Alterations in mRNA levels of D2 receptors and neuropeptides in striatonigral and striatopallidal neurons of rats with neuroleptic-induced dyskinesias.
Chronic neuroleptic treatment in rat produces vacuous chewing movements (VCMs), analogous to TD in humans. We hypothesized that these hyperkinetic movements were due to alterations in striatonigral and striatopallidal GABAergic spiny II neurons. Rats were treated for 36 weeks with haloperidol decanoate and withdrawn for 28 weeks. Striatonigral and striatopallidal neurons were assessed using in situ hybridization histochemistry for mRNA levels of D1 and D2 dopamine receptors, preproenkephalin (ENK), prodynorphin (DYN), protachykinin (substance P), and glutamate decarboxylase (GAD67) in the dorsolateral and ventromedial striatum as well as the nucleus accumbens. Rats that did not develop VCMs (-VCM) had increased D2 receptor and DYN mRNA, and reduced substance P mRNA in the dorsolateral striatum. Rats with persistent VCMs (+VCM) had increased D2 receptor, ENK, and DYN mRNA in both striatal regions, and increased ENK and DYN mRNA in the nucleus accumbens, compared with controls. Relative to -VCM rats, however, +VCM rats only had increased ENK mRNA in the nucleus accumbens. Considering the overall pattern of mRNA changes, the data suggest that alterations in both the D1-mediated striatonigral and the D2-mediated striatopallidal pathways play a role in the expression of the VCM syndrome. To the extent that gene expression parallels changes in neuronal activity, this implies that the VCM syndrome is associated with increased activity in both pathways.
Egan
M F
MF
Neuropsychiatry Branch, National Institute of Mental Health, NIMH Neuroscience Research Center at St. Elizabeths, Washington, DC 20032.
Hurd
Y
Y
Hyde
T M
TM
Weinberger
D R
DR
Wyatt
R J
RJ
Kleinman
J E
JE
D000818:Animals; D001480:Basal Ganglia Diseases / Q000378:metabolism* / Q000503:physiopathology; D004399:Dynorphins / Q000187:drug effects / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000503:physiopathology; D004745:Enkephalins / Q000187:drug effects / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000187:drug effects; D006220:Haloperidol / Q000009:adverse effects*; D017403:In Situ Hybridization; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000187:drug effects / Q000378:metabolism*
D004745:Enkephalins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013373:Substance P; D004399:Dynorphins; D005968:Glutamate Decarboxylase; D006220:Haloperidol