The hypothalamic arcuate, dorsomedial and paraventricular nuclei are involved in regulation of body weight and food intake and contain binding sites for the anorexigenic amylin. Effects of amylin on medial arcuate and paraventricular neurons studied in adult rats overweight through early postnatal overfeeding in small litters (SL) differed from those of control litters (CL). Now we observed that also dorsomedial neurons respond differentially to this satiety signal. They were significantly inhibited by amylin in SL but not CL rats. Since the histaminergic system seems to be involved in mediating effects of amylin, we studied the role of histamine H(1)-receptors. Single unit activity was recorded in brain slices of CL and SL rats in each of the three hypothalamic nuclei. The histamine H(1)-receptor antagonist pyrilamine differentially altered or reduced responses to amylin, not depending on the kind of litter but on the functional effect of the peptide. Pyrilamine prevented significant inhibition of medial arcuate neurons in controls as well as inhibition of dorsomedial and paraventricular neurons in SL rats. Searching for further mechanisms possibly contributing to the change of neuronal responses we found that in the presence of a GABA(A)-receptor antagonist amylin induced a significant inhibition of medial arcuate neurons in SL rats similar to that in CL without antagonist. Activation of medial arcuate neurons expressing the orexigenic neuropeptide Y and inhibition of dorsomedial and paraventricular neurons in SL rats may in vivo contribute to hyperphagia and overweight. Histamine H(1)-receptors and GABA(A)-receptors seem to be differentially involved in mediation of these effects.