Long-term Antidepressant Treatments Research Articles

Morphine sensitization as a model of mania: Comparative study of the effects of repeated lithium or carbamazepine administration

Repeated unavoidable stress induces in rats decreased reactivity to avoidable stressors and an anhedonia-like condition that are reverted by long-term antidepressant treatments and regarded as models of core symptoms of depression. Morphine-sensitized rats present resilience to stress-induced behavioral deficits and, if hyporeactivity to stress models a depressive symptom, stress resistance can be regarded as a manic symptom. This hypothesis is supported by the observation that long-term lithium administration reinstates sensitivity to stress in sensitized rats. The first aim of the study was to examine the effects of carbamazepine, a standard antimanic treatment, on the stress resilience of sensitized rats, to further characterize morphine sensitization as a model of manic symptom. Carbamazepine administration abolished stress resilience but did not interfere with the expression of sensitization. The second aim of the study was to assess whether repeated carbamazepine treatment affected the dopaminergic and behavioral responses to a natural reward, a palatable food (vanilla sugar, VS), in non food-deprived sensitized and control rats and compare these possible effects with those of repeated lithium administration. Control and sensitized rats showed increased extraneuronal dopamine levels in the nucleus accumbens shell after VS consumption and competence to acquire an instrumental VS-sustained appetitive behavior (VAB). Repeated carbamazepine treatment abolished the dopaminergic response to VS consumption and disrupted the competence to acquire VAB in control rats. Lithium-treated rats showed a dopaminergic response to VS and easily acquired the appetitive behavior. In sensitized rats, neither carbamazepine nor lithium administration interfered with the dopaminergic response to VS and the acquisition of VAB. In summary, the effect of carbamazepine on the stress resilience of sensitized rats further supported the hypothesis that morphine sensitization might model some symptoms of mania. Moreover, in control rats carbamazepine treatment elicited an anhedonia-like condition that clearly distinguished the effects of this drug from those of lithium.

The antidepressant effects of running and escitalopram are associated with levels of hippocampal NPY and Y1 receptor but not cell proliferation in a rat model of depression

One hypothesis of depression is that it is caused by reduced neuronal plasticity including hippocampal neurogenesis. In this study, we compared the effects of three long-term antidepressant treatments: escitalopram, voluntary running, and their combination on hippocampal cell proliferation, NPY and the NPY-Y1 receptor mRNAs, targets assumed to be important for hippocampal plasticity and mood disorders. An animal model of depression, the Flinders Sensitive Line (FSL) rat, was used and female rats were chosen because the majority of the depressed population is females. We investigated if these treatments were correlated to immobility, swimming, and climbing behaviors, which are associated with an overall, serotonergic-like and noradrenergic-like antidepressant response, in the Porsolt swim test (PST). Interestingly, while escitalopram, running and their combination increased the number of hippocampal BrdU immunoreactive cells, the antidepressant-like effect was only detected in the running group and the group with access both to running wheel and escitalopram. Hippocampal NPY mRNA and the NPY-Y1 receptor mRNA were elevated by running and the combined treatment. Moreover, correlations were detected between NPY mRNA levels and climbing and cell proliferation and NPY-Y1 receptor mRNA levels and swimming. Our results suggest that increased cell proliferation is not necessarily associated with an antidepressant effect. However, treatments that were associated with an antidepressant-like effect did regulate hippocampal levels of mRNAs encoding NPY and/or the NPY-Y1 receptor and support the notion that NPY can stimulate cell proliferation and induce an antidepressant-like response.

Housing conditions modulate escitalopram effects on antidepressive-like behaviour and brain neurochemistry

Despite limited understanding of the pathophysiology of depression and the underlying mechanisms mediating antidepressant effects, there are several efficient treatments. The anhedonia symptoms of depression are characterized by decreased motivation and drive and imply possible malfunctioning of the mesolimbic dopamine system, whereas cognitive deficits might reflect decreased plasticity in hippocampus. In female Flinders Sensitive Line (FSL) rats, a model of depression, we compared the effects of three long-term antidepressant treatments: voluntary running, escitalopram and the combination of both on antidepressant-like behaviour in the Porsolt swim test (PST), and on regulation of mRNA for dopamine and neuropeptides in striatal dopamine pathways and brain-derived neurotrophic factor (BDNF) in hippocampus. Escitalopram diet attenuated running behaviour in FSL rats but not in non-depressed controls rats. In the PST the running group had increased climbing activity (noradrenergic/dopaminergic response), whereas the combination of escitalopram and running-wheel access increased swimming (serotonergic response). Running elevated mRNA for dynorphin in caudate putamen and BDNF in hippocampus. The combined treatment down-regulated D1 receptor and enkephalin mRNA in accumbens. Escitalopram alone did not affect behaviour or mRNA levels. We demonstrate a novel behavioural effect of escitalopram, i.e. attenuation of running in 'depressed' rats. The antidepressant-like effect of escitalopram was dependent on the presence of a running wheel, but not actual running indicating that the environment influenced the antidepressant effect of escitalopram. Different patterns of mRNA changes in hippocampus and brain reward pathways and responses in the PST by running and escitalopram suggest that antidepressant-like responses by running and escitalopram are achieved by different mechanisms.

Pharmacologically Diverse Antidepressants Rapidly Activate Brain-Derived Neurotrophic Factor Receptor TrkB and Induce Phospholipase-Cγ Signaling Pathways in Mouse Brain

Previous studies suggest that brain-derived neurotrophic factor and its receptor TrkB are critically involved in the therapeutic actions of antidepressant drugs. We have previously shown that the antidepressants imipramine and fluoxetine produce a rapid autophosphorylation of TrkB in the rodent brain. In the present study, we have further examined the biochemical and functional characteristics of antidepressant-induced TrkB activation in vivo. We show that all the antidepressants examined, including inhibitors of monoamine transporters and metabolism, activate TrkB rapidly in the rodent anterior cingulate cortex and hippocampus. Furthermore, the results indicate that acute and long-term antidepressant treatments induce TrkB-mediated activation of phospholipase-Cgamma1 (PLCgamma1) and increase the phosphorylation of cAMP-related element binding protein, a major transcription factor mediating neuronal plasticity. In contrast, we have not observed any modulation of the phosphorylation of TrkB Shc binding site, phosphorylation of mitogen-activated protein kinase or AKT by antidepressants. We also show that in the forced swim test, the behavioral effects of specific serotonergic antidepressant citalopram, but not those of the specific noradrenergic antidepressant reboxetine, are crucially dependent on TrkB signaling. Finally, brain monoamines seem to be critical mediators of antidepressant-induced TrkB activation, as antidepressants reboxetine and citalopram do not produce TrkB activation in the brains of serotonin- or norepinephrine-depleted mice. In conclusion, our data suggest that rapid activation of the TrkB neurotrophin receptor and PLCgamma1 signaling is a common mechanism for all antidepressant drugs.

Chronic antidepressant treatments decrease pro-opiomelanocortin mRNA expression in the pituitary gland: effects of acute stress and 5-HT(1A) receptor activation.

Consistent findings in depressed patients are hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis with high plasma concentrations of adrenocorticotropic hormone and cortisol. Long-term antidepressant treatments seem to normalize this hyperactivity, suggesting a link between the HPA axis and the action of antidepressant treatments. The present study was carried out to study the effects of antidepressant treatments on pro-opiomelanocortin (POMC) mRNA expression, with a focus on interaction with acute stress and 5-HT(1A) receptor activation. Male rats were treated for 21 days with saline, citalopram, fluoxetine, moclobemide or desipramine, and the expression of POMC mRNA in the anterior pituitary was analysed by semi-quantitative in situ hybridization. All antidepressants, but not saline, cocaine and haloperidol, reduced POMC mRNA expression. The decrease in POMC mRNA was not observed until 9 days of citalopram treatment. Decreased POMC mRNA levels were also observed after 14 days of repeated electroconvulsive stimulation. The decreased POMC mRNA levels did not affect the stress-induced POMC mRNA increase, measured following swim stress and restraint stress. Finally, using Fos as a marker for neural activity, we showed attenuation of 8-OH-DPAT-stimulated activity in the paraventricular nucleus following 21 days of citalopram treatment. In conclusion, antidepressant treatments decrease basal POMC mRNA expression without affecting the acute stress response, and the reduced POMC mRNA may be related to reduced 5-HT(1A)-stimulated hypothalamic output.

Long-term lithium administration abolishes the resistance to stress in rats sensitized to morphine

Morphine sensitized rats appear protected from the sequelae of an unavoidable stress: when exposed to stress (after a 7-day morphine wash-out) and then tested for escape, they perform like naive animals. This protection appears similar to that induced by chronic imipramine treatment, as it is antagonized by the inhibition of D 1-dopamine receptors before exposure to unavoidable stress. Repeated unavoidable stress induces in rats a condition characterized by hyporeactivity to noxious stimuli and reverted by long-term antidepressant treatments, and this state is regarded as an experimental model of depression. The resistance to stress in morphine sensitized rats could be considered as the behavioral counterpart of the sensitivity to stress in control rats, i.e. as a model of mania. The aim of the present study was to validate such a putative model by studying whether the resistance to stress induced by morphine sensitization would respond to a long-term administration of lithium, the reference antimanic drug. Long-term lithium treatment induces in rats a condition of hyporeactivity to noxious stimuli, accompanied by decreased levels of dopamine in the nucleus accumbens shell. In morphine sensitized rats chronic lithium abolished the resistance to stress, but it did not modify the D 1-dopamine receptor mediated response to morphine, nor did it modify the levels of extraneuronal dopamine in the nucleus accumbens shell. Thus, lithium treatment abolished the resistance to stress in morphine sensitized rats, conferring predictive validity to the paradigm. Moreover, it did so through a mechanism which appeared to be independent of D 1-dopamine receptor activity.

Outcome of different types of long-term antidepressant treatments: a 3-year follow-up study of 14 182 patients

Background: Antidepressant efficacy studies are rare in large populations for prolonged periods. Methods: The efficacy of antidepressants was investigated by using disability pensions due to major affective disorders as the efficacy variable from a large Finnish population ( n=14 182) during a 3-year follow-up. Results: Of all males, 345 (6.0%) were receiving disability pension due to major affective disorder, and of all females, 498 (5.9%). A logistic regression analysis showed a significantly higher risk (age-adjusted ORs, 1.42–4.09) for disability pension in every antidepressant group except the amitriptyline group when compared with fluoxetine group. Those who used a combination of antidepressive agents (age-adjusted OR 4.09) or moclobemide (age-adjusted OR 2.18) had the highest risks. Conclusions: In the study population fluoxetine and amitriptyline were the most efficient antidepressants in the long-term treatment of depression.

Acute and long-term treatments with the selective serotonin reuptake inhibitor citalopram modulate the HPA axis activity at different levels in male rats.

It is well established that the maximal therapeutic effect of selective serotonin reuptake inhibitors (SSRI) are achieved in depressive patients after several weeks of treatment, but the adaptive processes leading to the therapeutic effects are unclear. It has been shown that hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis in depressive patients is affected by long-term antidepressant treatment. These changes occur in association with the mood normalising effect, suggesting that antidepressants affect the HPA axis and this effect is associated with the therapeutic effect. Male Wistar rats were treated with the SSRI, citalopram, to investigate time-related changes in components that may be involved in the desensitization of the HPA axis. A single injection of citalopram (10 mg/kg, s.c.), increased the plasma levels of ACTH and corticosterone in a dose-dependent manner and increased the number of c-Fos containing cells in the hypothalamic paraventricular nucleus. A daily treatment with the same compound (10 mg/kg, s.c.) for 14 days decreased the expression of POMC mRNA ( approximately 40%). In addition, a blunted response to citalopram was observed in animals long-term treated with citalopram. Also CRF-stimulated cAMP accumulation in the pituitary was altered. In conclusion, acute citalopram activated the HPA-axis at the hypothalamic level and long-term citalopram treatment desensitized the HPA-axis at the pituitary level. These results support the hypothesis that the therapeutic effects of long-term antidepressant treatments reduce HPA axis responsiveness.

Acute regulation and long-term modulation of presynaptic serotonin output.

This contribution summarizes the present knowledge about the mechanisms involved in the regulation of presynaptic serotonin release. Under conditions of a permanently altered environmental, (psychosocial, drug-induced, nutritional etc.) input, each one of these mechanisms may be adaptively adjusted to the novel use-dependent requirements. Examples of such long-term alterations of the 5-HT-output pattern in distant projection fields of the raphe-neurons are the downregulation of cortical serotonin-transporters after long-term food restriction, the loss of serotonergic nerve terminals caused by substituted amphetamines, the serotonergic hyperinnervation of the frontal cortex seen after olfactory bulbectomy in rats, or the long lasting changes in the levels of tryptophanhydroxylase, of serotonin-transporter depression or in the density of serotonergic nerve terminals in distant projection fields caused by long-term antidepressant treatments. All these long-lasting alterations and imbalances of a previously established serotonin-output-pattern will not only affect the impact of individual regional networks on whole brain information processing but also the established synaptic connectivity in distant projection fields of the central serotonergic system.

A molecular and cellular theory of depression.

Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.

Long-term antidepressant treatments alter 5-HT 2A and 5-HT 2C receptor-mediated hyperthermia in Fawn-Hooded rats

We have recently demonstrated that hyperthermia induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and m-chlorophenylpiperazine ( m-CPP) are separately mediated by selective stimulation of 5-HT 2A and 5-HT 2C receptors, respectively in Wistar rats. Furthermore, hyperthermia induced by either DOI or m-CPP was found to be significantly less in Fawn-Hooded rats (a rat strain suggested to represent a genetic model of depression) relative to Wistar rats. In the present study, we studied the effects of long-term antidepressant treatments on DOI (2.5 mg/kg)-induced and m-CPP (2.5 mg/kg)-induced hyperthermia in male Fawn-Hooded rats. Long-term (21 days) treatment with the tricyclic antidepressants, imipramine or clomipramine (each 5 mg/kg/day), attenuated DOI-induced hyperthermia, while m-CPP-induced hyperthermia was accentuated. On the other hand, long-term (21 days) treatment with the monoamine oxidase type-A inhibiting antidepressant, clorgyline (1 mg/kg/day), did not modify m-CPP-induced hyperthermia, but significantly attenuated DOI-induced hyperthermia. These findings demonstrate that long-term antidepressant treatments alter 5-HT 2A and 5-HT 2C receptor-mediated hyperthermia in a genetic animal model of depression.

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

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

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.

Receptor sensitivity and the mechanism of action of antidepressant treatment

• Considerable evidence suggests that the acute effects of antidepressant treatments on brain norepinephrine (NE) and serotonin (5-HT) systems cannot account fully for their delayed therapeutic action. This review evaluates the effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function. In contrast to variable effects on NE and 5-HT turnover and on presynaptic receptor sensitivity, almost all long-term antidepressant treatments produce consistent alterations in a number of measures of postsynaptic amine receptor sensitivity. Longterm treatment has been found to reduce β-adrenergic sensitivity while enhancing responses to serotonergic and α-adrenergic stimulation, suggesting that modulation of receptor sensitivity may be a mechanism of action common to tricyclic antidepressants, atypical antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy. These findings provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies of amine receptor function in patients.

Receptor sensitivity and the mechanism of action of antidepressant treatment. Implications for the etiology and therapy of depression.

Considerable evidence suggests that the acute effects of antidepressant treatments on brain norepinephrine (NE) and serotonin (5-HT) systems cannot account fully for their delayed therapeutic action. This review evaluates the effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function. In contrast to variable effects on NE and 5-HT turnover and on presynaptic receptor sensitivity almost all long-term antidepressant treatments produce consistent alterations in a number of measures of postsynaptic amine receptor sensitivity. Long-term treatment has been found to reduce beta-adrenergic sensitivity while enhancing responses to serotonergic and alpha-adrenergic stimulation, suggesting that modulation of receptor sensitivity may be a mechanism of action common to tricyclic antidepressants, "atypical" antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy. These findings provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies of amine receptor function in patients.