GHRP-6
Growth Hormone Releasing Peptide-6, Growth hormone-releasing hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2
A novel butyrylcholinesterase inhibitor induces antidepressant, pro-cognitive, and anti-anhedonic effects in Flinders Sensitive Line rats: The role of the ghrelin-dopamine cascade.
Olivier. Nadia N; Harvey. Brian H BH; Gobec. Stanislav S; Shahid. Mohammed M; Košak. Urban U; Žakelj. Simon S; Brink. Christiaan B CB
Key Findings
- The butyrylcholinesterase inhibitor improved depression‑like behavior, reward response, and cognition in rats.
- Treatment increased the brain’s ghrelin ratio and dopamine levels without changing serotonin or BDNF.
- Blocking the ghrelin receptor with D‑Lys‑3‑GHRP‑6 reversed the drug’s positive effects, confirming the ghrelin‑dopamine pathway’s role.
Practical Outcomes
- For biohackers, the study highlights ghrelin’s importance for mood and brain function. Using ghrelin‑activating peptides (like GHRP‑6) might boost dopamine‑related reward and cognition, but human data are lacking. The findings suggest caution when using ghrelin antagonists, as they could blunt mental‑performance benefits. More research is needed before adopting any dosing protocols.
Summary
In a rat model of depression, a new drug that blocks an enzyme called butyrylcholinesterase lifted mood, reward feeling, and memory performance. It did this by raising the levels of the hunger hormone ghrelin and dopamine in the brain. When researchers blocked the ghrelin receptor with a peptide (D‑Lys‑3‑GHRP‑6), all the good effects disappeared, showing that ghrelin signaling is key to the drug’s benefits.
Abstract
Major depressive disorder (MDD) is often treatment resistant, particularly in addressing anhedonia and cognitive deficits. Novel pharmacological strategies are needed. While butyrylcholinesterase, ghrelin, and dopamine (DA) have been well studied in the context of stress and MDD, their interaction remains unclear. The dose-dependent antidepressant effects of a novel butyrylcholinesterase inhibitor (BChEI) were evaluated in the Flinders Sensitive Line (FSL) rat model of MDD. Behavioural assessments included the forced swim test (despair), sucrose preference test (reward-related), and novel object recognition test (cognition). Brain-derived neurotrophic factor (BDNF), acetylcholine (ACh), and brain monoamines were analysed, as well as serum growth hormone and acyl- and desacyl-ghrelin. To confirm the role of ghrelin, pharmacological exploration was undertaken using the ghrelin receptor antagonist, D-Lys-3-GHRP-6. FSL rats had significantly lower ghrelin ratios, BDNF, ACh, DA and growth hormone levels. In FSL rats, both BChEI and escitalopram significantly reduced despair. BChEI significantly outperformed escitalopram in enhancing reward-related and cognitive behaviours. Biochemically, BChEI treatment significantly increased ghrelin ratios and brain DA levels without altering brain 5-HT, ACh or BDNF. D-Lys-3-GHRP-6 significantly reversed the antidepressant-like, rewarding, and pro-cognitive effects of BChEI, accompanied by significant reductions in BDNF and DA. FSL rats display impaired ghrelin, DA, serotonin, growth hormone, and BDNF signalling, akin to MDD. BChEI exerts antidepressant-like effects across despair, reward, and cognitive domains, most likely via the BChE-ghrelin-DA cascade. Reversal of these effects by ghrelin antagonism underscores the critical role of ghrelin, specifically via growth hormone secretagogue receptor-ghrelin interaction. These findings suggest a potentially novel multimodal neurobiological target for the treatment of MDD.
Study Information
pubmed
2025
2025-05-02T00:00:00.000Z
10.1016/j.biopha.2025.118093
6
101