Behavioral effects evoked by the beta globin-derived nonapeptide LVV-H6

LVV-hemorphin-6 (LVV-h6) is bioactive peptide and is a product of the degradation of hemoglobin. Since LVV-h6 effects are possibly mediated by opioid or AT4/IRAP receptors, we hypothesized that LVV-h6 would modify behavior. We evaluated whether LVV-h6 affects: i) anxiety-like behavior and locomotion; ii) depression-like behavior; iii) cardiovascular and neuroendocrine reactivity to emotional stress. Male Wistar rats ( ± 300 g) received LVV-h6 (153 nmol/kg i.p.) or vehicle (NaCl 0.9% i.p.). We used: i) open field (OF) test for locomotion; ii) elevated plus maze (EPM) for anxiety-like behavior; iii) forced swimming test (FST) for depression-like behavior and iv) air jet for cardiovascular and neuroendocrine reactivity to stress. Diazepam (2 mg/kg i.p.) and imipramine (15 mg/kg i.p.) were used as positive control for EPM and FST, respectively. To evaluate the LVV-h6 mechanisms, we used: the antagonist of oxytocin (OT) receptors (atosiban - ATS 1 and 0.1 mg/kg i.p.); the inhibitor of tyrosine hydroxylase (Alpha-methyl-p-tyrosine - AMPT 200 mg/kg i.p.) to investigate the involvement of catecholaminergic paths; and the antagonist of opioid receptors (naltrexone - NTX 0.3 mg/kg s.c.). We found that LVV-h6: i) evoked anxiolytic-like effect; ii) evoked antidepressant-like effect in the FST; and iii) did not change the locomotion, neuroendocrine and cardiovascular responses to stress. The LVV-h6 anxiolytic-like effect was not reverted by ATS and AMPT. However, the antidepressant effects were reverted only by NTX. Hence, our findings demonstrate that LVV-h6 modulates anxiety-like behavior by routes that are not oxytocinergic, catecholaminergic or opioid. The antidepressant-like effects of LVV-h6 rely on opioid pathways.