Decreased serum levels of proBDNF, but not mature BDNF during adolescent oxycodone intoxication preceding long-term social neglect and harsh environmental conditions

Abstract

Background: Adolescent opioid addiction is a global problem with a significant social and economic burden in the United States. Several studies have suggested that BDNF (mature BDNF) and its precursor play an essential role in alcohol dependence. However, the roles of the mBDNF/proBDNF pathway during adolescent opioid use are not clearly understood. Brain-derived neurotrophic factor (BDNF) plays a role in synaptic plasticity and neuroprotection. Furthermore, BDNF has well-established pro-survival effects, whereas its precursor protein, proBDNF, induces apoptosis. Thus, it has been suggested that the proBDNF/BDNF ratio could indicate neuronal health. Meta-analyses have identified serum levels of brain-derived neurotrophic factor (BDNF) as a potential biomarker for psychiatric disorders in an adult population. However, the lack of information on baseline circulating levels of BDNF and its precursor during the adolescent-onset is still unknown.

Aims: Therefore, this study aimed to determine blood (serum) levels circulating in adolescent drug naïve adolescent rats compared to levels expressed in oxycodone-treated rats.

Methods: Adolescent Sprague Dawley male and female rats were housed in an enriched environment (EE), standard environment (SC), or socially isolated environment (IC). We established oxycodone dependence using a repeated passive injection model. Rats were injected subcutaneously with incremental doses of oxycodone (OXY) (0.5, 1, 3, and 5mg/kg). After 2 hours of the last injection, the behavior of the animals was recorded for 20 minutes. Brains and truncal blood were collected to analyze brain-derived neurotrophic factors (BDNF). ELISA immunoassay was employed to determine the concentrations for pro and mature BDNF.

Results: oxycodone intoxication increased by 37% in proBDNF levels and decreased without significantly changed mature BDNF concentrations. Regardless of oxycodone, long-term exposure to an enriched environment propelled a 3-fold increase in mature BDNF levels. Moreover, continuous environmental enrichment reduced 23.3% proBDNF concentrations.

Conclusions: Our results suggested that the ratio of adolescents circulating proBDNF/mBDNF is significantly changed by oxycodone intoxication and environmental enrichment. More importantly, longterm exposure to social, cognitive, and visual stimulation shifts and increases circulating levels of matureBDNF in the adolescent rat.