Effects of monoamine uptake inhibitors given early postnatally on monoamines in the brain stem,caudate/putamen and cortex,and on dopamine D1 and D2 receptors in the caudate/putamen

Summary Rats were treated with desipramine 5mg/kg, nomifensine 10mg/kg, zimelidine 25 mg/kg or with 0.9% sodium chloride once a day during the second and third weeks after birth, and brain stem, caudate/putamen and cortical monoamines, and caudate/putamen dopamine D₁ (³[H]SCH 23390) and D₂ (³[H]spiroperidol) receptor binding were measured when rats were at two months of age. In the brain stem, the concentration of 3-methoxy-4-hydroxy-phenyl glycol was increased in nomifensine rats and the ratio of 5-hydroxyindoleacetic acid to 5-hydroxytryptamine was increased in zimelidine rats. In the caudate/putamen, the concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid and the ratio of homovanillic acid to dopamine were increased in desipramine rats; neither³[H]SCH 23390 nor³[H]spiroperidol binding were affected by any of the three monoamine uptake inhibiting antidepressants studied. In the cortex, the ratio of 5-hydroxyindoleacetic acid to 5-hydroxytryptamine was increased in desipramine and zimelidine rats. The findings suggest that desipramine but not nomifensine increases the metabolism of dopamine in the caudate/ putamen and nomifensine but not desipramine increases the metabolism of norepinephrine in the brain stem, and furthermore that the metabolism of serotonin is affected by desipramine as well as by zimelidine. It is possible that also treatment of women with these drugs during late pregnancy causes long-lasting changes in the brain of human fetus.     

Serotonin and norepinephrine in the spinal cord of man

The content of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) was analysed in 71 human spinal cords obtained post-mortem. The highest content of 5-HT, 5-HIAA and NE was found in the lumbar enlargement of the spinal cord. 5-HT and 5-HIAA content increased from fetal to adult spinal cord whereas the content of NE decreased. Characteristic segmental distribution of measured monoamines was present in adult spinal cord only. In two patients spinal cord lesion led to the reduction in spinal cord content of 5-HT, 5-HIAA and NE and loss of characteristic segmental distribution of these substances. These results are in general agreement with observations on spinal cord of different animal species.     

Characterization of “plasma proteins” secreted by cultured rat macroglial cells

The brain is isolated behind a blood-tissue barrier that restricts the access of circulating proteins to neural cells. There is evidence that some of these proteins are synthesized within the central nervous system. The present study examines the synthesis and secretion of such proteins by cultured macroglial cells. Primary glial cultures were derived from cortical and subcortical regions of neonatal rat brains, and subsequent secondary cultures were enriched in type-1 astrocytes, type-2 astrocytes, or oligodendrocytes. Newly synthesized proteins were immunoprecipitated from the culture media using antisera directed against whole rat serum. All three types of glial cells secreted a range of plasma proteins. In general, type-1 astrocytes secreted more of these proteins than did type-2 astrocytes or oligodendrocytes, although the one-dimensional polyacrylamide gel electrophoresis (PAGE) profiles were specific for each cell type. Antisera directed against specific plasma proteins identified three of the most abundant proteins secreted by type-1 astrocytes as transferrin, α-2-macroglobulin, and ceruloplasmin. Northern blot analysis of cellular RNA confirmed that type-1 astrocytes contained transferrin mRNA, and that it was more abundant in cultures derived from subcortical regions than from cortical regions. In situ hybridization studies revealed that virtually all type-1 and type-2 astrocytes contained transferrin mRNA. Since the proteins identified in this study have been proposed to have a variety of neurotrophic roles in the central nervous system, these data further extend the range of possible functions that glial cells may serve in the CNS.     

Synthesis and Evaluation of Azole-Substituted Tetrahydronaphthalenes as Inhibitors of P450 arom,P450 17, and P450 TxA2

In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH₃ substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C₁-spacer between the rings (compounds 2 – 26 ). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA₂ (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA₂ inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre- and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found: 7-OCH₃-2-(imidazol-4-ylmethylene)-1-tetralone ( 4 ) and 7-OCH₃-2-(imidazol-4-ylmethyl)-tetralin ( 12 ) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12 , the 6-OCH₃ derivative (compound 11 ) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA₂: 2-(imidazol-1-ylmethyl)-1-tetralone ( 13 ) is a selective inhibitor of P450 TxA₂, whereas 7-OCH₃-2-(imidazol-1-ylmethyl)-tetralin ( 17 ) as well as 2-(imidazol-1-ylmethyl)-tetralin ( 16 ) and 7-OCH₃-2-imidazol-1-yl-3,4-dihydronaphthalene ( 25 ) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests.     

Nicotine interactions with dopamine agonists: Effects on working memory function

Nicotine has been found to improve memory performance in a variety of tests including the radial-arm maze. Nicotine may have effects mediated by promoting the release of dopamine. The present study was conducted to determine the interactions of nicotine with D₁ and D₂ agonists. Rats were acutely administered nicotine, the D₁ agonist SKF 38393, and D₂/D₃ agonist quinpirole, and nicotine together with each of these agonists. Nicotine significantly improved choice accuracy in the radial-arm maze. The D₁ agonist SKF 38393 significantly impaired choice accuracy. Nicotine was effective in reversing this effect. The D₂/D₃ agonist quinpirole showed a trend toward potentiating the improvement in choice accuracy caused by 0.2 mg/kg (0.43 μmol/kg) of nicotine. These data show that, as with the nicotinic antagonist mecamylamine, there are significant interactions of dopamine systems with nicotine effects. © 1994 Wiley-Liss, Inc.     

Effect produced by acute and chronic administration of the selective 5-HT3 receptor antagonist BRL 46470 on the number of spontaneously active midbrain dopamine cells in the rat

This study examined the effect of acute and chronic administration of the selective 5-HT₃ receptor antagonist BRL 46470A, an analog of granisetron, on the number of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (A9 or SNC) and the ventral tegmental area (A10 or VTA) in the rat. In the A10 area, the acute administration of BRL 46470A decreased the number of spontaneously active DA cells at a dose of 0.1 mg/kg (0.28 μmol/kg) ip, yet increased the number of spontaneously active DA cells at a dose of 0.3 mg/kg (0.84 μmol/kg). The chronic administration (21 days) of BRL 46470A appeared to produce a multiphasic dose-response curve. Thus, the chronic treatment with BRL 46470A increased the number of spontaneously active A10 DA cells at 0.03 (0.084 μmol) and 0.3 mg/kg, but decreased the number of spontaneously active A10 DA cells at a dose of 0.1 mg/kg. In contrast, BRL 46470A did not decrease the number of spontaneously active A9 DA cells after either acute or chronic administration (0.01-0.3 mg/kg). However, BRL 46470A did increase the number of spontaneously active A9 DA cells at acute and chronic doses similar to those that were effective in A10. The iv administration of (+)-apomorphine (APO) not only failed to reverse the decrease produced by chronic administration of BRL 46470A at 0.1 mg/kg, but further decreased the number of spontaneously active A10 DA cells. Similar to the results obtained with granisetron, the pretreatment of naive rats with either 0.01 or 0.1 mg/kg iv of BRL 46470A significantly potentiated (2-fold) the suppressant action of APO on the basal firing rate of A10, but not A9 DA cells. Overall, our results indicate that similar to granisetron, chronic BRL 46470A at 0.1 mg/kg selectively decreases the number of spontaneously active A10 DA cells, via a mechanism not related to depolarization inactivation. Presently, it is not clear what factors may contribute to the multiphasic dose-response curve of BRL 46470A. © 1994 Wiley-Liss, Inc.     

Biochemical evidence for the involvement of central serotonergic neurotransmission in the action of the antidepressant drug Medifoxamine

Medifoxamine, an antidepressant agent which has an original chemical structure, has been shown through in vitro studies, utilising radioligand binding in tissue homogenates, to bind with moderately high affinity to 5-HT_1c and 5-HT₂ receptor subtypes and to 5-HT uptake sites (IC₅₀ 950, 980, and 1,500 nM, respectively). It has been shown to bind in vivo to rat brain 5-HT₂ receptors after acute treatment with high dose (50 mg/kg, i.e., 133.9 μmol/kg). After 14 days continuous treatment with low dose (20 mg/kg, 53.6 μmol/kg), a decrease in the capacity of [³H]-5-HT uptake and a dose-dependent down-regulation of 5-HT₂ receptors in rat cerebral cortex were observed. These results indicate that medifoxamine, which has been shown previously to act through dopaminergic systems, interacts also with central serotonergic neurotransmission and particularly with the 5-HT₂ receptors, which could contribute to its antidepressant effect.     

THE INTERACTION BETWEEN ENALAPRILAT AND SELECTED α-ADRENOCEPTOR ANTAGONISTS IN ISOLATED RAT TAIL ARTERIES

1. Isolated perfused rat tail artery preparations were used to investigate the effects of the angiotensin converting enzyme inhibitor enalaprilat on the actions of a series of α-adrenoceptor antagonists. The agonist used was phenylephrine. 2. Enalaprilat (1 μmol/L) potentiated the competitive α₁-adrenoceptor antagonist actions of phentolamine (10–100 nmol/L) and yohimbine (0.3–3.0 μmol/L) as well as the non-competitive antagonist action of phenoxybenzamine (50–100 pmol/L). 3. The competitive α₁-adrenoceptor antagonist action of prazosin (1–10 nmol/L) was not affected by enalaprilat. 4. For the competitive α₁-adrenoceptor antagonists, including prazosin, there appeared to be an inverse relationship between antagonist potency and the extent of potentiation by enalaprilat. 5. The results support the hypothesis and angiotensin II modulates vascular smooth muscle α₁-adrenoceptor function.     

Anabolic and catabolic hormonal response of elite runners to training at high altitude

A 2-week training period 2000 meters above sea level performed by 6 male elite Swedish runners influenced neither basal anabolic (total and non-sex hormone-binding globulin (SHBG)-bound testosterone (NST) and insulin-like growth factor-1 (IGF-1) nor catabolic (cortisol) hormones when comparing serum levels prior to and after the training camp. The anabolic vs catabolic hormone balance, expressed as the NST: cortisol ratio, also remained unchanged as well as SHBG and body mass. Thus, training at 2000 meters above sea level, often practised by elite runners to improve performance in competition at sea level, does not result in a catabolic situation after return to sea level, as measured by peripheral hormones. However, the adaptation to high altitude was associated with a slight (NS) decrease in testosterone as well as in anabolic vs catabolic balance as measured the third day at high altitude. Simultaneously, a decrease in subjective performance was claimed by the runners, but could not be shown by objective measurements. From day 3 to day 9 at high altitude, all runners claimed a subjective recuperation of performance. Total and non-SHBG-bound testosterone increased significantly from day 3 at high altitude to the first post-camp sea-level test. The results reflect the necessity of adaptation when travelling to races at different altitudes. The Swedish runners had significantly higher cortisol, total testosterone and NST levels compared with basal values of a group of 17 elite Kenyan runners living and training at high altitude. Since the NST cortisol and IGF-1 values were not lower, a catabolic state or malnutrition was not likely to be present. The results might reflect an adaptation to altitude or ethnic variations.