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Lawrence AJ

Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, Australia

Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Increasing our understanding of the brain circuits and chemicals that regulate alcohol intake and relapse offers the potential for more targeted therapeutic approaches to assist in relapse prevention. Stress is a key precipitant of relapse, and relaxin-3 signalling modulates both stress responses and alcohol intake. We therefore examined a role for the relaxin-3 system in alcohol-seeking. In mice deficient of the relaxin-3 receptor (RXFP3), stress (restraint, swim) revealed a phenotype of reduced alcohol preference compared to WT littermates. In iP rats, icv microinjection of a selective RXFP3 antagonist prevented yohimbine-induced reinstatement of alcohol-seeking, discrete microinjections implicated the dorsal BNST as a locus. Relaxin-3 neurons are predominantly located in the pontine nucleus incertus (NI) which is highly sensitive to CRF. Intra-NI microinjection of a selective CRF1 receptor antagonist (CP376395) attenuated yohimbine-induced reinstatement of alcohol-seeking whereas the CRF2 receptor antagonist (Astressin-2B) had no effect. After long-term voluntary alcohol intake in iP rats, qPCR revealed that the expression of mRNA encoding both CRF1 and RXFP3 receptors was upregulated in the NI. We also found expression of the mRNA encoding CRF within the NI, which was confirmed with immunohistochemistry in both iP rat brain and CRF-Cre x TdTomato reporter mice. These data suggest NI neurons contribute to reinstatement of alcohol seeking, via an involvement of CRF1 signaling. Furthermore, chronic ethanol intake leads to neuroadaptive changes in CRF and relaxin-3 systems within rat NI. The NI also receives orexinergic innervation and so we undertook analogous experiments. Bilateral NI injections of the OX2 receptor antagonist TCS-OX2-29 attenuated yohimbine-induced reinstatement of alcohol seeking, while the OX1 receptor antagonist SB-334867 had no effect. In line with these data, orexin-A depolarized NI neurons recorded in coronal brain slices, sensitive to bath application of TCS-OX2-29, but not SB-334867. These data suggest an excitatory orexinergic input to NI contributes to yohimbine-induced reinstatement of alcohol seeking, predominantly via local OX2 receptor signalling. Collectively, these data implicate CRF and orexin inputs to relaxin-3 neurons of the NI in alcohol-seeking.

Uploaded on: May 13, 2016 @ 04:49
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Your name: Andrew Lawrence
choose your track: 1. Preclinical CNS
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Affiliation: Florey Institute of Neuroscience & Mental Health
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