Anorexic action of a new potential neuropeptide Y antagonist [ d-Tyr 27,36, d-Thr 32]-NPY (27–36) infused into the hypothalamus of the rat

Neuropeptide Y (NPY) produces a vigorous feeding response in several species when it is injected into hypothalamic structures involved in eating behavior. The purpose of this study was to determine whether a unique carboxy terminal fragment of NPY would alter the pattern of eating induced in the rat either by NPY injected into the hypothalamus or by a 24-h period of food deprivation. In this case, two l-tyrosine residues and one t.-threonine residue of the NPY 27–36 fragment were transformed to their D-conformation to produce [ d-Tyr 27,36, d-Thr 32]-NPY (27–36), i.e., D-NPY 27–36. Guide cannulae for microinjection were implanted stereotaxically just dorsal to the paraventricular nucleus (PVN) or ventromedial hypothalamus (VMH) of 24 adult male Sprague-Dawley rats. Following postoperative recovery, a microinjection of artificial CSF or 1.1 jig or 3.3 μg of a peptide was made directly into the PVN or VMH as follows; native NPY; D-NPY 27–36; or [L-Tyr 27,36 L-Thr 32]-NPY (27–36), i.e., L-NPY 27–36. Food intakes were measured at intervals of 0.25, 0.5, 1.1, 2.0, 4.0, and 24 h. When D-NPY 27–36 was microinjected at NPY reactive sites in the PVN or VMH of the rat 15 min before a similar microinjection of NPY, the intense eating response induced by the peptide was reduced significantly. Not only was the effect dose dependent, but D-NPY 27–36 also augmented the latency to feed. A mixture of the two doses of NPY and DNPY 27–36 injected at the same hypothalamic loci did not attenuate the intake of food but tended to enhance the feeding response in the rats. After the rats were deprived of food for 24 h, D-NPY 27–36 microinjected in the same hypothalamic sites similarly caused a dose-dependent suppression of normal feeding behavior. However, the CSF control vehicle and L-NPY 27–36 microinjected in the PVN or VMH were without effect on the pattern of eating. Further, D-NPY 27–38 injected in the same hypothalamic sites affected neither body temperature nor water intakes of the rats significantly. These results demonstrate that the D substitution of this C-fragment of the NPY molecule, i.e., D-NPY 27–36, serves to inhibit feeding evoked in the rat by hypothalamic NPY as well as the natural eating response to food deprivation. Thus, the D-NPY 27–36 molecule may act as an antagonist at one or more subtypes of the NPY receptor in the brain of the rat.