Convergent evidence from microdialysis and presynaptic immunolabeling for the regulation of gamma-aminobutyric acid release in the globus pallidus following acute clozapine or haloperidol administration in rats.
Antipsychotic drugs (APDs) have been primarily characterized for their effects on dopaminergic terminal regions in the brain, especially within the corpus striatum. Efferent GABA pathways are the primary outflow of striatal processing via their projections to the substantia nigra and the globus pallidus (GP). In the current study, we analyzed changes in pallidal GABA function following acute APD administration by means of in vivo microdialysis, followed by immunolabeling of presynaptic GABA terminal density in the contralateral hemisphere of the same animals. Acute administration of the atypical APD, clozapine (10 or 30 mg/kg, s.c.), produced a dose-dependent decrease in extracellular GABA. A corresponding dose-dependent increase in the density of presynaptic terminal GABA immunolabeling in the GP was found. In contrast, the typical APD, haloperidol (1 or 3 mg/kg, s.c.), had no significant effects on either measure, although a non-significant increase in extracellular GABA and decrease in the density of GABA terminal immunolabeling was noted. Paw retraction tests conducted during the time of microdialysis showed that haloperidol produced a typical pattern of highly pronounced motor impairment, while clozapine showed an atypical profile of minimal catalepsy. These complementary results obtained from in vivo neurochemistry and presynaptic neurotransmitter labeling suggest that systemic clozapine suppresses neuronal GABA release within the GP. This decrease in released pallidal GABA may play a role in the low motor side-effect liability of atypical APDs.
See
Ronald E
RE
Department of Physiology and Neuroscience, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA. seere@musc.edu
Berglind
William J
WJ
Krentz
Lisa
L
Meshul
Charles K
CK
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000008:administration & dosage*; D018492:Dopamine Antagonists / Q000008:administration & dosage; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005552:Forelimb / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000008:administration & dosage; D005917:Globus Pallidus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006220:Haloperidol / Q000008:administration & dosage*; D006614:Hindlimb / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000032:analysis / Q000378:metabolism*
D018492:Dopamine Antagonists; D018756:GABA Antagonists; D005680:gamma-Aminobutyric Acid; D003024:Clozapine; D006220:Haloperidol