Reduced alcohol consumption in mice lacking preprodynorphin

Abstract

Many studies suggest a role for endogenous opioid peptides and their receptors in regulation of ethanol intake. It is commonly accepted that the κ-opioid receptors and their endogenous ligands, dynorphins, produce a dysphoric state and therefore may be responsible for avoidance of alcohol. We used mutant mice lacking preprodynorphin in a variety of behavioral tests of alcohol actions. Null mutant female, but not male, mice showed significantly lower preference for alcohol and consumed lower amounts of alcohol in a two-bottle choice test as compared with wild-type littermates. In the same test, knockout mice of both sexes showed a strong reduction of preference for saccharin compared to control mice. In contrast, under conditions of limited (4 hours) access (light phase of the light/dark cycle), null mutant mice did not show any differences in consumption of saccharin but they showed significantly reduced intake of sucrose. To determine the possible cause for reduction of ethanol preference and intake, we studied other ethanol-related behaviors in mice lacking the preprodynorphin gene. There were no differences between null mutant and wild type mice in ethanol-induced loss of righting reflex, acute ethanol withdrawal, ethanol-induced conditioned place preference or conditioned taste aversion to ethanol. These results indicate that deletion of preprodynorphin leads to substantial reduction of alcohol intake in female mice, and suggest thath this is caused by decreased orosensory reward of alcohol (sweet taste and/or palatability).

κ-Opioid Receptors in the Central Amygdala Regulate Ethanol Actions at Presynaptic GABAergic Sites

“…First, the ethanol interaction with the GABAergic system is altered following chronic ethanol treatment, such that GABA agonists or KOR antagonists (that can augment GABAergic IPSCs) block the reinforcing effects of ethanol in dependent rats (Walker and Koob, 2008). Second, KOR knockout mice (Kovacs et al, 2005), as well as dynorphin knockout mice (Blednov et al, 2006), drink less ethanol than WT mice, although both knockout mice should presumably exhibit disinhibition of GABAergic transmission in CeA (however, the 2005 study by Kovacs et alalso suggested KOR knockout mice may have disrupted taste sensation). Third, activation of m-and D-opioid receptors also decreases GABAergic IPSCs in the mouse CeA (Kang-Park et al, 2007, as with KOR activation.…”

“…Furthermore, a KOR antagonist selectively reduced ethanol self-administration in rats made dependent on ethanol but not in nondependent rats (Walker and Koob, 2008;Walker et al, 2011). Mice lacking KORs drank half as much ethanol as either wild-type (WT) or heterozygous mice (Kovacs et al, 2005), and mice lacking dynorphin also show reduced voluntary ethanol consumption (Blednov et al, 2006). While the mechanistic role of the dynorphin/KOR system in ethanol dependence is not clear, involvement in ethanol abuse and dependence is in line with the well-established role of the dynorphin/ KOR system in stress-induced depression-like behaviors and relapse to drug-seeking behaviors in both rats and mice (Beardsley et al, 2005;Carey et al, 2007Carey et al, , 2009Land et al, 2008).…”

Sex Differences in Animal Models: Focus on Addiction

“…As noted above, female rodents exhibited greater basal and stressinduced glucocorticoid secretion and a greater stress response than male rodents. Although less studied than sex differences associated with the dopamine system, there is some evidence that CRF and dynorphin responses are greater in female rats than in male rats during acute withdrawal (Bradshaw et al, 2000;Blednov et al, 2006;Silva and Madeira, 2012;Torres et al, 2013;Garcia-Carmona et al, 2015). However, females are less sensitive to the analgesic effects of m and k opioids (Negus et al, 2002;Barrett et al, 2002).…”

Mice lacking adenylyl cyclase type 5 (AC5) show increased ethanol consumption and reduced ethanol sensitivity

“…Acute KOR agonist treatment decreased ethanol consumption in rats (Lindholm et al 2001), but chronic administration of agonist increased both ethanol intake and preference (Hölter et al 2000). Ethanol-induced hypnotic response in prodynorphin KO mice was not significantly altered (Blednov et al 2006). Both prodynorphin KO mice and KOR KO mice showed decreased ethanol consumption.…”