Differential effects of long-term antidepressant treatments on 8-OHDPAT-induced increases in plasma prolactin and corticosterone in rats

Intravenous administration of 8-hydroxy-2(di-n-propylamino) tetralin (8-OHDPAT) to rats produced increases in plasma prolactin and corticosterone concentrations. Long-term or short-term treatment with the MAO type A inhibiting antidepressant, clorgyline, or tricyclic antidepressants (imipramine and clomipramine), did not change baseline levels of either prolactin or corticosterone. Long-term but not short-term clorgyline treatment attenuated 8-OHDPAT's effect on plasma prolactin but not on corticosterone. On the other hand, long-term but not short-term treatment with clomipramine and to some extent imipramine also, accentuated 8-OHDPAT's effect on plasma prolactin but not on corticosterone. These findings demonstrate that long-term antidepressant treatment in rats produces a differential effect on 8-OHDPAT-induced increases in plasma prolactin and corticosterone, which is consistent with other clinical and animal studies demonstrating a differential effect of long-term antidepressant treatment on two different 5-HT-mediated neuroendocrine functions.     

Differential effect of clomipramine treatment on m-chlorophenylpiperazine-induced increases in plasma prolactin and corticosterone in rats

Intravenous administration of m-chlorophenylpiperazine (m-CPP, a serotonin agonist) to rats increased plasma prolactin and corticosterone concentrations. Long-term (21-day) and short-term (3-day) treatment with the tricyclic antidepressant, clomipramine, did not have any significant effect on baseline levels of either prolactin or corticosterone. Long-term but not short-term clomipramine treatment significantly potentiated m-CPP's effect on plasma prolactin. On the other hand, both long-term and short-term clomipramine treatment significantly attenuated m-CPP's effect on plasma corticosterone. These findings are consistent with other animal and clinical studies demonstrating a differential effect of antidepressant treatment on two different serotonin-mediated neuroendocrine functions.     

Chronic antidepressant treatment increases the apomorphine-induced elevation of plasma corticosterone in rats

Plasma corticosterone concentrations in response to subcutaneous administration of apomorphine (25 and 200 micrograms kg-1) have been assessed in rats treated acutely (2 days) or repeatedly (15 days) with saline, clomipramine, electroshock and clomipramine + electroshock. Chronic, but not acute, antidepressant treatment decreased the corticosterone level which remained unchanged in control and in rats acutely treated with apomorphine. Chronic antidepressant treatment significantly increased the corticosterone response to apomorphine. Neuroendocrine evidence is provided for an increased responsiveness of dopamine receptors which are thought to mediate the apomorphine effect on corticosterone secretion following chronic antidepressant treatment.     

Differential effects of short-and long-term antidepressant treatments on the food-induced place preference conditioning in rats

The effect of antidepressant drugs (ADs) on the rewarding properties of food, given to food-deprived rats, was studied with a conditioned place preference paradigm. Repeated (once a day for 4 days) association of an initially non-preferred environment with the presentation of food resulted in development of an increased preferences for that environment. That effect was diminished when each conditioning session was preceded by administration of single doses of imipramine, desipramine, amitriptyline, mianserin and citalopram (short-term treatment). In contrast, long-term treatment (16 days) with the above ADs, as well as repeated (9) applications of electroconvulsive shock significantly enhanced the food-induced place preference conditioning. In a separate experiment it was also found that ADs, used as unconditioned stimuli, produced a conditioned aversion to the environment previously paired with administration of single doses of the drugs. The above findings are discussed in terms of the enhancement by prolonged antidepressant treatments of the brain reward mechanisms.     

Differential effects of chronic antidepressant treatments on micro- and delta-opioid receptors in rat brain

We performed an autoradiographic study of [D-Ala(2),MePhe(4),Gly-ol(5)]enkephalin (DAMGO)-sensitive [(3)H]naloxone binding to micro-opioid receptors and of [(3)H][D-Pen(2),D-Pen(5)]enkephalin (DPDPE) binding to delta-opioid receptors in the rat brain after 4- or 21-day treatments with paroxetine, reboxetine and moclobemide to investigate the participation of these receptors in the adaptive mechanisms occurring during the delay of action of new generation antidepressants. Paroxetine increased micro-opioid receptor binding site density in cingulate and insular cortices, dorsal endopiriform nucleus (4 days) and olfactory tubercle (21 days) and decreased it in thalamus (21 days). Reboxetine increased it in amygdala (4 days), hippocampus and thalamus (21 days) and decreased it in dorsal raphe (4 days). Moclobemide increased it in hippocampus (4 days) and decreased it in anterior olfactory nucleus, frontal cortex, amygdala and hypothalamus (21 days). Moclobemide increased delta-opioid receptor binding site density in frontal cortex and amygdala (4 days) and decreased it in amygdala and colliculi (21 days). Opioid receptors displayed distinct patterns of adaptations in response to the three antidepressants studied.     

Haloperidol treatments increased macrophage activity in male and female rats: influence of corticosterone and prolactin serum levels.

Haloperidol is a receptor D2 antagonist frequently used in the treatment of schizophrenic patients. Haloperidol increased prolactin release from anterior pituitary gland, and prolactin modulates immune system activity. Groups of six male and female rats received an acute 2 mg/kg haloperidol treatment (E1), or a long-term (E2) haloperidol treatments (2 mg/kg/day for 21 days); control rats were treated similarly, but with control solution (groups C1 and C2, respectively). In this work long-term haloperidol treatment (E2) increased macrophage spreading, phagocytosis and NO release in male and female rats. However, acute haloperidol treatment (E1) did not change macrophage activity. Corticosterone and prolactin serum levels were increased after acute (E1) and long-term (E2) haloperidol treatments in male and female rats, being this increment higher in female. Macrophage of male and female rats presented the same pattern of alterations after acute and long-term haloperidol treatments. Haloperidol-induced macrophage activation was discussed in the light of a possible indirect effect through prolactin increments in rats, or, alternatively, as a consequence of a direct action of macrophage dopamine receptor.     

Differential effects of ethanol on plasma catecholamine levels in rats

Acute ethanol administration (1-4 g/kg, i.p.) had no effect on plasma catecholamine levels in nonstressed animals except at the highest dose where levels of both catecholamines increased. In animals stressed for 30 min, the higher doses had a biphasic effect on plasma catecholamines; at earlier times during stress a reduction in stress-induced increases in both catecholamines was seen, whereas later during stress or after release from stress an increase was noted. Semi-chronic ethanol administration (0.5 and 2 g/kg/day, i.p.) had no significant effect on plasma catecholamine levels in nonstressed rats. In stressed rats, ethanol reduced stress-induced catecholamine increases but these reductions were less than those seen after acute administration. Although ethanol reduced the gross behavioral stress response, no correlation between gross behavioral and biochemical responses was detected. These data show that ethanol can indeed reduce the behavioral and biochemical stress responses in rats but that effects seen depend on the state (nonstressed vs stressed) of the animal, the dose of ethanol (low vs high) used, the length of ethanol administration (acute vs semi-chronic), and the time of measurement of the catecholamine level after ethanol administration.     

Differential effect of lithium treatment on fenfluramine-induced decreases in food intake and locomotor activity in rats

Administration of fenfluramine to rats decreased 1-h food intake and locomotor activity. Short-term (2-6 days) but not long-term (21-25 days) lithium treatment potentiated fenfluramine-induced suppression of food intake. However, neither short-term nor long-term lithium treatment had any significant effect on fenfluramine-induced suppression of locomotor activity. These findings demonstrate a differential effect of lithium treatment on fenfluramine-induced suppression of food intake and locomotor activity. Furthermore, these findings are consistent with results from several other animal and clinical studies demonstrating a differential effect of lithium treatment on two different serotonin-mediated functions.     

Acute and chronic antidepressant drug treatments induce opposite effects in the social behaviour of rats

Clinical studies indicate that the behavioural responses/reactions of depressed patients to environmental and social stimulation are modified during remission from depressive illness, and require continuous (at least 3 weeks) drug treatment. In order to determine whether antidepressant drugs modify the behavioural patterns of experimental animals in ways that may be related to their ability to modify human reactive behaviour, we have examined the effects of acute and chronic treatment with clomipramine, fluoxetine, iprindole, mianserin and phenelzine (antidepressants with markedly different acute pharmacology) on the behaviour exhibited by rats during social interaction (SI). Acute treatment of short-term isolated resident rats with non-sedative doses of each antidepressant drug selectively and dose-relatedly reduced aggressive behaviour exhibited during SI. Conversely, haloperidol (antipsychotic) or diazepam (anxiolytic) only reduced aggressive behaviour at sedative doses. In comparison, following chronic treatment, all antidepressants examined, but not haloperidol or diazepam, increased aggressive behaviour exhibited by resident rats during SI which returned to the pre-treatment level by 7 or (after phenelzine) 14 days after the cessation of treatment. It is concluded that the antidepressants examined induce selective, diametrically opposite effects on rodent aggressive behaviour following acute and chronic treatment which is indicative of antidepressant efficacy. Furthermore, it is argued that the increased aggressive behaviour following chronic antidepressant drug treatment may indicate a disinhibition of social behaviour in the rat that mirrors the externalization of emotions associated with the remission of depressive illness.     

Toluene depresses plasma corticosterone in pregnant rats

Combined exposure to stressors and chemicals may result in synergistic effects. The effects of prenatal exposure to the organic solvent toluene resemble those observed in offspring of gestationally stressed dams, a possible common mechanism being transfer of stress-/toluene-induced increments of corticosteroids from the maternal to the foetal compartment. Pregnant rats were subjected to either 1500 ppm toluene 6 hr/day and/or a schedule of "Chronic mild stress" during the last two weeks of gestation. Exposure to toluene was associated with reduced birth weight and lower maternal weight gain, the latter being enhanced by maternal stress. A depressant effect of toluene on maternal corticosterone was observed, hence the study does not provide immediate evidence that transfer of elevated levels of corticosterone from the maternal to the foetal compartment mediates the effects of prenatal exposure to toluene.     

Effects of chlorfenvinphos on plasma corticosterone and aldosterone levels in rats

Plasma corticosteroids concentrations, in rats intoxicated with chlorfenvinphos (p.o. single dose 6.15 mg/kg), were investigated. A significant increase of corticosterone was observed at 1 and 3 h and aldosterone from 1 to 6 h after treatment. Brain and blood AChE activity was diminished to about 10–30% for up to 24 h, with maximal inhibition in brain at 2 h after treatment. Maximal increase in plasma corticosteroids levels occured within 1 h, while the brain AChE was only slightly inhibited at that time. Results suggest that changes in plasma corticosteroids are not related to the decrease of AChE activity in brain.     

Differential effects of antidepressant treatment on brain monoaminergic receptors

Chronic (21 days) antidepressant administration to rats results in a decrease in both serotonin and β-adrenergic but not cholinergic muscarinic, receptor binding in selected brain regions, with the frontal cortex appearing to be somewhat more sensitive to this effect. Neither nisoxetine nor fluoxetine, potent and specific inhibitors of norepinephrine and serotonin uptake respectively, caused receptor binding changes after chronic administration, suggesting that inhibition of transmitter uptake, in itself, in insufficient to cause receptor subsensitivity. In vitro experiments indicated that antidepressants are relatively weak α₂-receptor blocking agents, but some are potent on the α₁-receptor system indicating that the norepinephrine releasing potency of some antidepressants may not be mediated by blockade of presynaptic autoreceptors.     

Delayed effects of antidepressant drugs in rats

The present study has addressed the question of what is more important for the occurrence of adaptive changes observed in the organism treated with antidepressant drugs: a daily dosing of the drug or the period of time necessary for the plastic events to develop. Here, we report on the effects of desipramine given to rats acutely (and tested following 2 drug-free weeks) as when the drug was administered repeatedly, on behavior in the forced swim test (i.e. significant shortening of immobility time by ca. 60%) and on the binding of [3H]CGP12177 to beta-adrenergic receptors in the rat brain cortex (significant decrease of the binding by ca. 15%). Additionally, using the procedure of the repeated forced swim test (six times over 21 days), we show that the shortening of immobility time induced by a single dose of imipramine persisted throughout the whole experimental period and was similar to that seen in a group of animals treated repeatedly with the drug. Also, the effects of citalopram on immobility and climbing were similar after acute treatment and delayed testing to those seen after repeated drug exposure. The results obtained in the present study may question some conclusions that are usually drawn from the behavioral and, especially, biochemical studies concerning the need for repeated treatment with antidepressant drugs to induce various adaptive changes in the brain, which are thought to be responsible for the therapeutic efficacy of these drugs.     

Effect of the anxiolytic drug buspirone on prolactin and corticosterone secretion in stressed and unstressed rats

Buspirone is an atypical anxiolytic drug that exerts its action at a receptor site other than the GABA-benzodiazepine-chloride ionophore complex. The present study examined the effect of buspirone on plasma prolactin and corticosterone levels in both control and stressed rats. In unstressed rats, buspirone produced dose-dependent increases in plasma prolactin and corticosterone levels. The minimal doses of buspirone which led to significant elevations in plasma prolactin and corticosterone levels were 1.0 and 2.0 mg/kg (IP), respectively. The effect of buspirone on both hormones was maximal 30 minutes after injection. The plasma levels of prolactin and corticosterone were significantly elevated in rats that were stressed using a conditioned fear paradigm. Buspirone produced a dose-dependent attenuation of the stress-induced increase in prolactin secretion. The stress-induced increase in corticosterone secretion was inhibited by the 0.5 mg/kg (IP) dose but not by the 2.0 mg/kg (IP) dose of buspirone, which increased corticosterone secretion both in stressed and unstressed rats. These data suggest that the effect of buspirone on plasma prolactin and corticosterone levels may be mediated by two different mechanisms of action.     

Study of mirtazapine antidepressant effects in rats

Mirtazapine is a widely used antidepressant and the aim of this study was to further investigate its antidepressant activity in rats. Thus, the efficacy of long-term mirtazapine treatment was assessed in three models of depressive symptoms induced by stress exposure: the acute escape deficit, the chronic escape deficit, and the stress-induced disruption of the acquisition of an appetitive behaviour sustained by a palatable food (vanilla sugar). Administration of mirtazapine for 2 wk prevented the escape deficit development induced by acute exposure to unavoidable stress. This protective effect was antagonized by the administration of a beta-adrenergic or a 5-HT1A receptor antagonist just before stress exposure; that is, mirtazapine effect was dependent on functional beta-adrenergic and 5-HT1A receptor systems. Repeated stress exposure indefinitely prolongs the condition of escape deficit and a 40-d mirtazapine treatment reversed this model of chronic escape deficit. In a Y-maze satiated rats learn to choose the arm baited with vanilla sugar, and exposure to stress during Y-maze training prevents this learning. Repeated mirtazapine administration completely antagonized the disrupting effect of chronic stress on the acquisition of this instrumental behaviour. We consider these effects to be crucial in the definition of antidepressant activity.     

Increase of plasma corticosterone induced by loperamide in rats

Loperamide given intracerebroventricularly and intraperitoneally to rats provoked, like morphine, a plasma corticosterone increase 60 min after injection. Loperamide intracerebroventricularly was 3.73 times less active than morphine, while intraperitoneally it was 10.13 times more potent. This increase, associated with a significant elevation in the plasma ACTH concentration, was antagonized by naloxone (10 mg/kg i.p.) injected 30 min before loperamide. In hypophysectomized rats loperamide intraperitoneally did not affect the plasma corticosterone levels. We conclude that loperamide can stimulate corticosterone secretin from the adrenal gland via the opiate receptors and that this effect is mediated by a direct or indirect induction of ACTH release.