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 s pecies when it is injected into hypothalamic structures involved in ea ting behavior. The purpose of this study was to determine whether a un ique carboxy terminal fragment of NPY would alter the pattern of eatin g induced in the rat either by NPY injected into the hypothalamus or b y a 24-h period of food deprivation. In this case, two L-tyrosine resi dues and one L-threonine residue of the NPY27-36 fragment were transfo rmed to their D-conformation to produce [D-Tyr(27-36),D-Thr(32)]-NPY ( 27-36), i.e., D-NPY27-36. Guide cannulae for microinjection were impla nted stereotaxically just dorsal to the paraventricular nucleus (PVN) or ventromedial hypothalamus (VMH) of 24 adult male Sprague-Dawley rat s. Following postoperative recovery, a microinjection of artificial CS F or 1.1 mu g or 3.3 mu g of a peptide was made directly into the PVN or VMH as follows: native NPY; D-NPY27-36; Or [L-Tyr(27-36), L-Thr(32) ]-NPY (27-36), i.e., L-NPY27-36. Food intakes were measured at interva ls of 0.25, 0.5, 1.1, 2.0, 4.0, and 24 h. When D-NPY27-36 was microinj ected 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-NPY27-36 also augmented the latency to feed. A mixtu re of the two doses of NPY and D-NPY27-36 injected at the same hypotha lamic 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-NPY27-36 microinjected in the same hypothalamic sites sim ilarly caused a dose-dependent suppression of normal feeding behavior. However, the CSF control vehicle and L-NPY27-36 microinjected in the PVN or VMH were without effect on the pattern of eating. Further, D-NP Y27-36 injected in the same hypothalamic sites affected neither body t emperature nor water intakes of the rats significantly. These results demonstrate that the D substitution of this C-fragment of the NPY mole cule, i.e., D-NPY27-36, serves to inhibit feeding evoked in the rat by hypothalamic NPY as well as the natural eating response to food depri vation. Thus, the D-NPY27-36 molecule may act as an antagonist at one or more subtypes of the NPY receptor in the brain of the rat.