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The suggestion that somatostatin is involved in the pathophysiology of obsessive-compulsive disorder and the evidence that selective serotonin reuptake inhibitors show significant antiobsessional effect prompted us to examine the effect of citalopram, a selective and potent serotonin reuptake inhibitor, on the somatostatinergic system in different brain regions of the rat. A single intraperitoneal injection of 10 mg/kg citalopram significantly reduced somatostatin levels in the striatum and nucleus accumbens after 4 but not 1, 8, or 24 h. No changes were found in hippocampus. In addition, we found that the K+-evoked overflow of somatostatin-like immunoreactivity from striatal slices was significantly increased 1 h after a single injection of citalopram and was still higher, although not significantly, 4 h after the drug injection. Levels of preprosomatostatin mRNA were unchanged in striatum and accumbens 1 and 4 h after a single drug administration. In rats treated with citalopram (10 mg/kg i.p.) twice daily for 14 days, the levels of somatostatin and its mRNA were significantly decreased in the striatum but not in other brain regions 24 h after the last dose. No change was found in the basal or K+-evoked overflow of somatostatin-like immunoreactivity at 1, 4, and 24 h after the last drug injection. These results suggest that acute and chronic treatment with citalopram reduces somatostatin levels in striatum by different mechanisms. Whereas a single dose of the drug reduces somatostatin levels by increasing the release of the peptide, repeated drug treatment reduces the biosynthesis of somatostatin.

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SR 57746A, 4-(3-trifluoromethylphenyl)-N-[2-(naphth-2-yl)ethyl]-1,2,3,6- tetrahydropyridine HCl, was studied for its specific 5-HT1A receptor agonist action and antidepressant-like effects in the rat. The compound showed a high affinity for 5-HT1A specific binding sites in the rat hippocampus (IC50 3 nM), moderate affinity (10(-7)-10(-6) M) for dopamine D2 receptor, 5-HT uptake, 5-HT2 and alpha 1-adrenoceptor binding sites and practically no effect on binding sites of monoamine, GABAA, benzodiazepine and histamine receptors. It inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes at concentrations of 10(-6) and 10(-5) M. The effect of 10(-6) M SR 57746A on forskolin-stimulated adenylate cyclase activity was completely antagonized by 10(-6) M (-)-propranolol. Administered per os as a three-dose course to rats, SR 57746A significantly increased struggling in the forced swimming test at doses from 0.3 to 3 mg/kg. Single doses had no such effect. The effect of a three-dose course with 1 mg/kg SR 57746A on rats' struggling was antagonized by pretreatment with 5 mg/kg i.p. metergoline, a non-selective 5-HT receptor antagonist, and by 20 mg/kg i.p. (-)-propranolol, an antagonist at 5-HT1 receptors. Three oral doses of 100 mg/kg parachlorophenylalanine, an inhibitor of 5-HT synthesis, and 100 mg/kg i.p. (+/-)-sulpiride, an antagonist at dopamine D2 receptors, also antagonized the effect of SR 57746A in the forced swimming test. The results show that SR 57746A has selectivity and high affinity for 5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

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Intracerebroventricularly (ICV) injected 5,7-dihydroxytryptamine (5,7-DHT), which reduced by 70-90% forebrain serotonin levels, significantly raised glial fibrillary acidic protein (GFAP) mRNA levels in the hippocampus and nucleus raphe dorsalis 5 days but not 15 days after the lesion. A significant increase of mitochondrial benzodiazepine receptors (MBR), measured by binding autoradiography of 3H-PK 11195, was found in the nucleus raphe dorsalis 5 and 15 days after the ICV 5,7-DHT and also in the hippocampus, ventral tegmental area, and substantia nigra at 15 days. No significant effect was observed in the striatum and cortex for either GFAP mRNA or MBR binding. Unlike the ICV route, bilateral injection of 5,7-DHT into the medial forebrain bundle, which caused a 65-90% reduction of serotonin levels in different forebrain regions, significantly raised GFAP mRNA and MBR binding only at the site of injection with no effect in hippocampus, striatum, and cortex. MBR binding slightly increased in the nucleus raphe dorsalis 15 days after the lesion. High doses of d-fenfluramine (10 mg/kg intraperitoneally twice daily for 4 days) caused 80-90% reduction of serotonin levels 5 days after the last injection but did not change the GFAP mRNA or the MBR binding in any of the brain regions considered. These findings suggest that the effect of 5,7-DHT on microglial and glial markers is probably related to a nonspecific interaction with other neuronal systems besides the serotonin or to direct interaction with glial cells; the use of these parameters for detecting selective degeneration of serotonin axons presents some obvious limitations.

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The expression and distribution of the mRNA coding for the growth-associated protein-43 (GAP-43), a putative marker for neuritic growth, for preprosomatostatin and the preproneuropeptide Y (ppNPY) were analysed in the rat hippocampus during the development of hippocampal kindling by an in situ hybridization technique and computer-assisted grain counting in the cell. The levels of GAP-43 mRNA increased significantly in the CA3 pyramidal neurons and hilar polymorphic neurons of the dentate gyrus 2 days after stage 2 of kindling (preconvulsive stage) but not stage 5 (full seizure expression) in the stimulated hippocampus. The distribution of GAP-43 mRNA was the same in the hippocampus of kindled rats as in sham-stimulated animals. Preprosomatostatin mRNA and ppNPY mRNA contents rose significantly in the hilar polymorphic neurons of the dentate gyrus of the stimulated and contralateral hippocampus at both stages of kindling, with the greatest effect at stage 5. In addition, the number of ppNPY mRNA neurons in the fascia dentata was significantly higher in kindled rats than in controls, but there were no differences in the number of preprosomatostatin mRNA-positive cells. Preprosomatostatin and ppNPY mRNAs were also increased in the neurons of the stratum oriens of the CA1-CA3 subfield of fully kindled animals, whereas at stage 2 only neurons of the CA1 stratum oriens showed a significant increase of preprosomatostatin mRNA. No changes in preprosomatostatin and ppNPY mRNA expression were observed in the various regions of the hippocampus after a single afterdischarge or 1 month after stage 5.(ABSTRACT TRUNCATED AT 250 WORDS)

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The levels of neuropeptide Y and somatostatin may change when serotoninergic neurotransmission is altered in different brain regions. To assess whether serotonin regulates the synthesis of these peptides, we measured the levels of preproneuropeptide Y (ppNPY) and preprosomatostatin (ppSOM) mRNA in different brain regions after intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), a selective serotonin neurotoxin. The mRNA of these peptides significantly increased in the striatum but not in hippocampus and frontal cortex. It thus appears that serotonin has an inhibitory effect on the biosynthesis of neuropeptide Y and somatostatin in striatum whereas it probably acts by stimulating the release of these peptides in hippocampus and frontal cortex.

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Repeated high doses of d-fenfluramine (dF; 10 mg/kg, i.p. twice daily for 4 days) markedly reduced serotonin (5-HT) concentrations in the hippocampus and striatum of rat brain up to 1 month after treatment, while tryptophan hydroxylase (TPH) levels were reduced only in the hippocampus 5 days after injection. Unlike dF, an intracerebroventricular (i.c.v.) injection of 5,7-dihydroxytryptamine (5,7-DHT 150 micrograms/20 microliters) induced a marked and long-lasting reduction of 5-HT and TPH in both brain regions. Thirty days after injection, 5,7-DHT, but not dF, markedly reduced the number of labelled neurons in the dorsal and ventral regions of the nucleus raphe dorsalis (NRD) and raised the levels of TPH mRNA in the spared neurons at all times examined. TPH mRNA levels were raised 5 and 15 days after dF treatment in the NDR suggesting that changes in the TPH gene expression or transcript stability result following 5-HT depletion. These data are in agreement with the suggestion that 5,7-DHT damages 5-HT nerve terminals and perikarya, but leave unanswered the question of the mechanism of the long-lasting reduction of 5-HT levels caused by high, repeated doses of dF.

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