Modulation of GABA transmission by diazoxide and cromakalim in the globus pallidus: implications for the treatment of Parkinson's disease.
An ATP-sensitive potassium channel (KATP) is known to modulate insulin release from pancreatic beta cells. It has been proposed that potassium channels related to KATP in the nervous system might similarly modulate neurotransmitter release. We have therefore investigated the effects of KATP opening agents on GABA release in the globus pallidus. Diazoxide and cromakalim decreased the K(+)-evoked release of [3H]GABA from pallidal slices. The maximum inhibition observed for diazoxide (59%) and cromakalim (66%) was achieved at a concentration of 100 microM. The effects of both cromakalim and diazoxide were significantly antagonized by the concurrent application of the sulfonylurea glibenclamide (100 microM). Intrapallidal injections of diazoxide in the reserpine-treated rat model of Parkinson's disease reduced akinesia in a dose-dependent manner. These data suggest that manipulation of neuronal potassium channels with pharmacological properties similar to KATP may prove useful in the treatment of Parkinson's disease.
Maneuf
Y P
YP
Division of Neuroscience, School of Biological Sciences, University of Manchester, United Kingdom.
Duty
S
S
Hille
C J
CJ
Crossman
A R
AR
Brotchie
J M
JM
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim; D003981:Diazoxide / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005917:Globus Pallidus / Q000737:chemistry / Q000187:drug effects*; D015640:Ion Channel Gating / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy; D015221:Potassium Channels / Q000819:agonists; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000378:metabolism
D000959:Antihypertensive Agents; D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D005680:gamma-Aminobutyric Acid; D012110:Reserpine; D003981:Diazoxide