A glutamate antagonist blocks perforant path stimulation-induced reduction of dynorphin peptide and prodynorphin mRNA levels in rat hippocampus.
Stimulation of the perforant path elicits a behavioral response, wet dog shakes (WDS), and reduction in hippocampal dynorphin A(1-8) immunoreactivity (DYN-IR) and prodynorphin mRNA (DYN mRNA) in rats. This study examined whether glutamate, the proposed endogenous transmitter released by perforant fibers, mediated the above responses. A glutamate antagonist, gamma-D-glutamylglycine (DGG, 25 micrograms/0.5 microliters), or artificial cerebrospinal fluid (ACSF, 0.5 microliters) was injected into the ventral hippocampus 10-20 min prior to acute or daily stimulation of the left perforant path in rats. In acute stimulation experiments, 4 consecutive stimulation trials elicited a total of 73 +/- 4 WDS at an average threshold intensity of 0.46 +/- 0.03 mA in ACSF-treated rats. The hippocampal DYN-IR in these animals decreased by more than 40% in both dorsal and ventral hippocampus relative to sham-stimulated rats. DGG injections significantly elevated the threshold for WDS (0.78 +/- 0.05 mA, P less than 0.01), reduced the number of WDS (45 +/- 6, P less than 0.01), and partially antagonized stimulation-induced reduction of DYN-IR in the ventral, but not dorsal, hippocampus. In daily stimulation experiments, rats received a single trial of stimulation once per day for 6 days. Daily DGG pretreatment almost completely abolished WDS at control threshold intensities, and significantly inhibited stimulation-induced decrease of DYN-IR in both dorsal and ventral hippocampus. In situ hybridization using a 35S-labeled oligodeoxyribonucleotide probe demonstrated a clear depletion of DYN mRNA signal in the dentate granule cell layer of ACSF-treated animals. This depletion was completely prevented in DGG-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Xie
C W
CW
Laboratory of Molecular and Integrative Neuroscience National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
McGinty
J F
JF
Lee
P H
PH
Mitchell
C L
CL
Hong
J S
JS
D000818:Animals; D004151:Dipeptides / Q000494:pharmacology*; D004399:Dynorphins / Q000187:drug effects / Q000378:metabolism*; D004745:Enkephalins / Q000235:genetics*; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006651:Histocytochemistry; D008297:Male; D009434:Neural Pathways / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D014202:Tremor / Q000188:drug therapy
D004151:Dipeptides; D004745:Enkephalins; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D011498:Protein Precursors; D012333:RNA, Messenger; C028929:gamma-glutamylglycine; D018698:Glutamic Acid; D004399:Dynorphins; C026770:dynorphin (1-8); C033660:preproenkephalin