Attention-deficit/hyperactivity disorder combined subtype exacerbates opioid use disorder consequences: Mediation by impulsive phenotypes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is highly prevalent and associated with opioid use disorder (OUD). Yet, little is known about the mechanisms by which ADHD (which is a heterogeneous construct/diagnosis) might alter the trajectory of OUD outcomes in persons who use heroin. AIM: We examined whether ADHD subtypes are related to heroin-use consequences and the extent to which the effects of ADHD on lifetime heroin-use consequences are mediated by two impulsivity factors that may be partly independent of ADHD: foreshortened time perspective and drug-use impulsivity. METHODS: Individuals who reported regular heroin use (N=250) were screened using the Assessment of Hyperactivity and Attention (AHA), Impulsive Relapse Questionnaire (IRQ), Stanford Time Perception Inventory (STPI), and a comprehensive assessment of lifetime and current substance use and substance-related consequences. This secondary analysis examined whether ADHD or intermediate phenotypes predicted heroin-use consequences. RESULTS: Relative to participants whose AHA scores indicated lifetime absence of ADHD (n=88), those with scores indicating persistent ADHD (childhood and adult, n=62) endorsed significantly more total lifetime heroin-use consequences despite comparable heroin-use severity. Likewise, there was a significant indirect effect of the combined ADHD subtype in childhood on lifetime heroin-use consequences. This effect was mediated by STPI scores indicating less future (and more hedonism in the present) temporal orientation and by IRQ scores indicating less capacity for delaying drug use. CONCLUSION: The combined ADHD subtype is significantly associated with lifetime heroin-use consequences, and this effect is mediated through higher drug-use impulsivity (less capacity for delay) and lower future temporal orientation.

A neuron-specific microexon ablates the novel DNA-binding function of a histone H3K4me0 reader PHF21A.

How cell-type-specific chromatin landscapes emerge and progress during metazoan ontogenesis remains an important question. Transcription factors are expressed in a cell-type-specific manner and recruit chromatin-regulatory machinery to specific genomic loci. In contrast, chromatin-regulatory proteins are expressed broadly and are assumed to exert the same intrinsic function across cell types. However, human genetics studies have revealed an unexpected vulnerability of neurodevelopment to chromatin factor mutations with unknown mechanisms. Here, we report that 14 chromatin regulators undergo evolutionary-conserved neuron-specific splicing events involving microexons. Of the 14 chromatin regulators, two are integral components of a histone H3K4 demethylase complex; the catalytic subunit LSD1 and an H3K4me0-reader protein PHF21A adopt neuron-specific forms. We found that canonical PHF21A (PHF21A-c) binds to DNA by AT-hook motif, and the neuronal counterpart PHF21A-n lacks this DNA-binding function yet maintains H3K4me0 recognition intact. In-vitro reconstitution of the canonical and neuronal PHF21A-LSD1 complexes identified the neuronal complex as a hypomorphic H3K4 demethylating machinery with reduced nucleosome engagement. Furthermore, an autism-associated PHF21A missense mutation, 1285 G>A, at the last nucleotide of the common exon immediately upstream of the neuronal microexon led to impaired splicing of PHF21A -n. Thus, ubiquitous chromatin regulatory complexes exert unique intrinsic functions in neurons via alternative splicing of their subunits and potentially contribute to faithful human brain development.