LOW-AFFINITY SULFONYLUREA BINDING-SITES RESIDE ON NEURONAL CELL-BODIES IN THE BRAIN

The antidiabetic sulfonylurea drugs bind to sites associated with an A TP-sensitive potassium (K-atp) channel on cell bodies and terminals of neurons which increase their firing rates or transmitter release when glucose concentrations rise or sulfonylureas are present. High-affini ty sulfonylurea binding sites are concentrated in areas such as the su bstantia nigra (SN) where glucose and sulfonylureas increase transmitt er release from GABA neurons. But there is a paucity of high-affinity sites in areas such as the hypothalamic ventromedial nucleus (VMN) whe re many neurons increase their activity when glucose rises. Here we as sessed both high- and low-affinity sulfonylurea binding autoradiograph ically with 20 nM [H-3]glyburide in the presence or absence of Gpp(MI) p. Neurotoxin lesions with 6-hydroxydopamine (6-OHDA), 5,7-dihydroxytr yptamine (5,7-DHT) and ibotenic acid were used to elucidate the cellul ar location of the two sites in the VMN, SN and locus coeruleus (LC). In the VMN, 25% of the sites were of low affinity. Neither 6-OHDA nor 5,7-DHT affected [3H]glyburide binding, while ibotenic acid reduced th e number of VMN neurons and abolished low-affinity without changing hi gh-affinity binding. In cell-attached patches of isolated VMN neurons, both 10 mM glucose and 100 mu M glyburide decreased the open probabil ity of the K-atp channel suggesting that the low-affinity binding site resides on these neurons. In the SN pars reticulata, ibotenic acid re duced the number of neurons and high-affinity [H-3]glyburide binding w as decreased by 20%, while 6-OHDA had no effect. In the SN pars compac ta, both 6-OHDA and ibotenic acid destroyed endogenous dopamine neuron s and selectively ablated low-affinity binding. In the LC, 6-OHDA dest royed norepinephrine neurons and abolished low-affinity binding. These data suggest that low-affinity sulfonylurea binding sites reside on c ell bodies of VMN, SN dopamine and LC norepinephrine neuron cell bodie s and that high-affinity sites may be on axon terminals of GABA neuron s in the SN.