THE IMMUNOLOGICAL IMPAIRMENT OF ARCUATE NEUROPEPTIDE-Y NEURONS BY RICIN-A CHAIN PRODUCES PERSISTENT DECREASE OF FOOD-INTAKE AND BODY-WEIGHT

Neuropeptide Y is demonstrated as a potent orexigenic peptide when inj ected into the rat hypothalamic paraventricular nuclei. The neuropepti de Y innervation of paraventricular nuclei originates from both hypoth alamic arcuate nuclei and brainstem neurons, whose specific role in th e control of food intake is still under discussion. To assess the role of the arcuate neuropeptide Y in the regulation of food intake, we pr opose a new method for immunologically impairing the neuronal secretio n of neuropeptide Y from a unique brain site. The monoclonal antibody to the neuropeptide Y precursor epitope, the C-flanking peptide, was m icroinjected with two cellular toxins (the ricin A chain and the monen sin) into the hypothalamic arcuate nuclei or paraventricular nuclei. O ne microinjection into the arcuate nuclei reduced the food intake and body weight gain for 10 days. It prevented the food intake stimulation usually induced by a 12 h food deprivation. This decrease of food int ake was not due to the aversive properties of monoclonal antibody or c ellular toxins, or the immunoneutralization of the biologically active neuropeptide Y, because (i) the acute effect of the microinjection in to the arcuate nuclei promoted a transient increase of the food intake likely induced by a strong release of neuropeptide Y from the arcuate neurons which were immunologically damaged, and (ii) the C-flanking p eptide monoclonal antibody binds neither neuropeptide Y nor its recept ors. The microinjection was inefficient when C-flanking peptide monocl onal antibody was replaced by non-specific rat immunoglobulins or when the C-flanking peptide monoclonal antibody/toxins mixture was injecte d into the paraventricular nuclei. The data bring further arguments in two domains. In the food intake regulation, our data confirm the majo r role of the hypothalamic arcuate nuclei in providing neuropeptide Y afferents to the paraventricular nuclei. On the other hand, cellular t oxins can be immunologically introduced into peptidergic neurons with an antibody unable to interact with biologically active peptide. This offers a new approach to inhibiting the secretion of a central neurope ptide.