Cue-induced cocaine craving enhances psychosocial stress and vice versa in chronic cocaine users

There is evidence that stress and craving contribute to the development, maintenance, and relapse in cocaine use disorder. Previous research has shown altered physiological responses to psychosocial stress as well as increased vegetative responding to substance-related cues in chronic cocaine users (CU). However, how psychosocial stress and cue-induced craving interact in relation to the physiological response of CU is largely unknown. Therefore, we investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. Participants were randomly exposed first to a video-based cocaine-cue paradigm and second to the Trier Social Stress Test (TSST) or vice versa in a crossed and balanced design to investigate possible mutually augmenting effects of both stressors on the physiological stress response. Plasma cortisol, ACTH, and noradrenaline as well as subjective stress and craving were assessed repeatedly over the course of the experimental procedure. Growth models and discontinuous growth models were used to estimate the responses during the cocaine-cue paradigm and TSST. Overall, both groups did not differ in their endocrinological responses to the TSST but CU displayed lower ACTH levels at baseline. The TSST did not elevate craving in CU. However, if the cocaine-cue video was shown first, CU displayed an enhanced cortisol response to the subsequent TSST. Cocaine-cues robustly evoked craving in CU but no stress response, while cue-induced craving was intensified after the TSST. Taken together, CU did not show an altered acute stress response during the TSST but stress and craving together seem to have mutually augmenting effects on their stress response.

Oxidative Stress and Cocaine Intoxication as Start Points in the Pathology of Cocaine-Induced Cardiotoxicity

Psychomotor stimulants are the most commonly used prohibited substances after cannabis. Globally, their use reaches epidemiological proportions and is one of the most common causes of death in many countries. The use of illicit drugs has negative effects on the cardiovascular system and is one of the causes of serious cardiovascular pathologies, ranging from abnormal heart rhythms to heart attacks and sudden cardiac death. The reactive oxygen species generation, toxic metabolites formation, and oxidative stress play a significant role in cocaine-induced cardiotoxicity. The aim of the present review is to assess acute and chronic cocaine toxicity by focusing on the published literature regarding oxidative stress levels. Hypothetically, this study can serve as a basis for developing a rapid and effective method for determining oxidative stress levels by monitoring changes in the redox status of patients with cocaine intoxication.

Cocaine exacerbates neurological impairments and neuropathologies in the iTat model of HIV-associated neurocognitive disorder through genome-wide alterations of DNA methylation and gene expression

HIV infection of the central nervous system causes HIV-associated neurocognitive disease (HAND) in up to 50% HIV-infected individuals. Cocaine use is prevalent in the HIV-infected population and has been shown to facilitate the HAND progression. However, the cellular and molecular mechanism of the cocaine-facilitated HAND progression remains largely unknown. In this study, we took advantage of the doxycycline inducible and brain-specific HIV Tat transgenic mouse model (iTat) of HAND and characterized effects of chronic cocaine exposure and long-term Tat expression on HAND-associated neurology and neuropathology. We found that cocaine exposure worsened the learning and memory of iTat mice, coupled with dendritic spine swelling, increased synaptophysin expression, and diminished microglia and astrocyte activation. We then employed the single-base resolution whole genome bisulfate sequencing and RNA sequencing and identified 14,838 hypermethylated CpG-related differentially methylated regions (DMR) and 15,800 hypomethylated CpG-related DMR that were linked to 52 down- and 127 up-regulated genes by cocaine and Tat. We further uncovered these genes to be mostly enriched at neuronal function- and cell morphology- and synapse formation-related ECM-receptor interaction pathway, and to be linked to behavioral and pathological changes altered by cocaine and Tat. Eight mostly affected genes included four in microglia Ift172, Eif2ak4, Pik3c2a, and Phf8, two in astrocytes Garem1 and Adgrb3, and two in neurons Dcun1d4 and Adgrb3. These findings demonstrated for the first time that cocaine and Tat interactively contributed to HAND neurology and neuropathology through genome-wide changes of DNA methylation and gene expression and suggest that targeting epigenetic changes serves as a potentially new therapeutic strategy to treat cocaine use disorder in people living with HAND.

Role of hippocampal NF-κB and GluN2B in the memory acquisition impairment of experiences gathered prior to cocaine administration in rats

Cocaine can induce severe neurobehavioral changes, among others, the ones involved in learning and memory processes. It is known that during drug consumption, cocaine-associated memory and learning processes take place. However, much less is known about the effects of this drug upon the mechanisms involved in forgetting.The present report focuses on the mechanisms by which cocaine affects memory consolidation of experiences acquired prior to drug administration. We also study the involvement of hippocampus in these processes, with special interest on the role of Nuclear factor kappa B (NF-κB), N-methyl-D-aspartate glutamate receptor 2B (GluN2B), and their relationship with other proteins, such as cyclic AMP response element binding protein (CREB). For this purpose, we developed a rat experimental model of chronic cocaine administration in which spatial memory and the expression or activity of several proteins in the hippocampus were assessed after 36 days of drug administration. We report an impairment in memory acquisition of experiences gathered prior to cocaine administration, associated to an increase in GluN2B expression in the hippocampus. We also demonstrate a decrease in NF-κB activity, as well as in the expression of the active form of CREB, confirming the role of these transcription factors in the cocaine-induced memory impairment.

Chronic Cocaine Use and White Matter Integrity: A Diffusion Tensor Imaging Study

Chronic substance use and its effects on brain function and structure has long been of interest to clinicians and researchers. Prior cross-sectional comparisons of diffusion tensor imaging (DTI) metrics have suggested deleterious effects of chronic substance use (i.e., cocaine use) on white matter integrity. However, it is unclear whether these effects would persist when accounting for confounding factors, such as chronic alcohol use, and how improving DTI technologies may enhance detection of substance use-related pathology. In this study, we sought to conduct a replication of previous work in this area and determine whether there are any patterns of persistent differences in white matter microstructure between individuals with a history of Cocaine Use Disorder (CocUD, according to DSM-IV) and healthy controls. 46 participants (21 healthy controls, 25 chronic cocaine users) were recruited from the Richmond, Virginia metropolitan area. Information regarding past and current substance use was collected from all participants. Participants also completed structural and DTI scans. Consistent with previous DTI studies, significant differences were found between CocUD and controls. These differences were in fractional anisotropy and axial diffusivity but not other diffusivity metrics. Lifetime alcohol consumption was greater in the CocUD group, but lifetime alcohol consumption did not show significant linear relationship with any of the DTI metrics in within-group regression analyses. These data align with previously reported declines in white matter integrity in chronic cocaine users. However, it is less clear whether comorbid alcohol consumption results in an additive deleterious effect on white matter microstructure.