Different alcohol exposures induce selective alterations on the expression of dynorphin and nociceptin systems related genes in rat brain

Abstract

Molecular mechanisms of adaptive transformations caused by alcohol exposure on opioid dynorphin and nociceptin systems have been investigated in the rat brain. Alcohol was intragastrically administered to rats to resemble human drinking with several hours of exposure: water or alcohol (20% in water) at a dose of 1.5 g/kg three times daily for 1 or 5 days. The development of tolerance and dependence were recorded daily. Brains were dissected 30 minutes (1- and 5-day groups) or 1, 3 or 7 days after the last administration for the three other 5-day groups (groups under withdrawal). Specific alterations in opioid genes expression were ascertained. In the amygdala, an up-regulation of prodynorphin and pronociceptin was observed in the 1-day group; moreover, pronociceptin and the kappa opioid receptor mRNAs in the 5-day group and both peptide precursors in the 1-day withdrawal group were also up-regulated. In the prefrontal cortex, an increase in prodynorhin expression in the 1-day group was detected. These data indicate a relevant role of the dynorphinergic system in the negative hedonic states associated with multiple alcohol exposure. The pattern of alterations observed for the nociceptin system appears to be consistent with its role of functional antagonism towards the actions of ethanol associated with other opioid peptides. Our findings could help to the understanding of how alcohol differentially affects the opioid systems in the brain and also suggest the dynorphin and nociceptin systems as possible targets for the treatment and/or prevention of alcohol dependence.

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

“…Intracranial peptide administration completely abolished somatic signs associated with acute withdrawal, while the expression of anxiety measured one week after termination of ethanol exposure (protracted withdrawal) was markedly reduced (Economidou et al, 2011). Paradoxically, in another study in Sprague-Dawley rats, acute ethanol intoxication (1 day binge exposure), ethanol dependence (5 day binge exposure), and ethanol withdrawal (1 day after 5 day binge exposure) were associated with significant increases in pronociceptin mRNA levels in the amygdala (D’Addario et al 2013). Perhaps the increase in pronociceptin transcript reflects an allostatic process, or the body’s attempt to adapt to and counter the high levels of ethanol administered in that study.…”

Alcohol: A stimulant activating brain stress responsive systems with persistent neuroadaptation

“…It was reported that Dyn mRNA levels in the central nucleus of amygdala were increased after acute withdrawal from multiple alcohol "binge" administrations in rats (D'Addario et al, 2013). The central nucleus of amygdala is a critical brain region mediating anxiety-related behavior, and is a likely site for the interaction of the dynorphin and alcohol, although few studies have explored this interaction.…”

Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment

“…Targeting KORs with U50,488 blocks the rewarding effects of ethanol during conditioning, importantly, this was seen with sub-anxiogenic doses of the KOR agonist (Logrip et al 2009). Mice lacking KORs show decreased alcohol self-administration (Kovacs et al 2005), and alcohol self-administration leads to an upregulation of dynorphin in the central amygdala, a region of the extended amygdala (D'Addario et al 2013). Mice lacking dynorphin show increased alcohol preference; however, in contrast to control littermates, they do not show increased alcohol consumption following a mild stressor (Racz et al 2013).…”