Relaxin-3/RXFP3 system regulates alcohol-seeking

Abstract

Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased selfadministration of alcohol in a dose-related manner and attenuated cue-and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/ RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of rewardseeking. addiction | dependenceA lcohol abuse is a major cause of morbidity and mortality worldwide, accounting for an estimated 3.8% of all global deaths and 4.6% of the global burden of disease and injury (1). Excessive alcohol use may also lead to alcohol dependence (also termed "alcohol addiction") (2, 3), which has a lifetime prevalence of ∼12.5% (4). Economic costs due to alcohol abuse were in the order of $235 billion in the United States in 2007, or ∼2.7% of GDP (1, 5). Despite the huge impact of alcohol use disorders on society, current first-line therapeutic agents, such as naltrexone and acamprosate, are far from adequate, with high relapse rates during treatment and problems with compliance (6-8). New therapeutic agents are clearly required, particularly for the reduction of hazardous drinking and prevention of relapse (9). To this end, a major goal in addiction neuroscience is to understand the neurobiology and neurocircuitry affected by alcohol use disorders and to identify factors implicated in these conditions, which may lead to improved and more targeted therapies (7-10). Here we investigate the neuropeptide relaxin-3 for its involvement in rodent models of alcohol-seeking and consumption.Relaxin-3 is the highly conserved, ancestral neuropeptide of the relaxin/insulin superfamily, and its cognate G-protein-coupled receptor is relaxin family peptide 3 receptor (RXFP3) (11-16). Relaxin-3 is predominantly expressed in gamma-aminobutyric acid (GABA) neurons in the hindbrain nucleus incertus, which projects widely to forebrain areas, including the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus, and lateral hypothalamus, which also express high levels ...

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

“…Interestingly, RXFP3 is expressed broadly throughout limbic centres and it is possible similar differential effects on neural outputs occur following RXFP3 activation. Therefore, future studies are warranted of local administration of RXFP3 agonist into candidate areas, such as regions of the extended amygdala or hypothalamus, similar to those of the effects of RXFP3 blockade on alcohol seeking and stress-induced reinstatement in rats [29]. Also, with the heterogeneous nature of neurons in these limbic structures [68,69], studies examining the neurochemical identity of RXFP3-expressing neurons are equally important.…”

“…Injections (1 µL) were made via an injector protruding beyond the guide cannula (see above) and into the lateral ventricle 15 min before each behavioural test. Doses used and the timing of behavioural testing (see Results) were based on studies that indicated effective doses in rats and mice and the time course of activity of these peptides post-icv injection [29,33,44]. indicate that 30-60 min post-injection is the period when anxiogenesis is highest [48].…”

“…Functionally, icv administration in adult Sprague-Dawley rats of the relaxin-3 agonist peptide, 'RXFP3-A2' , which is selective for RXFP3 over RXFP1 [40], reduced anxiety-like behaviour [33]. The precise brain sites influenced by RXFP3 to produce these behavioural changes in the anxiety tests studied are not known, but it might involve activation of RXFP3 strongly expressed within areas involved in aversion-motivated exploration such as the extended amygdala, the periaqueductal grey and hippocampus [29,[41][42][43].…”

“…The neuroanatomy of the relaxin-3/RXFP3 system suggests a broad role as an ascending neuromodulatory network [20,21], akin to the monoamine systems including serotonin, and noradrenaline [22][23][24][25]. Anatomical and functional data [15][16][17][18] suggest that relaxin-3/RXFP3 systems may interact directly with monoamine [19,26] and other peptide systems [27][28][29], and/or act at shared downstream limbic and hypothalamic target areas to modulate 'anxiety' and other stress-related responses [30][31][32][33][34].…”

CRF and the nucleus incertus: a node for integration of stress signals

“…CRF infusion into, or electrical stimulation of, the NI impairs long-term potentiation (LTP) of hippocampal-medial prefrontal cortical synapses 11 , whereas intra-NI infusion of the CRFR1 antagonist antalarmin reversed stress-induced suppression of LTP in this pathway 12 . Intra-NI infusion of the CRFR1 antagonist CP-376395, but not the CRFR2 antagonist astressin 2B, considerably reduced the reinstatement of alcohol seeking in rats that was induced by administration of the pharmacological stressor yohimbine 13 -an effect that is probably mediated by CRFR1 activation of relaxin-3-positive NI neurons 6,14 . The NI is therefore a stressresponsive nucleus and, through CRFR1, contributes to memory and learning, stressinduced reward seeking, impairments in neuronal plasticity, and arousal behaviours [9][10][11][12][13] .…”