GABA and GABAA receptor changes in the substantia nigra of the rat following quinolinic acid lesions in the striatum closely resemble Huntington's disease.
GABA and GABAA receptors have been studied in the substantia nigra of the rat following quinolinic acid lesions in the striatum. The regional distribution of GABA and GABAA receptors was investigated using immunohistochemical techniques with monoclonal antibodies to GABA and to the beta 2.3 subtypes of the GABAA receptor complex. The distribution, density and cellular localization of GABAA receptors were studied using quantitative receptor autoradiography and 6-hydroxydopamine-induced degeneration of dopaminergic pars compacta neurons. The subunit configuration of GABAA receptors was investigated using in situ hybridization histochemistry and subunit subtype-specific oligonucleotide probes. The results showed that in the normal substantia nigra GABA and GABAA receptors were mainly localized within the pars reticulata. GABAA receptors were mainly of the BZI variety, had a subunit subtype configuration that included alpha 1 and beta 2.3 subtypes, and showed a rostrocaudal gradient in the density of receptors; the density of receptors in the caudal third was 56% higher than that in the rostral third of the pars reticulata. Following quinolinic acid-induced degeneration of the striatonigral pathway, there was a marked loss of GABA immunoreactivity and a 59% increase in the density of GABAA receptors in the substantia nigra pars reticulata. There was a corresponding regional topography in the pattern of loss of GABA immunoreactivity and in the pattern of increase in GABAA receptors in the pars reticulata; the topography varied with the size and placement of the lesion in the striatum and correlated with the known topographical organization of the striatonigral projection. The quantitative autoradiographic results showed that following quinolinic acid lesions in the striatum: (i) the greatest increase in the density of GABAA receptors occurred in the middle third (91% increase) of the pars reticulata; (ii) the receptors were mainly of the GABAA/BZI variety; and (iii) 6-hydroxydopamine-induced degeneration of the dopaminergic pars compacta neurons did not significantly affect the density of receptors, indicating that the increased receptor binding was mainly localized on non-dopaminergic pars reticulata neurons. The immunohistochemical and in situ hybridization studies showed that, as in the normal substantia nigra, GABAA receptors in the substantia nigra pars reticulata on the lesioned side contained the alpha 1 and beta 2.3 GABAA receptor subtypes; the alpha 1 and beta 2.3 subtypes (but not the alpha 2) were increased after quinolinic acid lesions.(ABSTRACT TRUNCATED AT 400 WORDS)
Nicholson
L F
LF
Department of Anatomy, School of Medicine, University of Auckland, New Zealand.
Faull
R L
RL
Waldvogel
H J
HJ
Dragunow
M
M
D000818:Animals; D001345:Autoradiography; D004195:Disease Models, Animal; D005445:Flunitrazepam / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006816:Huntington Disease / Q000139:chemically induced / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D017378:Quinolinic Acid / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014316:Tritium
D012333:RNA, Messenger; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D014316:Tritium; D005445:Flunitrazepam; D017378:Quinolinic Acid