Adolescent intermittent ethanol exposure effects on kappa opioid receptor mediated dopamine transmission: Sex and age of exposure matter

Abstract

Underage alcohol drinking increases the risk of developing alcohol use disorder (AUD). In rodents, adolescent ethanol exposure augments ethanol consumption and anxiety-like behavior while reducing social interaction. However, the underlying mechanisms driving these adaptations are not understood. The dopamine and kappa opioid receptor (KOR) systems in the nucleus accumbens (NAc) are implicated in affective disorders and AUD, with studies showing augmented KOR function and reduced dopamine transmission in ethanol-dependent adult animals. Thus, this study, we examined the impact of adolescent intermittent ethanol (AIE) exposure on dopamine transmission and KOR function. Rats were exposed to water or ethanol (4 g/kg, intragastrically) every-other-day during early (PD25-45) or late (PD45-65) adolescence. While AIE exposure during early-mid adolescence (early AIE) did not alter dopamine release in male and female rats, AIE exposure during late adolescence (late AIE) resulted in greater dopamine release in males and lower dopamine release in females. To determine the impact of AIE exposure on KOR function, we bath applied cumulative concentrations of KOR agonist, U50,488 (0.01-1.0 µM), and measured its effect on dopamine release. Early AIE exposure potentiated KOR-mediated inhibition of dopamine release in female rats, while late AIE exposure attenuated this effect in male rats. Together these data suggest that AIE-exposure impact on neural processes is dependent on sex and exposure timing. These differences likely arise from differential developmental timing in males and females. This is the first study to show changes in KOR function following AIE exposure.

Adolescent ethanol exposure promotes mechanical allodynia and alters dopamine transmission in the nucleus accumbens shell

“…We used ex vivo FSCV to determine the impact of aCIE on dopamine kinetics in the NAc shell after forced protracted abstinence (3 to 4 weeks) in a separate group of rats that were not subject to behavioral testing. FSCV procedures that we use were similar to those used in previous studies [18,28]. Briefly, rats (n=32; 8 rats per group) were anesthetized with isoflurane and euthanized via rapid decapitation six hours into the dark cycle.…”

“…While there are a number of rodent studies demonstrating changes in dopamine transmission in the NAc following ethanol exposure in adulthood [8][9][10][11][12][13][14], studies examining the effect of adolescent ethanol exposure on accumbal dopamine are relatively few and with disparate results [15][16][17][18][19]. Furthermore, these previous studies have examined dopamine in the NAc core.…”