Spatial-Structural Mechanisms of Racialized Disparities in Overdose Mortality: A Spatiotemporal Analysis.

Efforts to understand and respond to the opioid crisis have focused on overdose fatalities. Overdose mortality rates (ratios of overdoses resulting in death) are rarely examined though they are important indicators of harm reduction effectiveness. Factors that vary across urban communities likely determine which community members are receiving the resources needed to reduce fatal overdose risk.

Aversion-induced drug taking and escape behavior involve similar nucleus accumbens core dopamine signaling signatures.

Dopamine release in the nucleus accumbens core (NAcC) has long been associated with the promotion of motivated behavior. However, inhibited dopamine signaling can increase behavior in certain settings, such as during drug self-administration. While aversive environmental stimuli can reduce dopamine, it is unclear whether such stimuli reliably engage this mechanism in different contexts.

Exploring the Association Between Structural Racism and Mental Health: Geospatial and Machine Learning Analysis.

Background: Structural racism produces mental health disparities. While studies have examined the impact of individual factors such as poverty and education, the collective contribution of these elements, as manifestations of structural racism, has been less explored. Milwaukee County, Wisconsin, with its racial and socioeconomic diversity, provides a unique context for this multifactorial investigation.

Role of mesolimbic cannabinoid receptor 1 in stress-driven increases in cocaine self-administration in male rats.

Stress is prevalent in the lives of those with substance use disorders (SUDs) and influences SUD outcomes. Understanding the neurobiological mechanisms through which stress promotes drug use is important for the development of effective SUD interventions. We have developed a model wherein exposure to a stressor, uncontrollable electric footshock, daily at the time of cocaine self-administration escalates intake in male rats.

The journey to overdose: Using spatial social network analysis as a novel framework to study geographic discordance in overdose deaths.

Introduction: Drug overdose deaths are often geographically discordant (the community in which the overdose death occurs is different from the community of residence). Thus, in many cases there is a journey to overdose.

Methods: We applied geospatial analysis to examine characteristics that define journeys to overdoses using Milwaukee, Wisconsin, a diverse and segregated metropolitan area in which 26.

Corticotropin releasing factor and drug seeking in substance use disorders: Preclinical evidence and translational limitations.

The neuropeptide, corticotropin releasing factor (CRF), has been an enigmatic target for the development of medications aimed at treating stress-related disorders. Despite a large body of evidence from preclinical studies in rodents demonstrating that CRF receptor antagonists prevent stressor-induced drug seeking, medications targeting the CRF-R1 have failed in clinical trials. Here, we provide an overview of the abundant findings from preclinical rodent studies suggesting that CRF signaling is involved in stressor-induced relapse.

Impact of the COVID-19 Pandemic on Opioid Overdose Deaths: a Spatiotemporal Analysis.

The effects of the opioid crisis have varied across diverse and socioeconomically defined urban communities, due in part to widening health disparities. The onset of the COVID-19 pandemic has coincided with a spike in drug overdose deaths in the USA. However, the extent to which the impact of the pandemic on overdose deaths has varied across different demographics in urban neighborhoods is unclear.

Examining Opioid Overdose Deaths across Communities Defined by Racial Composition: a Multiscale Geographically Weighted Regression Approach.

To provide data that can guide community-targeted practices, policies, and interventions in urban metropolitan areas, we used geospatial analysis to examine the community-level opioid overdose death determinants and their spatial variation across a study area. We obtained spatial datasets containing multiple, high-quality measures of socioeconomic conditions, public health status, and demographics for analysis and visualization in geographic information systems. We employed a multiscale modeling approach (multiscale geographically weighted regression; MGWR) to provide a comprehensive and robust analysis of opioid overdose death determinants, explain how geospatial patterns vary across scales across Milwaukee County in 2019, and examine the differential influence of factors locally, regionally, and globally.

Estradiol Regulation of the Prelimbic Cortex and the Reinstatement of Cocaine Seeking in Female Rats.

Relapse susceptibility in women with substance use disorders (SUDs) has been linked to the estrogen, 17β-estradiol (E2). Our previous findings in female rats suggest that the influence of E2 on cocaine seeking can be localized to the prelimbic prefrontal cortex (PrL-PFC). Here, we investigated the receptor mechanisms through which E2 regulates the reinstatement of extinguished cocaine seeking.

Neurochemical mechanisms and neurocircuitry underlying the contribution of stress to cocaine seeking.

In individuals with substance use disorders, stress is a critical determinant of relapse susceptibility. In some cases, stressors directly trigger cocaine use. In others, stressors interact with other stimuli to promote drug seeking, thereby setting the stage for relapse.

Chronic Stress Prevents Cortico-Accumbens Cue Encoding and Alters Conditioned Approach.

Chronic stress impairs the function of multiple brain regions and causes severe hedonic and motivational deficits. One brain region known to be susceptible to these effects is the PFC. Neurons in this region, specifically neuronal projections from the prelimbic region (PL) to the nucleus accumbens core (NAcC), have a significant role in promoting motivated approach.

Sex, stress, and prefrontal cortex: influence of biological sex on stress-promoted cocaine seeking.

Clinical reports suggest that females diagnosed with substance use disorder experience enhanced relapse vulnerability compared with males, particularly during stress. We previously demonstrated that a stressor (footshock) can potentiate cocaine seeking in male rats via glucocorticoid-dependent cannabinoid type-1 receptor (CB1R)-mediated actions in the prelimbic prefrontal cortex (PrL-PFC). Here, we investigated the influence of biological sex on stress-potentiated cocaine seeking.

What does the Fos say? Using Fos-based approaches to understand the contribution of stress to substance use disorders.

Despite extensive research efforts, drug addiction persists as a largely unmet medical need. Perhaps the biggest challenge for treating addiction is the high rate of recidivism. While many factors can promote relapse in abstinent drug users, the contribution of stress is particularly problematic, as stress is uncontrollable and pervasive in the lives of those struggling with addiction.

Enhanced CRFR1-Dependent Regulation of a Ventral Tegmental Area to Prelimbic Cortex Projection Establishes Susceptibility to Stress-Induced Cocaine Seeking.

The ability of stress to trigger cocaine seeking in humans and rodents is variable and is determined by the amount and pattern of prior drug use. This study examined the role of a corticotropin releasing factor (CRF)-regulated dopaminergic projection from the ventral tegmental area (VTA) to the prelimbic cortex in shock-induced cocaine seeking and its recruitment under self-administration conditions that establish relapse vulnerability. Male rats with a history of daily long-access (LgA; 14 × 6 h/d) but not short-access (ShA; 14 × 2 h/d) self-administration showed robust shock-induced cocaine seeking.

Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex.

Background: Clinical reports suggest that rather than directly driving cocaine use, stress may create a biological context within which other triggers for drug use become more potent. We hypothesize that stress-induced increases in corticosterone "set the stage" for relapse by promoting endocannabinoid-induced attenuation of inhibitory transmission in the prelimbic cortex (PL).

Methods: We have established a rat model for these stage-setting effects of stress.

Corticosterone regulates both naturally occurring and cocaine-induced dopamine signaling by selectively decreasing dopamine uptake.

Stressful and aversive events promote maladaptive reward-seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our laboratory and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine's effects on dopamine signaling.

17β-Estradiol Potentiates the Reinstatement of Cocaine Seeking in Female Rats: Role of the Prelimbic Prefrontal Cortex and Cannabinoid Type-1 Receptors.

Clinical observations imply that female cocaine addicts experience enhanced relapse vulnerability compared with males, an effect tied to elevated estrogen phases of the ovarian hormone cycle. Although estrogens can enhance drug-seeking behavior, they do not directly induce reinstatement on their own. To model this phenomenon, we tested whether an estrogen could augment drug-seeking behavior in response to an ordinarily subthreshold reinstatement trigger.

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3.

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3.

Pituitary Adenylate cyclase-activating polypeptide orchestrates neuronal regulation of the astrocytic glutamate-releasing mechanism system xc (.).

Glutamate signaling is achieved by an elaborate network involving neurons and astrocytes. Hence, it is critical to better understand how neurons and astrocytes interact to coordinate the cellular regulation of glutamate signaling. In these studies, we used rat cortical cell cultures to examine whether neurons or releasable neuronal factors were capable of regulating system xc (-) (Sxc), a glutamate-releasing mechanism that is expressed primarily by astrocytes and has been shown to regulate synaptic transmission.

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats.

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF.

CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats.

Rationale: Under some conditions, stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a subthreshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior.

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress.

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures.

Aversive stimuli drive drug seeking in a state of low dopamine tone.

Background: Stressors negatively impact emotional state and drive drug seeking, in part, by modulating the activity of the mesolimbic dopamine system. Unfortunately, the rapid regulation of dopamine signaling by the aversive stimuli that cause drug seeking is not well characterized. In a series of experiments, we scrutinized the subsecond regulation of dopamine signaling by the aversive stimulus, quinine, and tested its ability to cause cocaine seeking.