Antidepressants upregulate c-Fos expression in the lateral entorhinal cortex and hippocampal dorsal subiculum: Study in rats
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.
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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)
- et al.
Recall and recognition memory deficits in depression
J. Affect. Disord.
(1992) - et al.
Contextual recognition memory deficits in major depression are suppressed by cognitive support at encoding
Biol. Psychol.
(2012) - et al.
A magnetic resonance imaging study of the entorhinal cortex in treatment-resistant depression
Psychiatry Res.
(2008) - et al.
Spatial memory, habituation, and reactions to spatial and nonspatial changes in rats with selective lesions of the hippocampus, the entorhinal cortex or the subiculum
Behav. Brain Res.
(1998) - et al.
Responses of rat subicular neurons to convergent stimulation of lateral entorhinal cortex and CA1 in vivo
Brain Res.
(2000) - et al.
Contrasting regional Fos expression in adolescent and young adult rats following acute administration of the antidepressant paroxetine
Brain Res. Bull.
(2016) - et al.
A mixed glucocorticoid/mineralocorticoid receptor modulator dampens endocrine and hippocampal stress responsivity in male rats
Physiol. Behav.
(2017) Isolated removal of hypothalamic or other brain nuclei of the rat
Brain Res.
(1973)- et al.
Behavioural despair in rats: a new model sensitive to antidepressant treatments
Eur. J. Pharmacol.
(1978) - et al.
Recognition memory for pictorial material in subclinical depression
Acta Psychol. (Amst.)
(2010)