Protracted withdrawal from ethanol and enhanced responsiveness stress: Regulation via the dynorphin/kappa opioid receptor system

Abstract

Although recent work suggests that the dynorphin/kappa opioid receptor (DYN/KOR) system may be a key mediator in the stress-related effects of alcohol, the regulation of long-term changes associated with protracted withdrawal from ethanol via the DYN/KOR system has yet to be explored. The objective of the present study was to determine the role of the DYN/KOR system in the regulation of anxiety-related behaviors during an extended period of abstinence from ethanol in animals with a history of ethanol dependence. Male Wistar rats (n = 94) were fed an ethanol or control liquid diet for 25–30 days. Six weeks after its removal, rats were exposed to 20 minutes of immobilization, and the ability of the KOR-antagonist norbinaltorphimine (nor-BNI) (0–20 mg/kg, intraperitoneal [i.p.]) to attenuate the enhanced responsiveness to stress observed in rats chronically exposed to ethanol was investigated using the elevated plus maze. In addition, the ability of U50,488 (0–10 mg/kg, i.p.) to prime anxiety-like behavior during protracted withdrawal was also examined. Rats with a history of ethanol dependence showed a significant decrease in open-arm exploration after exposure to restraint, indicating an anxiety-like state, compared to similarly treated controls, an effect that was blocked by nor-BNI. nor-BNI also selectively decreased center time and open-arm approaches in ethanol-exposed rats. The highest dose of U50,488 decreased open-arm exploration and the total number of arm entries in ethanol-exposed and control rats. Although lower doses of U50,488 did not affect open-arm exploration in either group, the 0.1 mg/kg dose selectively decreased motor activity in the ethanol-exposed rats when compared to similarly pretreated controls. These findings further support the hypothesis that behaviors associated with withdrawal from ethanol are in part regulated by the DYN/KOR system, and suggest that these effects may be long-lasting in nature.

Antagonism of κ opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence

“…These findings are consistent with previous studies linking morphine abstinence and depressive-like behaviors [7,8,53,54]. In addition, these findings are broadly consistent with former work showing that the depressive-like behaviors developed after cocaine and ethanol withdrawal [10,29].…”

“…Importantly, recent studies demonstrated that the dynorphin/κ opioid receptor system was involved in mediating anxiety-and depressive-like behaviors after prolonged withdrawal from ethanol or cocaine [10,29], since κ opioid receptor antagonist norBNI attenuated the anxiety-and depressive-like behaviors observed during protracted withdrawal. To the best of our knowledge, the role of dynorphin/κ opioid receptor system in depressive-like behaviors induced by morphine withdrawal has not been fully understood.…”

“…There is increasing evidence showing that activation of κ opioid receptor produces depressive-like disorders in human and rodents [12][13][14][15][16][17][18][19], whereas blockade of κ opioid receptor produces antidepressive-like effects [20][21][22][23]. Chronic exposure to cocaine, morphine, heroin and alcohol have been shown to be associated with increased dynorphins expression in different brain regions, such as striatum, NAc and amygdala, and potentiated endogenous signaling through κ opioid receptor [24][25][26][27][28][29][30].…”

The role of the dynorphin/κ opioid receptor system in anxiety

“…Discrepancies among these studies may be due to, but are not limited to, the use of specific genetic constructs for generating mutant mice, experimental paradigms, size of the apparatus, intensity of illumination, test conditions, animal strains, and lab specific basal stress levels. Although with these limitations and variables, the findings clearly demonstrate that the dynorphin/κ opioid receptor system is involved in anxiety-related behavior [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][49][50][51] (see Table 1 for a summary of current literature), but it is difficult to define the exact role of κ opioid receptor signaling because both anxiolyticand anxiogenic-like effects are reported with κ opioid receptor agonists. Indeed, THC, a CB1 receptor agonist, microinjected at low doses in the prefrontal cortex and ventral hippocampus induced an anxiolytic-like response, while high doses caused an anxiogenic reaction [52] .…”

“…However, κ opioid receptor agonists exert biphasic effects on anxiety in rodents. Increasing evidence shows that selective κ opioid receptor agonists produce anxiety-like behaviors in the EPM test [33][34][35][36][37][38][39] . These findings were further supported by findings that anxiolytic effects are produced by deficiencies in the κ opioid receptor system in mice.…”