The therapeutic potential of low-intensity focused ultrasound for treating substance use disorder.

Substance use disorder (SUD) is a persistent public health issue that necessitates the exploration of novel therapeutic interventions. Low-intensity focused ultrasound (LIFU) is a promising modality for precise and invasive modulation of brain activity, capable of redefining the landscape of SUD treatment. The review overviews effective LIFU neuromodulatory parameters and molecular mechanisms, focusing on the modulation of reward pathways in key brain regions in animal and human models.

Sex Differences in the Development of an Opioid Addiction-Like Phenotype: A Focus on the Telescoping Effect.

Background: Women develop addiction and drug-related health consequences after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed clinically for multiple drugs, including opioids. Preclinical studies indicate that this is a biologically based phenomenon; however, these studies have focused exclusively on cocaine, and none have considered health effects.

Methods: In this study, we used a rat (Sprague Dawley) model to determine sex differences in the time course for the development of an opioid addiction-like phenotype, as defined by the development of physical dependence (withdrawal-induced weight loss) and an increase in motivation for fentanyl (under a progressive-ratio schedule).

Focused Ultrasound Modulates Dopamine in a Mesolimbic Reward Circuit.

Dopamine is a neurotransmitter that plays a significant role in reward and motivation. Dysfunction in the mesolimbic dopamine pathway has been linked to a variety of psychiatric disorders, including addiction. Low-intensity focused ultrasound (LIFU) has demonstrated effects on brain activity, but how LIFU affects dopamine neurotransmission is not known.

Impact of SMAASH-C, a novel nutritional supplement, on drug-seeking and toxicity in female and male rats.

Relapse to drug use after abstinence is a major challenge in treating substance use disorder. Exposure to drug-associated cues during abstinence can trigger intense craving and precipitate relapse. New and more effective anti-relapse interventions are critically needed, particularly for cocaine use disorder since no effective pharmacological intervention is available.

Transcriptional Profile of Exercise-Induced Protection Against Relapse to Cocaine Seeking in a Rat Model.

Background: Exercise has shown promise as a treatment for cocaine use disorder; however, the mechanism underlying its efficacy has remained elusive.

Methods: We used a rat model of relapse (cue-induced reinstatement) and exercise (wheel running, 2 hours/day) coupled with RNA sequencing to establish transcriptional profiles associated with the protective effects of exercise (during early withdrawal [days 1-7] or throughout withdrawal [days 1-14]) versus noneffective exercise (during late withdrawal [days 8-14]) against cocaine-seeking and sedentary conditions.

Results: As expected, cue-induced cocaine seeking was highest in the sedentary and late-withdrawal exercise groups; both groups also showed upregulation of a -associated transcript and enrichment of Drd1-Nmdar1 complex and glutamate receptor complex terms.

Role of nucleus accumbens dopamine 2 receptors in motivating cocaine use in male and female rats prior to and following the development of an addiction-like phenotype.

A hallmark of cocaine use disorder (CUD) is dysfunction of dopamine signaling in the mesolimbic pathway, including impaired dopamine 2 (D2) receptor signaling. One of the most replicated findings in human imagining studies is decreased striatal D2 receptor binding in individuals with a substance use disorder relative to healthy controls; however, the vast majority of the data is from males, and findings in smokers suggest this molecular shift may not translate to females. The goal of this study was to determine whether there are sex differences in the role of D2 receptors in motivating cocaine use prior to and following the development of an addiction-like phenotype (defined by an enhanced motivation for cocaine relative to the short-access, ShA, group).

Role of Hormones in Substance Use Disorders.

Addictive drugs, such as cocaine and heroin, have well-documented actions on behavior. The mechanisms that these drugs employ have been under investigation for decades although the investigation of how gonadal and pituitary hormones impact these mechanisms is a relatively new focus. Here we have assembled a group of primary-literature papers solicited from many of the leading addiction laboratories in the world.

Sex Chromosome Complement and Estradiol Modify Cocaine Self-Administration Behaviors in Male Mice.

Introduction: Women are more vulnerable to cocaine's reinforcing effects and have a more rapid course to addiction after initial cocaine use as compared to men. Studies in rodents similarly indicate an enhanced sensitivity to the reinforcing effects of cocaine in females versus males. Levels of estradiol (E2) are correlated with vulnerability to the rewarding actions of cocaine.

Estradiol Enhances the Development of Addiction-Like Features in a Female Rat Model of Opioid Use Disorder.

Introduction: Women are more vulnerable than men in many aspects of opioid use disorder (OUD); a major theory of sex differences in substance use disorders is that these differences are due to ovarian hormones with estradiol enhancing vulnerability in females. However, most of this evidence is for psychostimulants and alcohol; evidence with opioids is sparse. Thus, the goal of this study was to determine the impact of estradiol on vulnerability in females in a rat model of OUD.

Sex/Gender Differences in the Time-Course for the Development of Substance Use Disorder: A Focus on the Telescoping Effect.

Sex/gender effects have been demonstrated for multiple aspects of addiction, with one of the most commonly cited examples being the "telescoping effect" where women meet criteria and/or seek treatment of substance use disorder (SUD) after fewer years of drug use as compared with men. This phenomenon has been reported for multiple drug classes including opioids, psychostimulants, alcohol, and cannabis, as well as nonpharmacological addictions, such as gambling. However, there are some inconsistent reports that show either no difference between men and women or opposite effects and a faster course to addiction in men than women.

Sex differences in the neuroadaptations associated with incubated cocaine-craving: A focus on the dorsomedial prefrontal cortex.

Introduction: Women have a shorter course from initial cocaine use to meeting the criteria for cocaine use disorder as compared to men. Preclinical findings similarly indicate that females develop key features of an addiction-like phenotype faster than males, including an enhanced motivation for cocaine and compulsive use, indicating that this phenomenon is biologically based. The goals of this study were to determine whether cocaine-craving, another key feature of addiction, also develops sooner during withdrawal in females than males and to determine whether there are sex differences in the molecular mechanisms associated with its development focusing on markers known to mediate cocaine-craving in males (i.

Impact of high-access exercise prior to and during early adolescence on later vulnerability to opioid use and relapse in male rats.

Middle- and high-school athletes participating in certain team sports are at greater risk of opioid misuse and addiction than those who do not. While this risk is thought to be due to increased access to opioids, in this study we explored the possibility that the sensitizing effects of discontinued high-intensity exercise may also contribute. Specifically, using male rat models with fentanyl, we tested the hypothesis that high-access exercise (24 h/day access to a running wheel) during pre/early adolescence (two weeks, postnatal-day 24-37) would enhance vulnerability to opioid use and relapse during late adolescence/adulthood.

Sex- and Dose-Dependent Differences in the Development of an Addiction-Like Phenotype Following Extended-Access Fentanyl Self-Administration.

Opioid use disorder (OUD) is a major epidemic in the United States, and fentanyl is a major culprit. The National Institute on Drug Abuse has highlighted an urgent need for research on the risks and outcomes of OUD with fentanyl; a better understanding of sex/gender differences is also critically needed given that the opioid epidemic has been particularly impactful on women. In response to this need, we developed a rat model of OUD with fentanyl and showed that sex impacts relapse vulnerability following extended-access self-administration under a low fentanyl dose.

Females develop features of an addiction-like phenotype sooner during withdrawal than males.

Rationale: Women meet criteria for substance use disorder after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed for multiple drugs, including cocaine. Preclinical findings similarly indicate an enhanced vulnerability in females to developing an addiction-like phenotype; however, it is not yet known if this phenotype develops faster in females versus males.

Objectives: The goal of this study was to determine using a rat model whether two key features of addiction in humans, an enhanced motivation for cocaine and compulsive use, emerge sooner during withdrawal from extended access cocaine self-administration in females versus males.

A buprenorphine-validated rat model of opioid use disorder optimized to study sex differences in vulnerability to relapse.

Rationale: Opioid use disorder (OUD) is a major epidemic in the USA. Despite evidence indicating that OUD may be particularly severe for women, preclinical models have yet to establish sex as a major factor in OUD.

Objectives: Here, we examined sex differences in vulnerability to relapse following intermittent access fentanyl self-administration and protracted abstinence and used buprenorphine, the FDA-approved treatment for OUD, to test the validity of our model.

Shifts in the neurobiological mechanisms motivating cocaine use with the development of an addiction-like phenotype in male rats.

Rationale: The development of addiction is accompanied by a shift in the mechanisms motivating cocaine use from nucleus accumbens (NAc) dopamine D receptor (DR) signaling to glutamate AMPA-kainate receptor (AMPA-R) signaling.

Objective: Here, we determined whether similar shifts occur for NAc-DR signaling and following systemic manipulation of DR, DR, and AMPA-R signaling.

Methods: Male rats were given short-access (20 infusions/day) or extended-access to cocaine (24 h/day, 96 infusions/day, 10 days).

Sexual Differentiation and Substance Use: A Mini-Review.

The organizational/activational hypothesis suggests that gonadal steroid hormones like testosterone (T) and estradiol (E2) are important at 2 different times during the lifespan when they perform 2 different functions. First steroids "organize" brain structures early in life and during puberty, and in adults these same hormones "activate" sexually dimorphic behaviors. This hypothesis has been tested and proven valid for a large number of behaviors (learning, memory, social, and sexual behaviors).

Sex chromosome complement influences vulnerability to cocaine in mice.

Women acquire cocaine habits faster and are more motivated to obtain drug than men. In general, female rodents acquire intravenous cocaine self-administration (SA) faster and show greater locomotor responses to cocaine than males. Sex differences are attributed to differences in circulating estradiol.

Tamoxifen Blocks the Development of Motivational Features of an Addiction-Like Phenotype in Female Rats.

Women become addicted sooner after initiating cocaine use as compared to men. Preclinical studies reveal a similar vulnerability in females, with findings from ovariectomized rats suggesting that estradiol mediates the enhanced vulnerability. However, since ovariectomy depletes not only estradiol, but all ovarian hormones, its role in a physiological context is not clear.

Mechanisms underlying the efficacy of exercise as an intervention for cocaine relapse: a focus on mGlu5 in the dorsal medial prefrontal cortex.

Rationale: Exercise shows promise as a treatment option for addiction; but in order to prevent relapse, it may need to be introduced early in the course of treatment.

Objective: We propose that exercise, by upregulating dorsal medial prefrontal cortex (dmPFC)-nucleus accumbens (NAc) transmission, offsets deficits in pathways targeting glutamate, BDNF, and dopamine during early abstinence, and in doing so, normalizes neuroadaptations that underlie relapse.

Methods: We compared the effects of exercise (wheel running, 2-h/day) during early (days 1-7), late (days 8-14), and throughout abstinence (days 1-14) to sedentary conditions on cocaine-seeking and gene expression in the dmPFC and NAc core of male rats tested following 24-h/day extended-access cocaine (up to 96 infusions/day) or saline self-administration and protracted abstinence (15 days).

Exercise during abstinence normalizes ultrastructural synaptic plasticity associated with nicotine-seeking following extended access self-administration.

Nicotine-craving progressively increases, or incubates, over abstinence following extended access self-administration. While not yet examined for nicotine, the incubation of cocaine-seeking is accompanied by changes in synaptic plasticity in the nucleus accumbens. Here, we determined whether such changes also accompany enhanced nicotine-seeking following extended access self-administration and abstinence, and whether exercise, a potential intervention for nicotine addiction, may exert its efficacy by normalizing these changes.