Abstract
Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from negative moods and to relieve innate hypersensitivity to stress. This phenotype resembling a subset of alcohol use disorder (AUD) patients, appears to be linked to a dysregulation of the equilibrium between stress and antistress mechanisms in the extended amygdala. Here, comparing water and alcohol exposed msP and Wistar rats we evaluate the transcript expression of the anti-stress opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOP as well as of dynorphin (DYN) and its cognate κ-opioid receptor (KOP). In addition, we measured the transcript levels of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF1R), brain-derived neurotrophic factor (BDNF) and of the tropomyosin receptor kinase B receptor (Trk-B). Results showed an innately up-regulation of the CRFergic system, mediating negative mood and stress responses, as well as an inherent up-regulation of the anti-stress N/OFQ system, both in the amygdala (AMY) and bed nucleus of the stria terminalis (BNST) of msP rats. The up-regulation of this latter system may reflect an attempt to buffer the negative condition elicited by the hyperactivity of pro-stress mechanisms since results showed that voluntary alcohol consumption dampened N/OFQ. Alcohol exposure also reduced the expression of dynorphin and CRF transmissions in the AMY of msP rats. In the BNST, alcohol intake led to a more complex reorganization of these systems increasing receptor transcripts in msP rats, along with an increase of CRF and a decrease of N/OFQ transcripts, respectively. Moreover, mimicking the effects of alcohol in the AMY we observed that the activation of NOP receptor by intracerebroventricular administration of N/OFQ in msP rats caused an increase of BDNF and a decrease of CRF transcripts. Our study indicates that both stress and anti-stress mechanisms are dysregulated in the extended AMY of msP rats. The voluntary alcohol drinking, as well as NOP agonism, have a significant impact on neuropeptidergic systems arrangement, bringing the systems back to normalization.
Highlights
The major finding of our study is that Marchigian Sardinian alcohol-preferring (msP) and Wistar rats have a different organization of AMY and bed nucleus of the stria terminalis (BNST) neurochemical circuits involved in the regulation of stress and alcohol drinking
When we analyzed brain-derived neurotrophic factor (BDNF) mRNA, we found no significant differences between msP
The present results highlight how chronic intermittent EtOH exposure (CIE) drinking may result in a divergent regulation of stress-related neuropeptidergic systems, depending on the regions examined and the mechanisms involved
Summary
Marchigian Sardinian alcohol-preferring (msP) rats have been genetically selected for high 10% EtOH preference; they exhibit an innate propensity to excessive drinking, with an anxious phenotype that ameliorates following EtOH consumption [2,3] Based on these findings, it has been proposed that genetic selection in msP rats co-segregates with the expression of a highly anxious and stress vulnerable phenotype resembling a specific subpopulation of alcoholic patients that attempt to drink to self-medicate from negative mood [4,5]. It has been proposed that genetic selection in msP rats co-segregates with the expression of a highly anxious and stress vulnerable phenotype resembling a specific subpopulation of alcoholic patients that attempt to drink to self-medicate from negative mood [4,5] In this regard, it is well known that alcohol use disorder (AUD) shows high comorbidity with mood disorders [6,7]. Under this condition, drinking is preferentially motivated by negative rather than positive reinforcement mechanisms [8,9,10]
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