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.2023 Nov;133(5):526-534.
doi: 10.1111/bcpt.13929. Epub 2023 Aug 22.

Kappa opioid receptor agonist U50,488 inhibits dopamine more in caudal than rostral nucleus accumbens core

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Kappa opioid receptor agonist U50,488 inhibits dopamine more in caudal than rostral nucleus accumbens core

Anushree N Karkhanis et al. Basic Clin Pharmacol Toxicol.2023 Nov.

Abstract

The nucleus accumbens (NAc) core is involved in regulating stress and shaping reward seeking behaviours. Multiple neuromodulators, including dynorphin/kappa opioid receptor (KOR) and dopamine systems, converge in this area to influence behavioural outcomes. KOR activation acutely inhibits dopamine release and chronically depresses overall dopamine transmission. Recently, studies in the NAc shell have revealed that the impact of KOR activation on behaviour is regionally specific, and these rostro-caudal differences are likely driven by greater control of KORs over dopamine inhibition in the caudal compared with rostral subregion. Given the importance of NAc core, particularly the interaction between KORs and dopamine in regulating reward seeking behaviours, we examined the impact of KOR activation on dopamine release and uptake along the rostro-caudal axis in the NAc core of male and female mice. Using ex vivo fast scan cyclic voltammetry, we observed that KOR mediated inhibition of dopamine release was significantly greater in caudal compared with rostral NAc core with no significant sex differences observed. These data suggest that KORs regulate dopamine release differentially along the rostro-caudal axis, providing a new axis on which to examine the process by which the KOR/dopamine system controls reward encoding.

Keywords: U50,488; dopamine; kappa opioid receptors; nucleus accumbens core; rostro-caudal.

© 2023 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

None.

Figures

FIGURE 1
FIGURE 1
Evoked dopamine release and uptake in rostral and caudal nucleus accumbens (NAc) core. (A) Representative traces of transient dopamine signals in response to single pulse electrical stimulation in rostral (top, dashed line) and caudal (bottom, solid line) NAc core of male (middle, blue) and female (right, pink) mice with the target area highlighted on the coronal slices diagram (left). (B) Stimulated dopamine release. There was no significant difference in baseline dopamine release in rostral compared with caudal NAc core in female (white/pink—rostral; solid pink—caudal) or male (white/ blue—rostral; solid blue—caudal) mice. There were also no significant sex differences in evoked dopamine release. (C) Dopamine uptake as measured by tau was also not different between the rostral and caudal NAc core in female (white/pink—rostral; solid pink—caudal) or male (white/ blue—rostral; solid blue—caudal) mice. No sex differences were observed in uptake. C, caudal; KOR, kappa opioid receptor; R, rostral.
FIGURE 2
FIGURE 2
Impact of kappa opioid receptor (KOR) activation on dopamine release in rostral and caudal nucleus accumbens (NAc) core. (A) KOR activation mediated inhibition of dopamine release was greater in caudal (closed circles and solid line) compared with rostral (open circles and dotted line) NAc core in male mice. (B) Potency of KORs (EC50) was greater in the caudal (closed circles), indicated by lower EC50, compared with rostral (open circles) NAc core of male mice. (C) Maximal KOR-mediated reduction in dopamine release, efficacy, was statistically trending to be greater in the caudal (closed circles) compared with rostral (open circles) NAc core of male mice. (D) In female mice, KOR activation mediated inhibition of dopamine release was greater in caudal (closed circles and solid line) compared with rostral (open circles and dotted line) NAc core. This augmented function was driven by greater potency (E) and efficacy (F) of KORs in the caudal (closed circles) compared with rostral (open circles) NAc core. U50,488, KOR agonist; C, caudal; EC50, concentration of drug that results in the half-maximal response in the tissue; KOR, kappa opioid receptor; NAc, nucleus accumbens; R, rostral. ****p < 0.0001, main effect of U50,488 concentration; #p < 0.0001, δδδp < 0.001, δδp < 0.01, δp < 0.05, post hoc pairwise comparison.
FIGURE 3
FIGURE 3
Impact of kappa opioid receptor (KOR) activation on dopamine release in males vs females in the rostral and caudal nucleus accumbens (NAc) core. (A) KOR activation mediated inhibition of dopamine release was not significantly different in the rostral NAc core of female (pink) and male (blue) mice. (B) Likewise, KOR activation mediated inhibition of dopamine release was not significantly different in the caudal NAc core of female (pink) and male (blue) mice. U50, 488, KOR agonist. ****p < 0.0001.
FIGURE 4
FIGURE 4
Impact of kappa opioid receptor (KOR) activation in the rostral and caudal nucleus accumbens (NAc) core on uptake of dopamine. The percent change in tau at both the 10 and 30 nM doses of U50,488 did not show consistent changes in any of the groups analysed. F, female; M, male; R, rostral; C, caudal.
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