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.