The role of gut-immune-brain signaling in substance use disorders

Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking

“…Demand curves were generated by curve-fitting individual animals' intake using an equation: log(Q) = log(Q0) + k × (e−α × Q0 × C−1) 6,7 . Previous work has demonstrated that Pmax is correlated with break points on a progressive ratio schedule of reinforcement, confirming that the threshold procedure accurately assesses reinforcing efficacy 2,5 . The value k was set to 2 for all animals 6,7 .…”

“…Shifts in responding across the dose curve can be analyzed using behavioral economics principles, to assess a variety of behavioral economic measures as described previously 1,2 . Behavioral economic analysis was used to determine the parameters of maximal price paid (Pmax) and consumption at a minimally constraining price (Q0), as described previously [3][4][5] . Demand curves were generated by curve-fitting individual animals' intake using an equation: log(Q) = log(Q0) + k × (e−α × Q0 × C−1) 6,7 .…”

“…As such, there are currently no FDA-approved medications for psychostimulant use disorders. This urgent need has led to increased interest in examining peripheral factors beyond the blood-brain barrier, which may serve as useful therapeutic targets or biomarkers 4,5 .…”

“…It has become increasingly clear that the resident population of bacteria within the gastrointestinal tract, collectively termed the gut microbiome, modulates brain function 6,7 . Robust literature indicates that connections between the brain and the gut microbiome modulate neuropsychiatric disease pathogenesis in animal models and clinical studies of autism, depression, anxiety, and substance use disorders 5,[8][9][10][11][12][13][14][15] . Indeed, previously published work demonstrates gut microbiome depletion results in significantly altered behavioral and transcriptional responses to cocaine and opioids 11,[16][17][18][19][20][21] .…”

Covid-19 interface with drug misuse and substance use disorders

“…For example, host proteins involved in the pathogenesis of SARS-CoV2 infections, in parallel to host immune signaling, impact the kynurenine pathway, a major regulator of serotonergic and glutamatergic systems involved in SUDs and neuropsychiatric disorders; in tandem, kynurenine functionality is tightly regulated by inflammatory events ( Anastasio et al, 2020 ; Attademo and Bernardini, 2021 ; Klempin et al, 2018 ; Linker et al, 2019 ; Morales-Puerto et al, 2021 ; Singer et al, 2012 ). Given that patient cytokine patterns and interferon responses correlate to Covid-19 disease severity and neurological complications, dysregulation of serotonergic and glutaminergic signaling could generate a cascade of pathophysiology that contributes to the escalation of SUDs ( Galani et al, 2021 ; Kohno et al, 2019 ; Lucerne and Kiraly, 2021 ; Nennig and Schank, 2017 ; Solomon, 2021 ). Thus, Covid-19 medical risks factors due to dysregulated peripheral and CNS immunity, may increase the vulnerability to engage in drug abuse behaviors.…”