Peptides and stress-induced relapse

How do neuropeptides regulate the brain's reward circuitry, especially in times of acute stress.

Aims

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’.

Support us

Brain health affects all Australians.
You can support our research by making a donation or a bequest.

Newsletter

Latest breakthroughs, news, events & more.