Homocysteic acid lesions in rat striatum spare somatostatin-neuropeptide Y (NADPH-diaphorase) neurons.
L-Homocysteic acid (L-HCA) is a sulfated amino acid which is present in mammalian striatum and is a putative excitatory striatal neurotransmitter. In the present study we examined the histologic and neurochemical effects of L-HCA induced striatal lesions to determine how closely changes resemble those of Huntington's disease (HD). Increasing doses of L-HCA injected into the anterior striatum resulted in dose-dependent reductions in both substance P-like immunoreactivity (SP-LI) and gamma-aminobutyric acid (GABA) while there was a relative sparing of both somatostatin-like immunoreactivity (SS-LI) and neuropeptide Y-like immunoreactivity (NPY-LI). Immunocytochemical studies showed a relative sparing of NADPH-diaphorase neurons (which colocalize with SS and NPY) within regions in which there was a significant depletion of enkephalin stained neurons. The lesions were blocked by pretreatment with MK-801, a systemically effective non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors or coinjection of equimolar concentrations of 2-amino-5-phosphonovalerate (APV). These findings are similar to those produced with the NMDA agonist quinolinic acid, and suggest that other endogenous NMDA agonists, such as L-HCA, could be potential excitotoxins in HD.
Beal
M F
MF
Neurology Services, Massachusetts General Hospital, Boston.
Kowall
N W
NW
Swartz
K J
KJ
Ferrante
R J
RJ
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013004:Somatostatin / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D003986:Dibenzocycloheptenes; D009478:Neuropeptide Y; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D006710:Homocysteine; C007956:homocysteic acid; D013373:Substance P; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate