Decreased hypothalamic serotonin levels in adult rats treated neonatally with clomipramine

doi:10.1016/S0091-3057(96)00276-6

Pharmacology Biochemistry and Behavior

Volume 55, Issue 4, December 1996, Pages 647-652

https://doi.org/10.1016/S0091-3057(96)00276-6 Get rights and content

Abstract

Early postnatal treatment with the antidepressant drug clomipramine has repeatedly been shown to lead to behavioural and physiological changes in adult rats. To provide some neurochemical correlates to these studies we have measured a number of monoaminergic parameters in the brains of adult (one year old) rats that were treated twice daily with 15 mg/kg clomipramine from postnatal day 2–14. The most consistent finding was that the hypothalamic levels of serotonin (5-HT) were decreased and those of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) were increased in rats irrespectively whether they went through a range of behavioural and physiological tests or not. The numbers of β-adrenoceptors in the frontal cortex and of α₂-adrenoceptors in the amygdala/piriform cortex were not changed. The decrease in hypothalamic 5-HT concentrations appears to be up to now the most consistent neurochemical alteration in adult rats that were neonatally treated with antidepressant drugs. It is, however, not clear what the relation is with the functional changes in these rats, that are proposed by some authors as an animal model for depression.

References (30)

S. De Boer et al.
Neurobehavioral teratogenic effects of clo-miprainine and alpha-methyldopa
Neurotoxicol. Teratol.
(1989)
E.B.H.W. Erdtsieck-Ernste et al.
Perinatal influence of β-adrenergic drugs on the noradrenergic system of the rat brain
Gen. Pharmacol.
(1993)
L.A. Hilakivi et al.
Increased adult behavioral despair in rats neonatally exposed to desipramine or zimeldine: an animal model of depression?
Pharmacol. Biochem. Behav.
(1987)
J. Hyttel
Citalopram — pharmacological profile of a specific sero-tonin uptake inhibitor with antidepressant activity
Prog. Neuro-Psychopharmacol. & Biol. Psychiat.
(1982)
G.A. McPherson
Analysis of radioligand binding experiments. A collection of computer programs for the IBM PC
J. Pharmacol. Methods
(1985)
M. Mirmiran et al.
Suppression of active sleep by chronic treatment with chlorimipramine during early postnatal development: effects upon adult sleep and behavior in the rat
Brain Res.
(1981)
M. Mirmiran et al.
Effects of experimental suppression of active (REM) sleep during early development upon adult brain and behavior in the rat
Devel. Brain Res.
(1983)
M.V. Ugrumov et al.
Development of the hypothalamic 5-hydroxytryptamine system during ontogenesis in rats: uptake and release of 5-hydroxytryptamine in vitro
Neuroscience
(1989)
J. Velazquez-Moctezuma et al.
Neonatal treatment with clomipramine increased immobility in the forced swim test: an attribute of animal models of depression
Pharmacol. Biochem. Behav.
(1992)
J. Velazquez-Moctezuma et al.
Behavioral effects of neonatal treatment with clomipramine, sco-polamine. and idazoxan in male rats
Pharmacol. Biochem. Behav.
(1993)

G. Vogel et al.

A new animal model of endogenous depression: a summary of present findings

Neurosci. Biobehav. Rev.

(1990)

P. Yavari et al.

Decreased raphe unit activity in a rat model of endogenous depression

Brain Res.

(1993)

G.J. Boer et al.

Alpha-2-adreno-ceptor assayed in rat brain by the new ligand [³H]RX821002

Biog Amines

(1993)

J.T. Coyle et al.

Development of the uptake and storage of L-[³H]norepinephrine in the rat brain

J. Neurochemistry

(1971)

J. Del Río et al.

Long-lasting changes after perinatal exposure to antidepressants

Cited by (47)

Structural and metabolic activity differences in serotonergic cell groups in a rat model of individual differences of emotionality and stress reactivity
2022, Neuroscience Letters
Citation Excerpt :
For example, pharmacologically enhancing synaptic 5-HT levels during early brain development via perinatal exposure to selective-serotonin reuptake inhibitor (SSRI) antidepressant medications interferes with 5-HT circuit formation. Early-life SSRI exposure permanently alters the 5-HT system, leading to diminished basal firing of dorsal raphe 5-HT neurons [9], diminished expression of tryptophan hydroxylase (TPH2) and the 5-HT reuptake transporter (SERT) in the raphe [10], reduced 5-HT fiber density in the hippocampus [11], and altered monoamine levels in several brain regions [12–15]. Early-life SSRI exposure also disrupts emotional behavior, leading to abnormal social behavior, behavioral inhibition, anhedonia, and passive stress coping (for review see [8]).
Serotonin regulates a diverse set of functions, including emotional behavior, cognition, sociability, appetite, and sleep. Serotonin is also a key trophic factor that shapes neurodevelopmental processes. Genetic and environmental factors that drive individual differences in the serotonergic system have the capacity to impact brain structure and behavior, and likely contribute to pathophysiological processes involved in neuropsychiatric disorders. Using adult rats selectively bred for low novelty exploration (Low Responders, LR), we previously demonstrated pronounced increases in the levels of their anxiety- and depression- relevant behaviors as compared to the selectively bred High Novelty Responder (HR) rats. These behavioral differences were accompanied by alterations in the expression of genes that regulate serotonin synthesis in the brainstem, and its signaling in the forebrain. The present study extends these observations with a focus on the organization and the metabolism of brainstem serotonin cell groups that provide serotonergic innervation of the hippocampus and other limbic regions of male HR/LR rats. Using design-based stereology, we found the median raphe (MnR) in adult male LR rats contains increased number of serotonergic neurons as compared to the HRs. This is preceded by an increase in the metabolic activity of the caudal dorsal raphe (DRC) and the intrafascicular DR (DRI) during early postnatal development. These findings suggest that structural and functional differences in the raphe-limbic projections shape behavioral inhibition throughout the lifespan.
N-acetyl cysteine ameliorates depression-induced cognitive deficits by restoring the volumes of hippocampal subfields and associated neurochemical changes
2020, Neurochemistry International
Depression is highly comorbid with anxiety disorders and associated with profound cognitive impairment. Moreover, cognitive deficits associated with hippocampal dysfunction are central in depression and anxiety disorders. Furthermore, depression is accompanied by glutamatergic dysfunction which can further impair the functioning of the hippocampus. Recent studies have shown that N-acetyl cysteine (NAC), a glutamate modulator produces an antidepressant-like effect by normalization of the periterminal release of glutamate and/or antioxidant effects. However, the effects of repeated NAC treatment on depression-induced anxiety, cognitive deficits, and associated neurochemical and structural alterations are relatively unknown. Accordingly, we investigated whether chronic NAC treatment could reverse cognitive deficits, and associated hippocampal volume loss and monoaminergic alterations in the neonatal clomipramine (CLI) model of depression. We found that chronic NAC treatment produces antidepressive and antianhedonic-like effects. NAC treatment also reversed CLI-induced anxiety. Interestingly, repeated NAC treatment improved the performance of CLI rats in rewarded alternation task in T-maze. The antidepressive-like and procognitive effects of NAC was associated with normalization of volume loss in CA1, dentate gyrus (DG) and hilar subfields of the hippocampus. Furthermore, NAC restored CLI-induced decrease in levels of monoamines and normalized enhanced metabolism in the hippocampus. Taken together, chronic NAC treatment ameliorates depressive and anxiety-like behavior, spatial learning deficits, and reverses CLI-induced pathological alterations at structural and neurochemical levels in the hippocampus. Our findings might help in evolving NAC as a viable pharmacotherapy for reversal of cognitive deficits in depression and associated disorders.
Chronic treatment with estradiol restores depressive-like behaviors in female Wistar rats treated neonatally with clomipramine
2017, Hormones and Behavior
Neonatal administration of clomipramine (CMI) induces diverse behavioral and neurochemical alterations in adult male rats that resemble major depression disorder. However, the possible behavioral alterations in adult female rats subjected to neonatal treatment with clomipramine are unknown. Therefore, the aim of this study was to explore the effect of neonatal treatment with CMI on adult female rats in relation to locomotion and behavioral despair during the estrus cycle. Also evaluated was the effect of chronic treatment with E2 on these female CMI rats. We found no effects on spontaneous locomotor activity due to neonatal treatment with CMI, or after 21 days of E2 administration. In the FST, neonatal treatment with CMI increased immobility and decreased active swimming and climbing behaviors. Influence of the ovarian cycle was detected only in relation to climbing behavior, as the rats in the MD phase displayed less climbing activity. Chronic E2 administration decreased immobility but increased only swimming in CMI rats. These results suggest that neonatal treatment with CMI induces despair-like behavior in female rats, but that chronic E2 administration generates antidepressant-like behavior by decreasing immobility and increasing swimming, perhaps through interaction with the serotonergic system.
Models of Depression
2017, Models of Seizures and Epilepsy: Second Edition
Although the bidirectional connection between epilepsy and depression has been well established, a majority of animal studies of comorbidity focus on depressive impairments stemming from a primary epileptogenic insult. The present chapter analyzes whether and how preexisting depression affects the susceptibility of animals to epilepsy. First, approaches to model depression in rodents are reviewed. Next, documented epilepsy-related findings associated with the respective depression models are summarized. In a majority of cases, depression appears to increase the predisposition to, and the severity of, epilepsy in experimental animals. At the same time, depressive state alone apparently is not sufficient to induce epilepsy; instead, depression-related perturbations prime the brain for, and facilitate the development of, epilepsy upon the occurrence a secondary epileptogenic event. Conversely, several models of depression are characterized by the increased resistance to seizures, and many models have no documented seizure phenotype.
Of rodents and humans: A comparative review of the neurobehavioral effects of early life SSRI exposure in preclinical and clinical research
2016, International Journal of Developmental Neuroscience
Selective serotonin reuptake inhibitors (SSRIs) have been a mainstay pharmacological treatment for women experiencing depression during pregnancy and postpartum for the past 25 years. SSRIs act via blockade of the presynaptic serotonin transporter and result in a transient increase in synaptic serotonin. Long-lasting changes in cellular function such as serotonergic transmission, neurogenesis, and epigenetics, are thought to underlie the therapeutic benefits of SSRIs. In recent years, though, growing evidence in clinical and preclinical settings indicate that offspring exposed to SSRIs in utero or as neonates exhibit long-lasting behavioral adaptions. Clinically, children exposed to SSRIs in early life exhibit increased internalizing behavior reduced social behavior, and increased risk for depression in adolescence. Similarly, rodents exposed to SSRIs perinatally exhibit increased traits of anxiety- or depression-like behavior. Furthermore, certain individuals appear to be more susceptible to early life SSRI exposure than others, suggesting that perinatal SSRI exposure may pose greater risks for negative outcome within certain populations. Although SSRIs trigger a number of intracellular processes that likely contribute to their therapeutic effects, early life antidepressant exposure during critical neurodevelopmental periods may elicit lasting negative effects in offspring. In this review, we cover the basic development and structure of the serotonin system, how the system is affected by early life SSRI exposure, and the behavioral outcomes of perinatal SSRI exposure in both clinical and preclinical settings. We review recent evidence indicating that perinatal SSRI exposure perturbs the developing limbic system, including altered serotonergic transmission, neurogenesis, and epigenetic processes in the hippocampus, which may contribute to behavioral domains (e.g., sociability, cognition, anxiety, and behavioral despair) that are affected by perinatal SSRI treatment. Identifying the molecular mechanisms that underlie the deleterious behavioral effects of perinatal SSRI exposure may highlight biological mechanisms in the etiology of mood disorders. Moreover, because recent studies suggest that certain individuals may be more susceptible to the negative consequences of early life SSRI exposure than others, understanding mechanisms that drive such susceptibility could lead to individualized treatment strategies for depressed women who are or plan to become pregnant.
Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response
2015, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Interestingly, neonatal exposure to SSRIs is a model of depression that is also consistent with the high serotonin hypothesis. Adult rats exposed to SSRIs as neonates show increased serotonin transmission (indexed by the 5-HIAA/5-HT ratio) in the hypothalamus (Feenstra et al., 1996; Hilakivi et al., 1987), and exhibit a depressive behavioral profile (Ansorge et al., 2004; Hansen et al., 1997). In the Flinders Sensitive Line rat, a breed that exhibits many depressive symptoms (Table 4), serotonin and 5-HIAA levels are elevated in the PFC, hippocampus and other regions relative to control rats (Zangen et al., 1997).
The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.

View all citing articles on Scopus

View full text

ArticleDecreased hypothalamic serotonin levels in adult rats treated neonatally with clomipramine

Abstract

Neurotoxicol. Teratol.

Gen. Pharmacol.

Pharmacol. Biochem. Behav.

Prog. Neuro-Psychopharmacol. & Biol. Psychiat.

J. Pharmacol. Methods

Brain Res.

Devel. Brain Res.

Neuroscience

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Neurosci. Biobehav. Rev.

Brain Res.

Alpha-2-adreno-ceptor assayed in rat brain by the new ligand [3H]RX821002

Biog Amines

Development of the uptake and storage of L-[3H]norepinephrine in the rat brain

J. Neurochemistry

Long-lasting changes after perinatal exposure to antidepressants

Article
Decreased hypothalamic serotonin levels in adult rats treated neonatally with clomipramine

Alpha-2-adreno-ceptor assayed in rat brain by the new ligand [³H]RX821002

Development of the uptake and storage of L-[³H]norepinephrine in the rat brain