Expression of pronociceptin and its receptor is downregulated in the brain of human alcoholics.
Animal studies demonstrated a role of neuropeptide nociceptin (NC) and its receptor (opiate receptor like-1, OPRL1) in ethanol-induced reward; activation of the OPRL1 by natural or synthetic ligands reduced ethanol self-administration and prevented relapse to ethanol drinking. The endogenous NC may function in neuronal circuits involved in reinforcing or conditioning effects of ethanol as a "brake" to limit ethanol intake (Roberto, M., Siggins, G.R. 2006. Nociceptin/orphanin FQ presynaptically decreases GABAergic transmission and blocks the ethanol-induced increase of GABA release in central amygdala. Proc. Natl. Acad. Sci. USA 103. 9715-9720), whereas repeated ethanol intake may downregulate the endogenous NC/OPRL1 system resulting in activation of ethanol consumption. To address this hypothesis, we evaluated whether expression of the pronociceptin (PNOC) and OPRL1 genes is altered in human alcoholics. mRNAs transcribed from these genes were analyzed by quantitative RT-PCR in the prefrontal and orbitofrontal cortices, central amygdala and hippocampal dentate gyrus, structures controlling alcohol consumption. Reduction in PNOC mRNA (1.7-fold) was found in the hippocampus of alcoholics, whereas OPRL1 mRNA levels were decreased (1.4-fold) in the central amygdala. No changes in expression of these genes in other brain areas analyzed were evident. We hypothesise that chronic ethanol intake downregulates PNOC and OPRL1 gene expression in the hippocampus and amygdala, respectively. The findings may be also interpreted as inherited molecular differences between alcoholics and controls. The PNOC/OPRL1 downregulation may underlie impairment of cognitive control over alcohol seeking in alcoholics. Stimulation of the OPRL1 receptors with synthetic agonists may increase threshold for activation of ethanol-related behaviour by environmental cues, and thus may reduce cue- or stress-primed relapse to ethanol consumption.
Kuzmin
Alexander
A
The Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden.
Bazov
Igor
I
Sheedy
Donna
D
Garrick
Therese
T
Harper
Clive
C
Bakalkin
Georgy
G
D000437:Alcoholism / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011498:Protein Precursors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000378:metabolism; D044465:White People; D000094942:Nociceptin Receptor
D011498:Protein Precursors; D012333:RNA, Messenger; D011957:Receptors, Opioid; C119224:pronociceptin; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human