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The NPY Y1 receptor antagonist BIBP 3226 blocks NPY induced feeding via a non-specific mechanism
D G Morgan1, C J Small, S Abusnana
1ICSM Endocrine Unit at the Hammersmith Hospital, Francis Fraser Labs., London, UK.
Abstract:
We have previously shown that intracerebroventricular BIBP 3226 inhibits NPY induced feeding in rats. However, this was associated with abnormal behaviour, likely to be due to interaction with Y1 receptors involved in mechanisms other than the control of food intake. In order to minimise such interactions we investigated the effects of paraventricular nucleus (PVN) injections of BIBP 3226 and its inactive enantiomer BIBP 3435. Intra-PVN injection of NPY (0.1-2.5 nmol/animal) increased food intake, with an EC50 of approximately 0.15 nmol/animal. Injections of BIBP 3226 and BIBP 3435 (0.25-25 nmol) reduced NPY-induced food intake in a dose responsive manner, with BIBP 3226 reducing food intake by 95%, and BIBP 3435 by 65% at the highest dose tested. The reversibility of the effect of BIBP 3226 was investigated by measuring the feeding response to NPY (0.5 nmol) in animals 1 week after BIBP 3226 injection. The response to NPY was less in animals which had received high doses of BIBP 3226. Animals previously injected with saline vehicle alone showed a normal NPY feeding response. These results suggest that BIBP 3226 may be inhibiting NPY-induced food intake in a non-specific manner, not secondary to inhibition of the Y1 receptor. This does not, however rule out a role for the Y1 receptor in the control of food intake by NPY.
Insights
Intracerebroventricular BIBP 3226 inhibits neuropeptide Y (NPY) induced feeding but causes abnormal behavior. Paraventricular nucleus injections of BIBP 3226 reduced NPY feeding, suggesting non-specific inhibition unrelated to Y1 receptors.
Area of Science:
- Neuroscience
- Endocrinology
- Behavioral Science
Background:
- Neuropeptide Y (NPY) is a key regulator of feeding behavior.
- Previous studies indicated intracerebroventricular BIBP 3226 inhibits NPY-induced feeding but caused abnormal behaviors, suggesting off-target effects.
- Y1 receptors are implicated in NPY's control of food intake.
Purpose of the Study:
- To investigate the effects of paraventricular nucleus (PVN) injections of BIBP 3226 and its inactive enantiomer BIBP 3435 on NPY-induced feeding.
- To determine if BIBP 3226's effects are specific to Y1 receptor inhibition or due to non-specific mechanisms.
- To assess the reversibility of BIBP 3226's effects on feeding behavior.
Main Methods:
- Rats received intra-PVN injections of NPY to stimulate feeding.
- BIBP 3226 and BIBP 3435 were administered intra-PVN in a dose-response manner.
- Feeding responses were measured after NPY and drug administration.
- Reversibility was assessed by measuring NPY-induced feeding one week after BIBP 3226 injection.
Main Results:
- Intra-PVN NPY injection dose-dependently increased food intake (EC50 ≈ 0.15 nmol/animal).
- Both BIBP 3226 and BIBP 3435 dose-dependently reduced NPY-induced feeding.
- BIBP 3226 inhibited feeding by 95% and BIBP 3435 by 65% at the highest dose.
- High doses of BIBP 3226 resulted in a reduced NPY feeding response even one week post-injection.
Conclusions:
- BIBP 3226 may inhibit NPY-induced food intake non-specifically, independent of Y1 receptor inhibition.
- The findings do not exclude a role for Y1 receptors in NPY-mediated food intake control.
- Further research is needed to elucidate the precise mechanisms of BIBP 3226 and NPY in feeding regulation.