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

ABSTRACTUnderage 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.

Download Full-text

Adolescent Intermittent Ethanol Exposure Effects on Kappa Opioid Receptor Mediated Dopamine Transmission: Sex and Age of Exposure Matter

Brain Sciences ◽

10.3390/brainsci10080472 ◽

2020 ◽

Vol 10 (8) ◽

pp. 472

Author(s):

Mary B. Spodnick ◽

Raymond T. Amirault ◽

Trevor T. Towner ◽

Elena I. Varlinskaya ◽

Linda P. Spear ◽

...

Keyword(s):

Opioid Receptor ◽

Dopamine Release ◽

Ethanol Exposure ◽

Kappa Opioid Receptor ◽

Female Rats ◽

Kappa Opioid ◽

Male And Female Rats ◽

Dopamine Transmission ◽

Underlying Mechanisms ◽

The Impact

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 unclear. The dopamine and kappa opioid receptor (KOR) systems in the nucleus accumbens (NAc) are implicated in affective disorders, including AUD, with studies showing augmented KOR function and reduced dopamine transmission in ethanol-dependent adult animals. Thus, here we examine the impact of adolescent intermittent ethanol (AIE) exposure on dopamine transmission and KOR function in the NAc. Rats were exposed to water or ethanol (4 g/kg, intragastrically) every other day during early (postnatal day (PD) 25–45) or late (PD 45–65) adolescence. While AIE exposure during early 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 on KOR function, we measured the effect of KOR activation using U50,488 (0.01–1.00 µM) on dopamine release. Early-AIE exposure potentiated KOR-mediated inhibition of dopamine release in females, while late-AIE exposure attenuated this effect in males. Interestingly, no differences in KOR function were observed in early-AIE exposed males and late-AIE exposed females. 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.

Download Full-text

Kappa-opioid receptor-dependent changes in dopamine and affective behavior occur differentially across the nucleus accumbens shell rostro-caudal axis

10.1101/2020.05.09.085761 ◽

2020 ◽

Author(s):

Breanne E. Pirino ◽

Mary B. Spodnick ◽

Andrew T. Gargiulo ◽

Genevieve R. Curtis ◽

Jessica R. Barson ◽

...

Keyword(s):

Nucleus Accumbens ◽

Opioid Receptor ◽

Dopamine Release ◽

Neural Circuit ◽

Ex Vivo ◽

Kappa Opioid Receptor ◽

Affective Behavior ◽

Kappa Opioid ◽

Affective Behaviors ◽

The Impact

ABSTRACTNeural circuit engagement within the nucleus accumbens (NAc) shell is implicated in the regulation of both negative and positive affect. Classically, the dynorphin/kappa opioid receptor (KOR) system in the NAc was believed to promote dysphoric behavior, while dopamine was viewed as interacting with reward behavior, and KOR activation was known to inhibit dopamine release. Recently, however, both the KOR and dopamine systems have, separately, been shown to have differential effects across the rostro-caudal axis of the NAc shell on hedonic responses. Whether or not this is due to interactions between KORs and dopamine, and if it extends to other affective behaviors, remains to be determined. In this study, we examined in rats the relationship between the KOR and dopamine systems in both the rostral and caudal NAc shell using ex vivo fast scan cyclic voltammetry and the impact of KOR activation on affective behavior using approach-avoidance assays. We report here that activation of KORs in the caudal NAc shell significantly inhibits dopamine release, stimulates novelty-induced rearing behavior, increases avoidance behavior, and reduces locomotor activity. In contrast, activation of KORs in the rostral NAc shell inhibits dopamine release to a lesser extent and instead increases approach behavior. Taken together, these results indicate that there is heterogeneity across the rostro-caudal axis of the NAc shell in the effects of KOR stimulation on affective behaviors, and they suggest that this might be due to differences in KOR control over dopamine release.

Download Full-text

Chronic sucrose intake augments antinociception induced by injections of mu but not kappa opioid receptor agonists into the periaqueductal gray matter in male and female rats

Brain Research ◽

10.1016/s0006-8993(01)03039-6 ◽

2001 ◽

Vol 920 (1-2) ◽

pp. 97-105 ◽

Cited By ~ 27

Author(s):

Robin B Kanarek ◽

Silvia Mandillo ◽

Claudia Wiatr

Keyword(s):

Opioid Receptor ◽

Gray Matter ◽

Kappa Opioid Receptor ◽

Female Rats ◽

Sucrose Intake ◽

Kappa Opioid ◽

Periaqueductal Gray Matter ◽

Male And Female ◽

Male And Female Rats ◽

Opioid Receptor Agonists

Download Full-text

Effects of Kappa Opioid Receptor Agonists on Fentanyl vs. Food Choice in Male and Female Rats: Contingent vs. Non-Contingent Administration

10.1101/2020.07.28.225060 ◽

2020 ◽

Author(s):

E. Andrew Townsend

Keyword(s):

Opioid Receptor ◽

Food Choice ◽

Food Reinforcement ◽

Abuse Liability ◽

Kappa Opioid Receptor ◽

Female Rats ◽

Self Administration ◽

Kappa Opioid ◽

Male And Female ◽

Male And Female Rats

AbstractRationaleStrategies are needed to decrease the abuse liability of mu opioid receptor (MOR) agonists. One strategy under consideration is to combine MOR agonists with kappa opioid receptor (KOR) agonists.ObjectivesThe effects of KOR-agonists (U50488, nalfurafine) on fentanyl-versus-food choice were compared under conditions where the KOR agonists were added to the self-administered fentanyl (contingent delivery) or administered as pretreatments (non-contingent delivery) in male and female rats. The effects of increasing and decreasing the magnitude of the alternative food reinforcer were also determined.MethodsRats were trained to respond under a concurrent schedule of fentanyl (0, 0.32-10 μg/kg/infusion) and food reinforcement. In Experiment 1, U50488 and nalfurafine were co-administered with fentanyl as fixed-proportion mixtures (contingent administration). In Experiment 2, U50488 (1-10 mg/kg) and nalfurafine (3.2-32 μg/kg) were administered as acute pretreatments (non-contingent administration). nor-BNI (32 mg/kg) was administered prior to contingent and non-contingent KOR-agonist treatment in Experiment 3. Experiment 4 evaluated the effects of increasing and decreasing the magnitude of the non-drug reinforcer.ResultsBoth U50488 and nalfurafine decreased fentanyl choice when administered contingently, demonstrating that KOR agonists punish opioid choice. Non-contingent U50488 and nalfurafine administration decreased rates of fentanyl and food self-administration without altering fentanyl choice. Both contingent and non-contingent U50488 and nalfurafine effects on fentanyl choice were attenuated by nor-BNI. Fentanyl choice was sensitive to increases and decreases in the magnitude of the non-drug reinforcer.ConclusionsThese results demonstrate that the effects of KOR agonists on fentanyl reinforcement are dependent upon the contingencies under which they are administered.

Download Full-text