Elsevier

Brain Research Bulletin

Volume 153, November 2019, Pages 102-108
Brain Research Bulletin

Antidepressants upregulate c-Fos expression in the lateral entorhinal cortex and hippocampal dorsal subiculum: Study in rats

https://doi.org/10.1016/j.brainresbull.2019.08.015Get rights and content

Highlights

  • The study aimed to find common brain targets for antidepressants.

  • Seven drugs of different classes were examined.

  • Influence of the drugs on c-Fos expression in thirty brain areas was tested.

  • The lateral entorhinal cortex and dorsal subiculum were sensitive to all the drugs.

Abstract

Neural circuits involved in the development of depression are currently poorly understood. To provide insight into this issue, we evaluated the influence of seven clinically effective antidepressants on neuronal activity in thirty rat brain areas. Drugs belonging to all major groups of antidepressants (imipramine, reboxetine, fluoxetine, bupropion, mirtazapine, agomelatine, and phenelzine) were examined; since antidepressants typically require weeks of continued administration before they achieve a therapeutic effect, we administered these drugs for 21 days. The experiments were conducted with male Wistar rats. To identify the neuroanatomical targets for antidepressants, the alterations of c-Fos expression in different brain areas were measured using ELISA assay. The drugs were examined at doses sufficient to produce behavioral effect in the rat forced swim test (FST). All the drugs at the behaviorally relevant doses activated two brain areas, the lateral entorhinal cortex and dorsal subiculum of the hippocampus; none of the drugs affected the c-Fos expression in the medial orbital, prelimbic and infralimbic cortex, caudate putamen, nucleus accumbens core, bed nucleus of stria terminalis, hipothalamic paraventricular nucleus, medial amygdaloid nucleus, lateral habenula, substantia nigra pars compacta and pars reticulata, ventral tegmental area, hippocampal ventral subiculum, dorsal and ventral periaqueductal gray matters, and medial entorhinal cortex. These findings suggest that the stimulation of the lateral entorhinal cortex and hippocampal dorsal subiculum play a role in therapeutic effects of antidepressants.

Introduction

Depressive disorders are recognized as one of the most common and debilitating diseases worldwide (Smith, 2014). Despite decades of study, the mechanism of depression remains uncertain. In particular, unclear are the brain areas involved in the development of these disorders.

In all likelihood, the elucidation of the depression-related neuroanatomical circuit(s) could be promoted through the identification of brain targets for clinically effective anti-depressive medications. Drugs of different chemical structure are currently used to ameliorate depressive symptoms in clinics; in experiments, these compounds are found to influence monoaminergic and melatoninergic processes (Connolly and Thase, 2012). The neuroanatomical targets for these drugs were examined in many studies. In particular, an ability of antidepressants to influence neuronal activity has been tested in different brain areas; in these studies, expression of c-Fos, an immediate early gene product, has been used as a marker of the neuronal activity.

In rats, acute administration of imipramine (a norepinephrine and serotonin reuptake inhibitor) increased c-Fos protein expression in the central amygdala and hippocampal dentate gyrus but not in the medial and basolateral amygdala and CA1 and CA3 hippocampal fields (Li et al., 2013). Fluoxetine (selective serotonin reuptake inhibitor) was found to increase c-Fos levels in the central amygdala and the nucleus accumbens shell; the drug failed to affect the nucleus accumbens core (Miyata et al., 2005). Other serotonin reuptake inhibitors, citalopram and paroxetine, also increased c-Foc expression in the central amygdala (Morelli and Pinna, 1999; Karanges et al., 2016). A single injection of imipramine and citalopram decreased c-Foc expression in the nucleus accumbens shell (Morelli and Pinna, 1999); paroxetine increased this index in the hypothalamic paraventricular nucleus, bed nucleus of the stria terminalis, periaqueductal gray and dorsal raphe (Karanges et al., 2016). Five daily injections of amitriptyline (a norepinephrine and serotonin reuptake inhibitor) enhanced c-Fos-immunoreactivity in the locus coeruleus (Hiroki et al., 2017); whereas no influence on c-Fos levels in this area was observed after acute administration of paroxetine (Karanges et al., 2016). Sumner and co-authors appraised the available evidence and suggested that the central amygdala is a common neuroanatomical target for antidepressants (Sumner et al., 2004). However, the results of further studies have challenged this notion. Reboxetine (selective norepinephrine reuptake inhibitor) did not change the c-Fos expression in the central amygdala although markedly increased this index in the shell of the nucleus accumbens and cingulated cortex (Miyata et al., 2005). Imipramine injected daily for five consecutive days failed to effect on the central and medial amygdaloid nuclei while decreased c-Fos expression in the basolateral amygdala and hippocampal CA1 and CA3 fields (Nguyen et al., 2017).

In the majority of the experimental studies that examined the effect of antidepressants on c-Fos-related neuronal activation, an acute or short-term administration of the drug was employed. Meanwhile, the possibility of these studies to characterize the neuroanatomical targets for anti-depressive medication is questionable. Indeed, antidepressants typically require weeks of continued administration before they achieve a therapeutic effect (Gelenberg and Chesen, 2000; Posternak and Zimmerman, 2005). Given this, the results of the acute or short-term administration can incorrectly point to the therapeutic targets. This is supported by the study of Veening and co-authors, where substantionally different patterns of brain c-Fos expression were found in rats after single and 13-days administration of the conventional antidepressant fluvoxamine (Veening et al., 1998).

To identify the neuroanatomical targets for long-term administration of antidepressants, we studied the influence of the 21-day drug exposure on c-Fos expression in thirty rat brain areas. In our experiments, the structures reportedly involved in the antidepressant-induced alteration of c-Fos expression, were examined. Conventional antidepressants from different classes - imipramine (a norepinephrine and serotonin reuptake inhibitor), reboxetine (a norepinephrine reuptake inhibitor), fluoxetine (a serotonin reuptake inhibitor), bupropion (a norepinephrine and dopamine reuptake inhibitor), mirtazapine (an antagonist at the central presynaptic α2 adrenergic receptors), agomelatine (an agonist at melatonin MT1 and MT2 receptors), and phenelzine (a monoamine oxidase inhibitor) - were tested.

Section snippets

Animals and housing

A total of three hundred and twenty male Wistar rats weighing 280–300 g at the time of testing, were included in the experiments. The animals were housed four per cage in a well-ventilated colony room having a 12 -h light/dark cycle (lights on at 7:00 AM) and temperature of 22 °C. The animals received standard laboratory rat chow and tap water ad libitum. The rats were adapted to these conditions for a minimum of two weeks before the experiments. For carrying out the experiments, the animals

Behavioral action of the drugs

All the drugs produced marked behavioral effects in the FST. In the animals treated with IMI, RBX, FLX, BPR, MRZ, AGM, and PNZ, the mean immobility time (in seconds) was, respectively, 113 (106; 130), 108 (96; 118), 96 (86; 105), 122 (104; 143), 126 (107; 134), 112 (98; 120), and 138 (120; 145) vs 176 (164; 188) in the vehicle-treated control. The duration of immobility in the antidepressant-treated animals significantly differed from that in the control group, U8,8-values = 1, 0, 0, 2, 3.5, 0,

Discussion

Thus, it was found here that the seven antidepressants of different chemical classes, when injected to rats, activate the parahippocampal lateral entorhinal cortex (LEntCx) and hippocampal dorsal subiculum (dSUB) (Table 2). The activation was produced by the relatively long-term treatment which is typically required for clinical benefit of antidepressants (Gelenberg and Chesen, 2000; Posternak and Zimmerman, 2005). These findings suggest a causative role of the LEntCx and dSUB stimulation in

Declaration of Competing Interest

None.

Acknowledgments

I.D.I. is indebted to his long-standing mentors, Prof. Igor Efimovich Kovalev and Prof. Lev Aramovich Piruzyan. Technical support of this research by “Timpharm Ltd.” (Moscow, Russia) is highly appreciated. The study was supported by the Ministry of Science and Higher Education of the Russian Federation (project АААА-А18-118012390247-0).

References (37)

  • J.P. Rénéric et al.

    In the rat forced swimming test, NA-system mediated interactions may prevent the 5-HT properties of some subacute antidepressant treatments being expressed

    Eur. Neuropsychopharmacol.

    (2002)
  • J.G. Veening et al.

    Patterns of c-fos expression induced by fluvoxamine are different after acute vs. chronic oral administration

    Eur. Neuropsychopharmacol.

    (1998)
  • R.A. Augustine et al.

    Quantitation of prolactin receptor mRNA in the maternal rat brain during pregnancy and lactation

    J. Mol. Endocrinol.

    (2003)
  • M. Ballmaier et al.

    Hippocampal morphology and distinguishing late-onset from early-onset elderly depression

    Am. J. Psychiatry

    (2008)
  • M. Bourin et al.

    Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin receptors

    J. Psychiatry Neurosci.

    (2004)
  • E.H. Chang et al.

    Neurophysiological correlates of object recognition in the dorsal subiculum

    Front. Behav. Neurosci.

    (2012)
  • K.R. Connolly et al.

    Emerging drugs for major depressive disorder

    Expert Opin. Emerg. Drugs

    (2012)
  • A.J. Gelenberg et al.

    How fast are antidepressants?

    J. Clin. Psychiatry

    (2000)
  • Cited by (0)

    View full text