Heroin

The dopamine (DA) hypothesis posits the increase of mesolimbic dopamine levels as a defining commonality of addictive drugs, initially causing reinforcement, eventually leading to compulsive consumption. While much experimental evidence from psychostimulants supports this hypothesis, it has been challenged for opioid reinforcement. Here, we monitor genetically encoded DA and calcium indicators as well as cFos in mice to reveal that heroin activates DA neurons located in the medial part of the VTA, preferentially projecting to the medial shell of the nucleus accumbens (NAc). Chemogenetic and optogenetic manipulations of VTA DA or GABA neurons establish a causal link to heroin reinforcement. Inhibition of DA neurons blocked heroin self-administration, while heroin inhibited optogenetic self-stimulation of DA neurons. Likewise, heroin occluded the self-inhibition of VTA GABA neurons. Together, these experiments support a model of disinhibition of a subset of VTA DA neurons in opioid reinforcement.

The opioid epidemic has resulted in a threefold increase in drug overdose deaths in the United States during 1999-2015 (1). Whereas American Indians/Alaska Natives (AI/AN) have experienced larger increases in drug overdose mortality than have other racial/ethnic groups in the United States (2), little is known about the regional impact of opioids in tribal and urban AI/AN communities. To address this data gap, death records from the Washington State Center for Health Statistics, corrected for misclassification of AI/AN race, were examined to identify trends and disparities in drug, opioid-involved, and heroin-involved overdose mortality rates for AI/AN and non-Hispanic whites (whites) in Washington. Although AI/AN and whites had similar overdose mortality rates during 1999-2001, subsequent overdose rates among AI/AN increased at a faster rate than did those among whites. During 2013-2015, mortality rates among AI/AN were 2.7 and 4.1 times higher than rates among whites for total drug and opioid-involved overdoses and heroin-involved overdoses, respectively. Washington death certificates that were not corrected for misclassification of AI/AN race underestimated drug overdose mortality rates among AI/AN by approximately 40%. National statistics on the opioid epidemic, which report that overdose mortality rates are significantly higher among whites than among AI/AN, are not reflective of regional prevalences, disparities, and trends. Comprehensive efforts to address the opioid epidemic in AI/AN communities rely on strong partnerships between tribal governments and local, state, and federal entities. Additional measures are needed for community-based surveillance, treatment, and prevention to effectively respond to the epidemic across diverse tribal and urban AI/AN communities.

MicroRNAs (miRNAs) are a class of evolutionarily conserved, 18-25 nucleotide non-coding sequences that post-transcriptionally regulate gene expression. Recent studies implicated their roles in the regulation of neuronal functions, such as learning, cognition and memory formation. Here we report that miR-218 inhibits heroin-induced behavioral plasticity. First, network propagation-based method was used to predict candidate miRNAs that played potential key roles in regulating drug addiction-related genes. Microarray screening was also carried out to identify miRNAs responding to chronic heroin administration in the nucleus accumbens (NAc). Among the collapsed miRNAs, top-ranked miR-218 was decreased after chronic exposure to heroin. Lentiviral overexpression of miR-218 in NAc could inhibit heroin-induced reinforcement in both conditioned place preference (CPP) test and heroin self-administration experiments. Luciferase activity assay indicated that miR-218 could regulate 3' untranslated regions (3' UTR) of multiple neuroplasticity-related genes and directly target methyl CpG binding protein 2 (Mecp2). Consistently, Mecp2308/y mice exhibited reduced heroin seeking behavior in CPP test. These data reveal a functional role of miR-218 and its target, MeCP2, in the regulation of heroin-induced behavioral plasticity.

Astrocytes regulate synaptic activity across large brain territories via their complex, interconnected morphology. Emerging evidence supports the involvement of astrocytes in shaping relapse to opioid use through morphological rearrangements in the nucleus accumbens (NAc). However, a comprehensive assessment of astrocyte structural diversity within and between NAc subdivisions is lacking because of limitations in existing methodologies to quantify meaningful alterations in astrocyte structure. We developed a methodological pipeline that integrates supervised and unsupervised learning techniques to rigorously quantify astrocyte morphological features and spatial organization across the brain, leveraging expression of cytoskeletal markers. Application of this pipeline reveals that morphological characteristics of individual astrocytes predict their location within the NAc. Our analysis also indicates that after heroin use, astrocyte structural plasticity is impaired in portions of the NAc associated with the extinction of conditioned responses and is uniquely engaged in the dorsomedial portion of the NAc shell, an undercharacterized subdivision of the structure.