Peptides and stress-induced relapse
How do neuropeptides regulate the brain's reward circuitry, especially in times of acute stress.
We would like to determine the following:
- Mechanism by which acute stress activates RLN3 neurons to precipitate relapse to alcohol-seeking.
- Nature of RXFP3-mediated modulation of neural signalling within BNST and the neurochemical phenotype of RXFP3-expressing neurons in forebrain areas implicated in regulation of stress-induced relapse to alcohol-seeking.
- Ability of stress and/or alcohol to regulate RLN3, CRF and orexin systems.
- Brain loci within the extended amygdala, in addition to the BNST, where RXFP3 signalling regulates stress-induced relapse to alcohol-seeking. This will be achieved by a combination of behavioural, anatomical and electrophysiological studies.
Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for RXFP3 (relaxin family peptide 3 receptor), the cognate receptor for the neuropeptide, relaxin‐3, decreased self-administration of alcohol in a dose‐related manner and attenuated cue‐induced reinstatement following extinction. Given the established role for relaxin 3 signalling in stress responses we also examined stress-induced reinstatement of alcohol-seeking using yohimbine as a chemical stressor. The selective RXFP3 antagonist, R3(B1-22)R, prevented yohimbine-induced reinstatement of alcohol-seeking, an effect greater than that for cue-driven alcohol-seeking. By comparison, RXFP3 antagonist treatment produced no significant change in selfadministration of sucrose, suggesting a selective effect for alcohol. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity or cognition in the paradigms assessed. These data suggest relaxin‐3/RXFP3 signalling regulates alcohol intake and relapse‐like behavior, adding to current knowledge of the brain chemistry of reward-seeking.
We have extended these findings by using targeted microinjections into brain nuclei that are (i) known components of alcohol-seeking circuitry and (ii) localise dense expression of RXFP3. In this regard, we have shown that local microinjections of R3(B1-22)R into the bed nucleus of the stria terminalis reduce alcohol self-administration, and also markedly attenuate stress-induced reinstatement of alcohol-seeking. In addition, we have shown in rats that expression of relaxin-3 mRNA in the nucleus incertus correlates with alcohol intake, suggesting that high basal expression of relaxin-3 in the nucleus incertus may pre-dispose high levels of alcohol intake. We hypothesise that stress activates ascending networks containing relaxin-3 to regulate alcohol-seeking via actions at RXFP3 within the BNST and possibly other component areas of the ‘extended amygdala’.
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