Marinella Blengio

Biochemical and behaviour changes induced by acute stress in a chronic variate stress model of depression : the effect of amitriptyline

This paper examines the biochemical and behaviour changes induced by an acute stress (five 10-s, 1-mA foot-shocks) in three groups of rats: (1) never stressed, (2) subjected to chronic variate stress for 20 days, (3) subjected to the same chronic stress and treated with 5 mg/kg per day amitriptyline. After 15 min, acute stress led to a marked reduction in cortical beta-adrenoceptor and 5-HT2 receptor density, whereas the density of the 5-HT1A receptors was unchanged. Chronic stress also increased beta-adrenoceptor and 5-HT2 receptor density and had no effect on 5-HT1A. Acute stress diminished the density of beta-adrenoceptors in chronically stressed animals, but did not alter that of the two 5-HT populations. Amitriptyline alone reduced beta-adrenoceptor and 5-HT2 receptor densities only. Acute stress applied to animals treated with amitriptyline reduced 5-HT1A receptors, and caused a further beta-adrenoceptor decrease, but had no further effect on the 5-HT2 receptors. On behaviour, chronic stress diminished reactivity to the acute stress. This reduction was fully abolished by amitriptyline. An open-field study showed that acute stress reduced motor activity, increased latency times and diminished rearing in the controls, whereas chronic stress reduced motor activity only. No significant changes in behaviour were induced by the acute stress in animals subjected to chronic stress. The combination of chronic stress with amitriptyline was accompanied by a diminution of exploratory activity that persisted after the acute stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of estradiol on the ontogenesis of striatal dopamine D1 and D2 receptor sites in male and female rats

Since estradiol (E2) either increases or reduces the number of dopamine receptors in the corpus striatum of adult rats, depending on the dose and length of administration, the sensitivity of the two receptor subpopulations (D1 and D2) to E2 during ontogenesis was investigated. Rats of both sexes received either 10 micrograms/kg E2 for 3 days or 50 micrograms/kg for 6 days, and were sacrificed at the age of 15, 21, 40 and 120 days. D1 receptors (identified by [3H]SCH 23390 binding) displayed no changes in density and affinity in function of age, sex or E2 dose, whereas the D2 receptors (identified by [3H]spiperone binding) fell after the lower dose in all groups, and the higher dose resulted in supersensitivity in males of all ages, but only in the 15-day-old females. These findings show that the effect of E2 is bivalent on D2 density only. The effect of its brief administration at a low dose is not sex-dependent, whereas at higher doses administered for longer periods it appears to involve mechanisms linked to sexual differentiation after birth.

Hypothalamic Histamine Release in Normal and Stressed Rats Is Affected by Sex and Aging

Changes in the baseline and in the 40 mM K+-evoked release of histamine from hypothalamus slices were compared in male and female rats aged 2, 6, 12, 18, and 24 months. The baseline release declined in the 12-, 18-, and 24-month males. In contrast, the K+-evoked release remained constant in the males, but in the females it decreased in animals more than 2 months old. The efficiency of the H3 receptors was also determined by measuring the reduction of the K+-evoked release induced by the H3 receptor agonist (R)-alpha-methylhistamine. This substance significantly decreased the amount of HA released in all age groups, except the 24-month-old males. Histamine release was also measured after exposure to a weak electrical stress. In 2- and 6-month-old males, there was a marked reduction of both the baseline and the K+-evoked release, and also of the inhibitory effect of the H3 agonist. There were no changes in the 12- and 18-month age groups, but both releases were enhanced in the 24-month group. In females, electrical stress had no significant effect, except in the youngest age group. Stress-dependent release of plasma corticosterone was decreased in males older than 12 months and in females older than 6 months. These changes gave a good correlation with variation in the H3 receptors. This study, therefore, demonstrates that aging modifies, in a sex-dependent way, the basal and stress-stimulated functions of the hypothalamic presynaptic histaminergic neurons.

Effects of different types of stress on histamine-H3 receptors in the rat cortex

The role of the histamine (HA) H3 receptor (estimated by binding of [3H]N-alpha-methyl HA in the brain cortex) in the response of male rats to four types of stress was evaluated: acute weak foot-shock stress (0.5 mA x 1 s x 5 times), acute intense foot-shock stress (1mA x 10 s x 5 times), acute restraint stress (60 min at 24 degrees C) and chronic variate stress. Two groups of rats received chronic treatment with a tricyclic antidepressant: amitriptyline (5 mg/kg i.p.); one group was also chronically stressed. HA-H3 receptor density rapidly decreased in acute intense foot-shock and chronic variate stress, but was unchanged in acute weak foot-shock and restraint stress. Amitripytline counteracted the chronic variate stress-induced decrease, and increased HA-H3 receptor density when chronically administered in the non-stressed control group. These results indicate that cortical HA-H3 receptor density is affected by the response to stress in function of the type, duration and intensity of the stressor.

Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

UNLABELLED We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modifications induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17 beta-estradiol (E2) at both low (0.1 micrograms/kg) and high (20 micrograms/kg) doses confirmed its ability to increase the number of striatal 3H-Spiperone (3H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E2, to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophyseal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. IN CONCLUSION TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of its antiestrogenic activity.

Stress-induced changes in histaminergic system : effects of diazepam and amitriptyline

The involvement of the histaminergic system in the regulation of weak stress was studied in rats. The parameters examined were the brain receptors and corticosterone (CS) plasma levels. The benzodiazepine diazepam [(2 mg/kg intraperitoneally (IP)] influenced neither foot-shock-induced changes in CS levels nor [3H]-histamine [(3H)-HA] binding site constants, whereas the tricyclic antidepressive amitriptyline (10 mg/kg IP) partially counteracted a plasma CS increase and prevented changes in [3H]-HA binding in the stressed rat brain. These observations are in agreement with the known activities of amitriptyline on monoaminergic metabolism and receptors. Moreover, these data provide further experimental evidence of the functional role of the central histaminergic system in organized stress response.

Sexual dimorphism in [3H]histamine binding sites of rat cerebral cortex

[3H]Histamine binding sites, identified on rat brain homogenate membranes, displayed sexual dimorphism with higher density and lower affinity in preparations from adult female compared to the males. The ontogenetic development of [3H]histamine binding sites was studied in male and female brain cortex neural membranes. Histamine binding sites were detectable in newborn-10 day old rats. Density increased with age, reaching adult levels at 37-45 days. No significant differences between sexes were observed in the binding constants until 37 days after birth, when the [3H]histamine binding characteristics began to differentiate according to sex. Sexual dimorphism in brain histamine binding site development appeared to depend on ovarian steroids. Binding patterns in immature female rats which were ovariectomized at 21 days and killed at 37+ were similar to those found in males. On the other hand, when oestradiol replacement was administered for 10 days to ovariectomized rats a total recovery of [3H]histamine binding pattern was obtained, which was comparable to that observed in intact female rats of the same age.

Differential effects of indolepyruvic acid and 5-hydroxytryptophan on indole metabolism in the pineal gland of the rat during the light-dark cycle

The effect of two serotonin precursors, 5-hydroxytryptophan (5-OH-TRP) and indolepyruvic acid (IPA), a tryptophan ketoanalogue, on rat pineal indole metabolism during the light-dark cycle was investigated. 5-OH-TRP drastically increased the production of 5-hydroxyindoleacetic acid at a dose of only 10 mg/kg, whereas 50-100 mg/kg was needed to reach higher serotonin levels. It had no effect on the pathway leading to the production of N-acetylserotonin and melatonin. IPA, on the other hand, led to a marked dose-related increase in tryptophan, 5-OH-TRP, serotonin and 5-OH-indoleacetic acid, and was also active on N-acetylserotonin and melatonin synthesis in both phases. The different behaviour of these two substances with regard to melatonin synthesis was also confirmed by their effects on N-acetyltransferase, since IPA increased, whereas 5-OH-TRP decreased its activity. These data suggest that an increase in serotonin does not necessarily lead to an increase in melatonin, and that IPA may in fact induce this effect by altering the activity on N-acetyltransferase, which is regarded as a key enzyme in pineal hormone synthesis.

Are the catecholestrogens involved in estrogen-induced striatal dopamine receptor supersensitivity?

The ability of tamoxifen, an antiestrogen agent, to antagonise the striatal dopamine receptor hyperactivity induced in rats by chronic treatment with 17 beta-estradiol and 2-hydroxyestradiol or with two receptor blockers (haloperidol and sulpiride) was compared. It was found that tamoxifen antagonised both the increase in [3H]spiperone binding sites and the stereotyped behaviour induced by apomorphine in animals treated with the two steroids but had no effect in animals receiving the two dopamine blockers. These results run counter to the view that introduction of a catechol group in a steroid molecule is of decisive importance in the induction of striatal dopamine receptor hypersensitivity.

Stress and brain histaminergic system: Effects of weak electric foot-shock

A weak electric foot-shock stressful stimulus (0.5 mA x 1 s x 5 times) significantly increases plasma corticosterone (CS) levels and modifies [3H]-histamine ([3H]-HA) binding site constants related to H2 receptors in rat cortical membranes. Progressive and total recovery of basal binding characteristics occurs 90 min later. A double-foot-shock stress procedure delays [3H]-HA binding characteristic recovery instead of strengthening stress effects. This finding is further evidence of involvement of the brains histamine receptors in the response to mild stress.