Altered expression of somatostatin signaling molecules and clock genes in the hippocampus of subjects with substance use disorder

Abstract

Substance use disorders are a debilitating group of psychiatric disorders with a high degree of comorbidity with major depressive disorder. Sleep and circadian rhythm disturbances are commonly reported in people with substance use disorder and major depression and associated with increased risk of relapse. Hippocampal somatostatin signaling is involved in encoding and consolidation of contextual memories which contribute to relapse in substance use disorder. Somatostatin and clock genes also have been implicated in depression, suggesting that these molecules may represent key converging pathways involved in contextual memory processing in substance use and major depression. We used hippocampal tissue from a cohort of subjects with substance use disorder (n = 20), subjects with major depression (n = 20), subjects with comorbid substance use disorder and major depression (n = 24) and psychiatrically normal control subjects (n = 20) to test the hypothesis that expression of genes involved in somatostatin signaling and clock genes is altered in subjects with substance use disorder. We identified decreased expression of somatostatin in subjects with substance use disorder and in subjects with major depression. We also observed increased somatostatin receptor 2 expression in subjects with substance use disorder with alcohol in the blood at death and decreased expression in subjects with major depression. Expression of the clock genes Arntl, Nr1d1, Per2 and Cry2 was increased in subjects with substance use disorder. Arntl and Nr1d1 expression in comparison was decreased in subjects with major depression. We observed decreased expression of Gsk3β in subjects with substance use disorder. Subjects with comorbid substance use disorder and major depression displayed minimal changes across all outcome measures. Furthermore, we observed a significant increase in history of sleep disturbances in subjects with substance use disorder. Our findings represent the first evidence for altered somatostatin and clock gene expression in the hippocampus of subjects with substance use disorder and subjects with major depression. Altered expression of these molecules may impact memory consolidation and contribute to relapse risk.

Extracellular Matrix Abnormalities in the Hippocampus of Subjects with Substance Use Disorder

“…qPCR was conducted as described previously 43, 48 and in the Supplemental Materials. The primers used are listed in Supplemental Table 21.…”

“…Human subjects for brightfield microscopy and RNA studies Fresh frozen blocks containing the hippocampus from subjects with SUD (n=20), SUD and comorbid MDD (n=24), MDD (n=20), and psychiatrically normal controls (n=20) were provided by the UMMC Postmortem Brain Core (Table 1, Cohort A). Details are described in our previous report 43 and in the Supplemental Materials.…”

“…However, considering that this is representative of the real-world population of SUD it is important to examine the molecular pathology when these factors are present in the same subjects when considering development of therapeutic treatment strategies for this population. Our cohort consists of extensive information including retrospective clinical assessments, history of specific drugs of abuse and presence or absence of drugs of abuse and psychiatric medications in the blood at death from toxicology reports that can be accounted for using ANCOVA analyses, as conducted in our previous study using this same cohort 42 . Furthermore, the inclusion of samples from rhesus monkeys with chronic alcohol use provides a valuable cause and effect comparison for the most common drug of abuse in our human subjects.…”

Circadian rhythm disruptions associated with opioid use disorder in synaptic proteomes of human dorsolateral prefrontal cortex and nucleus accumbens

“…Further understanding of the impact of long-term opioid use and opioid overdose on the human brain is important for considering new avenues of treatment and intervention. Investigating the molecular alterations in postmortem brains from subjects with OUD provide valuable insights into the neurobiological mechanisms and potential therapeutic targets for opioid addiction [ 2 – 8 ].…”

Circadian rhythm disruptions associated with opioid use disorder in the synaptic proteomes of the human dorsolateral prefrontal cortex and nucleus accumbens

“…Understanding the impact of long-term opioid use and overdose on the human brain is critical for developing new interventions, therapeutics, and for evaluating current OUD treatments. In-depth investigations into the cellular and molecular changes in human postmortem brain may provide valuable insights into the biological mechanisms associated with OUD and lead to new therapeutic strategies for treating opioid addiction [2][3][4][5][6][7][8].…”