Functional effects of D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2 and differential changes in somatostatin receptor messenger RNAs, binding sites and somatostatin release in kainic acid-treated rats.
In situ hybridization histochemistry for somatostatin receptors-1, -2, -3 and -4 section and receptor autoradiography using [125I]CGP 23996, [125I]somatostatin-28, [125I]seglitide and [125I]Tyr3 octreotide were carried out to determine the expression of somatostatin receptor messenger RNAs and binding sites in the hippocampus and cerebral cortex of rats 21 days following generalized limbic seizures induced by subcutaneous injection of 12mg/kg kainic acid. In control rats, somatostatin-1 to somatostatin-4 receptor messenger RNAs were found in the pyramidal layer and granule cell layer of the dentate gyrus. After kainate treatment, the CA1 subfield displayed a selective decrease in somatostatin-3 and somatostatin-4 receptor hybridization signals of 35 and 41%, respectively, whereas no changes were observed in the remaining hippocampal areas. Somatostatin-1 and somatostatin-2 receptor messenger RNA expression in the hippocampus remained unaffected by kainate treatment. No effect of kainate was observed in the expression of somatostatin receptor messenger RNAs in the cerebral cortex. In control rats, the selective somatostatin-2 receptor ligands, [125I]seglitide and [125I]Tyr3 octreotide and the non-selective somatostatin receptor ligands [125I]CGP 23996 and [125I]somatostatin-28, labelled preferentially the stratum oriens and radiatum CA1, the granule and molecular layers of the dentate gyrus and the deep layers of the cerebral cortex. [125I]somatostatin-28 and [125I]CGP 23996 labelled sites were selectively decreased by 32 and 39%, respectively, in the stratum radiatum CA1 after kainate treatment. [125I]CGP 23996 binding was also decreased by 35% in the stratum oriens CA1 and by 36% on average in the stratum oriens and radiatum CA3. [125I]seglitide and [125I]Tyr3 octreotide binding was not affected by kainate in any hippocampal region. The granule and molecular layers of the hippocampus and the layers IV-VI of the cerebral cortex did not show changes in binding sites for any of the radioligands analysed. A 18 and 35% decrease in the spontaneous and 50 mM KCl-induced somatostatin release from hippocampal slices was found two days after kainate, a likely reflection of neuronal cell loss. No differences in somatostatin release were observed 21 days after kainate treatment. At this latter time, the rats had an enhanced susceptibility to tonic-clonic seizures induced by intraperitoneal injection of 30 mg/kg pentylenetetrazol, a subconvulsant dose in naive rats. Bilateral infusion of 6 micrograms RC 160, a selective somatostatin-2 receptor agonist, in the dentate gyrus 21 days after kainate, significantly reduced (P < 0.05) the number of animals with tonic-clonic seizures induced by pentylenetetrazol.(ABSTRACT TRUNCATED AT 400 WORDS)
Pérez
J
J
SANDOZ Pharma Ltd, Basel, Switzerland.
Vezzani
A
A
Civenni
G
G
Tutka
P
P
Rizzi
M
M
Schüpbach
E
E
Hoyer
D
D
D000595:Amino Acid Sequence; D000700:Analgesics; D000818:Animals; D001345:Autoradiography; D001665:Binding Sites / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010433:Pentylenetetrazole / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000819:agonists / Q000096:biosynthesis* / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
D000700:Analgesics; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C051458:vapreotide; D013004:Somatostatin; C038136:CGP 23996; D007608:Kainic Acid; D010433:Pentylenetetrazole