviors. These include circuits involved in stress, reward, and motivation, with substance use influencing gut microbial abnormalities, suggesting significant gut-brain interactions in drug addiction. Given the overwhelming rates of opioid overdose deaths driven by abuse and addiction, it is essential to characterize mechanisms mediating the abuse potential of opioids. We discuss in this review the role of gut microbiota in factors that influence opioid addiction, including incentive salience, reward, tolerance, withdrawal, stress, and compromised executive function. We present clinical and preclinical evidence supporting a bidirectional relationship between gut microbiota and opioid-related behaviors by highlighting the effects of opioid use on gut bacteria, and the effects of gut bacteria on behavioral responses to opioids. Further, we discuss possible mechanisms of this gut-brain communication influencing opioid use. By clarifying the relationship between the gut microbiome and opioid-related behaviors, we improve understanding on mechanisms mediating reward-, motivation-, and stress-related behaviors and disorders, which may contribute to the development of effective, targeted therapeutic interventions in opioid dependence and addiction.

Nicotine Gateway Effects on Adolescent Substance Use.

Given the rise in teenage use of electronic nicotine delivery systems ("vaping") in congruence with the increasing numbers of drug-related emergencies, it is critical to expand the knowledge of the physical and behavioral risks associated with developmental nicotine exposure. A further understanding of the molecular and neurochemical underpinnings of nicotine's gateway effects allows emergency clinicians to advise patients and families and adjust treatment accordingly, which may minimize the use of tobacco, nicotine, and future substances. Currently, the growing use of tobacco products and electronic cigarettes among teenagers represents a major public health concern. Adolescent exposure to tobacco or nicotine can lead to subsequent abuse of nicotine and other substances, which is known as the gateway hypothesis. Adolescence is a developmentally sensitive time period when risk-taking behaviors, such as sensation seeking and drug experimentation, often begin. These hallmark behaviors of adolescence are largely due to maturational changes in the brain. The developing brain is particularly vulnerable to the harmful effects of drugs of abuse, including tobacco and nicotine products, which activate nicotinic acetylcholine receptors (nAChRs). Disruption of nAChR development with early nicotine use may influence the function and pharmacology of the receptor subunits and alter the release of reward-related neurotransmitters, including acetylcholine, dopamine, GABA, serotonin, and glutamate. In this review, we emphasize that the effects of nicotine are highly dependent on timing of exposure, with a dynamic interaction of nAChRs with dopaminergic, endocannabinoid, and opioidergic systems to enhance general drug reward and reinforcement. We analyzed available literature regarding adolescent substance use and nicotine's impact on the developing brain and behavior using the electronic databases of PubMed and Google Scholar for articles published in English between January 1968 and November 2018. We present a large collection of clinical and preclinical evidence that adolescent nicotine exposure influences long-term molecular, biochemical, and functional changes in the brain that encourage subsequent drug abuse.

Distinct ipRGC subpopulations mediate light's acute and circadian effects on body temperature and sleep.

The light environment greatly impacts human alertness, mood, and cognition by both acute regulation of physiology and indirect alignment of circadian rhythms. These processes require the melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), but the relevant downstream brain areas involved remain elusive. ipRGCs project widely in the brain, including to the central circadian pacemaker, the suprachiasmatic nucleus (SCN). Here we show that body temperature and sleep responses to acute light exposure are absent after genetic ablation of all ipRGCs except a subpopulation that projects to the SCN. Furthermore, by chemogenetic activation of the ipRGCs that avoid the SCN, we show that these cells are sufficient for acute changes in body temperature. Our results challenge the idea that the SCN is a major relay for the acute effects of light on non-image forming behaviors and identify the sensory cells that initiate light's profound effects on body temperature and sleep.

Cardioprotection via the skin: nociceptor-induced conditioning against cardiac MI in the NIC of time.

Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9-T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease. NEW & NOTEWORTHY This study shows that an electrical stimulus to skin sensory nerves elicits a very powerful cardioprotection against myocardial infarction. This stimulus works by a neurogenic mechanism similar to that previously elucidated for remote cardioprotection of trauma. Nociceptor-induced conditioning is equally potent when applied before ischemia or at reperfusion and has great potential clinically.