A single brain-derived neurotrophic factor injection modifies hypothalamo-pituitary-adrenocortical axis activity in adult male rats

Immobilization stress induces in adult male rats rapid activation of brain derived neurotrophic factor (BDNF) expression in the hypothalamic paraventricular nucleus (PVN) preceding the increases in corticotropin releasing hormone (CRH) and arginin-vasopressin (AVP) expression. The BDNF mRNA signal belatedly co-localizes with CRH and AVP mRNA signals in the PVN, as determined by in situ hybridization. Intracerebroventricular BDNF injections (5 microg/rat) in non-anesthetized adult male rats induce a gradual increase in the CRH mRNA signal whereas AVP mRNA signal progressively decreases in the parvocellular and magnocellular PVN portions. At the same time, the CRH hypothalamic content decreases while the AVP content increases. These variations are accompanied by increases in ACTH and corticosterone plasma concentrations. These results strongly suggest that BDNF could be a stress-responsive intercellular messenger since when it is exogenously administered acts as an important and early component in the activation and recruitment of hypothalamic CRH and AVP neurons.     

三环抗抑郁药的相互作用

<正>在抗抑郁药的使用频度中,三环抗抑郁药(TCAs)之所以日渐向后排,不是因为它疗效不好,而是因为它不良反应大,不易耐受,过量时危险性大,故医生在使用TCAs期间,不但要掌握TCAs药效学,而且要熟悉TCAs的药物相互作用,这里将专门讨论TCAs的药物相互作用。1概论多数精神药物主要经肝细胞色素P450单氧合酶(CYP)代谢,称为Ⅰ相氧化代谢;次要经葡萄糖醛     

Hydroxylated metabolites of tricyclic antidepressants: preclinical assessment of activity.

Studies investigating a possible relationship between the plasma concentration of tricyclic antidepressants and clinical response have measured only the tertiary and secondary amine forms of these drugs. The present study shows that the hydroxy metabolites of tricyclic antidepressants might also be active. Hydroxylated imipramine, desipramine, chlorimipramine, and nortriptyline inhibit the uptake of norepinephrine and serotonin into synaptosomes to the same extent as do their parent compounds. Hydroxylated nortriptyline and imipramine reverse or prevent reserpine-induced motor retardation and ptosis. Following chronic imipramine, significant steady-state concentrations of unconjugated hydroxylated metabolites are present in rat tissues including the cerebrospinal fluid. Accounting for steady-state concentrations of hydroxylated metabolites of tricyclic antidepressants in man may help to clarify whether there is a relationship between active drug concentration and clinical effect.     

Chronic intraventricular administration of cholecystokinin octapeptide (CCK-8) suppresses feeding in rats

Cholecystokinin octapeptide (CCK-8) is known to suppress feeding in sheep, pigs, golden hamsters and rats following acute intracerebroventricular (i.c.v.) injection. In this study, we report the effects of chronically administered i.c.v. CCK-8 on long-term food intake in rats. After baseline food intake was established over a period of 3 days, rats were implanted with Alzet osmotic minipumps, which delivered 1.0 microliter/h. Three groups of animals were prepared which received saline (vehicle) or CCK-8 at 12.25 micrograms/day (low dose) or CCK-8 at 122.5 micrograms/day (high dose). Surgical preparation of the animals with the intraventricular cannula and the osmotic minipump resulted in an initial reduction in food consumption in all groups. In the saline group daily food consumption returned to presurgery values by day 4. Similar results were observed with the low dose of CCK-8. In contrast, in animals receiving the high concentrations of CCK-8, the initial fall in feeding was more prominent and though it rose during the 7-day infusion interval, it remained statistically below control during this period. After termination of the infusion, daily food consumption rose to normal levels during the next 3 days. For comparison, the cumulative difference between daily food consumption over the period of 8 days during infusion and pre-infusion control was 39.9 +/- 10.0 g/24 h in the saline group. In CCK-8-infused animals, food consumption after pump implantation was reduced by an integrated value of 35.5 +/- 5.0 g/24 h at low dose and 117.4 +/- 20.2 g/24 h at high dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Retinal lipidosis in albino rats treated with chlorphentermine and with tricyclic antidepressants

Summary Retinal pigment epithelium is known to be engaged in continuous phagocytosis and digestion of old discs of visual cell outer segments, which have a high phospholipid content. The present ultrastructural study was focused mainly on the effects, upon pigment epithelium, of several drugs that are thought to interfere with the enzymatic degradation of phospholipids.Albino rats received high oral doses of chlorphentermine, iprindole, l-chloroamitriptyline, imipramine, or clomipramine. After treatment for several weeks the pigment epithelial cells were doubled in height due to deposition of excessive amounts of abnormal cytoplasmic inclusions which had a crystalloid substructure. Such inclusions which are known from previous studies to be associated with drug-induced phospholipid storage are suggested to contain non-digestible phospholipids, which in pigment epithelium originate mainly from phagocytosed outer segment discs. The alterations were reversible by withdrawal of the drugs. The functional implications of the epithelial alterations remain to be elucidated.Additional examination of the neuroretina revealed numerous abnormal inclusions, mainly of multilamellated structure. Ganglion cells were affected most. The neuroretinal alterations were reminiscent of those described in human cases of inherited lipidoses.     

Decreased GABA B receptors in helpless rats: reversal by tricyclic antidepressants

Recently, sufficient evidence has accumulated to suggest that a central GABAergic dysfunction may be primarily related to the physiopathology of affective disorders and that antidepressant mechanisms have an intrinsic GABAergic component. In depressed patients GABA levels are reported to be low in the cerebral spinal fluid and plasma, and GABA synthesis is decreased in some brain areas, including the frontal cortex. GABA mimetics exhibit antidepressant-like actions in behavioral models in the olfactory bulbectomized rat and in the learned helplessness paradigm. In the olfactory bulbectomized rat, GABA B receptors are down regulated in the frontal cortex and in the learned helplessness paradigm, GABA release is diminished in the hippocampus. These decreases are reversed by antidepressants in parallel with their behavioral activities. In this study, data obtained indicate that in the learned helplessness paradigm, GABA B receptors are decreased in the frontal cortex and this decrease is reversed by imipramine and desipramine (16 mg/kg/day) in animals which are considered to be 'responders' to antidepressant treatments.     

Altered pharmacokinetics of tricyclic antidepressants in burns

A case of self-inflicted burns which occurred in the setting of a major depression with psychotic features is described. The case emphasises the difficulties in utilising plasma (serum) tricyclic antidepressant levels to determine adequacy of treatment and risk of toxicity. The case discussion demonstrates the altered pharmacokinetics of tricyclic antidepressants that can occur during disorders such as burns, surgery and medical illness.     

The effects of tricyclic and 'atypical' antidepressants on spontaneous locomotor activity in rodents

With the exception of amineptin, buproprion and nomifensine all tricyclic and 'atypical' antidepressants have been reported to reduce spontaneous motor activity in rodents, after both acute and chronic administration. However, with the diversity of chemical actions of these drugs it is unlikely that a single neurochemical mechanism is underlying this one behavioral effect. These widespread sedative effects have implications for interpreting behavioral changes in other test situations, since sedation generally occurs at doses that fall within the dose-range effective in other tests. We also review the effects on spontaneous motor activity of withdrawal from chronic antidepressant treatment.     

The analgesic effect of tricyclic antidepressants

The analgesia produced by tricyclic antidepressants (TCAs) in rats and the role of serotonin in this analgesia have been investigated in this study. Rats received intraperitoneal injections of imipramine and amitriptyline, which are TCAs, and the serotonin synthesis inhibitor, pCPA. An acute analgesic effect was measured 90 min after the first injections; a chronic effect was measured 24 h after the last injections, on the 7th and 15th days using the hot-plate method. Both antidepressants elevated the pain threshold acutely, while pretreatment with pCPA largely blocked the analgesia. Based on these data it was found that in the acute case both of the antidepressants potentiate an endogenous analgesia mechanism, which acts on the serotonergic system. After long-term use, amitriptyline, which acts on serotonin, had an analgesic effect and this effect was blocked by pCPA. Imipramine, which acts on noradrenaline, had no effect on the pain threshold in chronic use. Consequently, serotonin is an important link in TCA analgesia; noradrenaline has no effect.     

Placental passage of tricyclic antidepressants.

BACKGROUND: The use of antidepressants during pregnancy continues to garner considerable attention, though there are limited investigations that have sought to quantify fetal exposure. METHODS: Maternal and umbilical cord sera were collected at delivery from ten women taking nortriptyline and seven taking clomipramine. Placental passage was calculated as the ratio of umbilical cord to maternal serum concentration. Obstetrical outcome data were gathered from subjects at delivery. RESULTS: The placental passage ratio of nortriptyline and its active metabolite, cis-10-hydroxynortriptyline, were .68 +/- .40, 1.40 +/- 2.40, respectively. Clomipramine and desmethylclomipramine ratios were .60 +/- .50, .80 +/- .60. Obstetrical complications, such as pre-term delivery and pregnancy induced hypertension, were increased compared to the national average. CONCLUSIONS: The in vivo ratios of umbilical cord to maternal serum drug concentrations demonstrate considerable fetal exposure and differ greatly from previous results utilizing ex vivo perfusion.     

Modifications of the sexual activity in male rats following administration of antiserotoninergic drugs

The influence of cyproheptadine (CPH), methysergide and 5-hydroxytryptamine (5-HT) was studied on male sexual activity. Wistar rats from a colony of the Department were used. Measures of sexual parameters (number of ejaculations, initial latency, ejaculation latency, refractory period and neuromotor activity) indicate that cyproheptadine and methysergide facilitate male sexual activity. However, 5-HT inhibits male sexual reflex. Our experimental results suggest that the serotoninergic system exerts an inhibitory role on the sexual parameters which comprise the copulatory model of the male rat and also demonstrate that cyproheptadine facilitates sexual behavior of the male rat.