Cortical 5-HT1A receptor downregulation by antidepressants in rat brain

Srinivas, B. N.; Subhash, M. N.; Vinod, K. Yaragudri

doi:10.1016/s0197-0186(00)00123-6

Cited by 25 publications

(9 citation statements)

References 33 publications

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“…In addition, it has been shown in vitro that these drugs, independently and selectively, act as agonists and antagonists at receptors for a variety of neurotransmitters and neurohormones [26,27]. For example, TCAs have moderate to high affinity for 5-HT 1A [15,26], muscarinic, cholinergic, and histaminergic receptors, and SSRIs have high affinity for at least four 5-HT receptor subtypes [14,27]. It is a possibility that the drugs ''on board'' might interfere in the binding assay and thus reduce the binding sites for [ 3 H]paroxetine.…”

Section: Discussionmentioning

confidence: 99%

“…In this study we have used radioligand binding technique using a ligand with very high affinity to study the density of SERT. Comparative efficacies of various ADs on 5-HT receptors and adrenergic receptor subtypes have been already studied and selective up-regulation of cortical receptors has been reported earlier [14,15]. However, the comparative effects of TCAs, and SSRIs have not been studied.…”

Section: Introductionmentioning

confidence: 99%

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In vivo Effect of Antidepressants on [3H]paroxetine Binding to Serotonin Transporters in Rat Brain

Nadgir

Malviya

2008

Neurochem Res

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Amine transporters are major target for development of various pharmacological agents to treat behavioral disorders. Serotonin transporters (SERT) have been implicated in the etiology of depression and drugs acting on SERT can be effective in treating depression. The aim of the present study was to study the in vivo effect of various antidepressants on [(3)H]paroxetine binding to SERT in regions of rat brain. Rats were treated with tricyclic antidepressant (TCAs) such as amitriptyline (AMI), serotonin/norepinephrine reuptake inhibitor (SNRIs) such as clomipramine (CMI), and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) and citalopram (CIT) (10 mg/kg body wt.) for 30 days. Density of SERT was measured in cortex and hippocampus using [(3)H]paroxetine (0.03-1.0 nM) in presence and absence of 10 muM fluoxetine as displacer. It was observed that the density of cortical SERT was significantly decreased with CMI (68%, P < 0.0001), FLX (67%, P < 0.0001), CIT (54%, P < 0.0001), and AMI (52%, P < 0.0001) treatment, when compared to the density of 120.7 +/- 4.0 fmol/mg protein in control rats, without altering the affinity (Kd) of [(3)H]paroxetine to the transporters. The density of SERT in hippocampus was also significantly decreased with FLX (65%, P < 0.0001), CMI (54%, P < 0.0001), CIT (52%, P < 0.0001) and AMI (46%, P < 0.0001) treatment, when compared to the density of 74.0 +/- 2.6 fmol/mg protein in control rats, without altering the affinity of [(3)H]paroxetine to the transporters. Displacement study showed high affinity for CMI > CIT > FLX. The results suggest that chronic antidepressant treatment significantly down-regulates both cortical and hippocampal SERT in rat brain and SSRIs have high affinity for SERT than TCAs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In vivo Effect of Antidepressants on [3H]paroxetine Binding to Serotonin Transporters in Rat Brain

Nadgir

Malviya

2008

Neurochem Res

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“…Chronic stress and antidepressant treatment, which produce opposite changes in positively motivated behavior, have been shown also to produce a series of opposing changes in receptor and neuronal function in this system. These effects which include alterations in α 1 -adrenergic (Maj and Rogóz, 1999), 5HT1 (Ossowska et al, 2001;Srinivas et al, 2001), 5HT2A (Ossowska et al, 2001;Esposito, 2006), D1 (Ossowska et al, 2001;Huzarska et al, 2006), D2 (D'Aquila et al, 2000), GR and MR (Holsboer, 2001;Schule, 2007) as well as in neurotrophin release (Duman and Monteggia, 2006) and neuronal morphology McEwen, 2003). These multiple correlated effects appear to be the results of a combination of factors including altered neurotransmitter, cytokine, corticosteroid and neurotrophin release (Duman and Monteggia, 2006;Bisagno et al, 2000;McEwen, 2000).…”

Section: ) Positive Motivational Networkmentioning

confidence: 99%

A final common pathway for depression? Progress toward a general conceptual framework

Stone

Yang

Quartermain

2008

Neuroscience & Biobehavioral Reviews

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Functional neuroimaging studies of depressed patients have converged with functional brain mapping studies of depressed animals in showing that depression is accompanied by a hypoactivity of brain regions involved in positively motivated behavior together with a hyperactivity in regions involved in stress responses. Both sets of changes are reversed by diverse antidepressant treatments. It has been proposed that this neural pattern underlies the symptoms common to most forms of the depression, which are the loss of positively motivated behavior and increased stress. The paper discusses how this framework can organize diverse findings ranging from effects of monoamine neurotransmitters, cytokines, corticosteroids and neurotrophins on depression. The hypothesis leads to new insights concerning the relationship between the prolonged inactivity of the positive motivational network during a depressive episode and the loss of neurotrophic support, the potential antidepressant action of corticosteroid treatment, and to the key question of whether antidepressants act by inhibiting the activity of the stress network or by enhancing the activity of the positive motivational system. Keywords depression; neuroimaging; fos; final common pathway; cytokines; corticosteroids; monoamines; neurotrophins; theory The quest for a final common pathway has long been goal of research in depression. Famous candidates in this search have included dysregulated brain monoamines (Schildkraut, 1965;

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“…A down regulation of 5-HT 1A receptors has been proposed as a general hypothesis of alteration in 5-HT receptor function in subjects with depressive symptoms (Blier and de Montigny, 1994; Srinivas et al 2001), as well as the possible involvement of other 5-HT receptors ( e.g., 5HT 2 , Stahl, 1994). Further, many clinical and preclinical studies have reported a down regulation of 5-HT 1A and 5-HT 2 sites with antidepressant treatments ( e.g., Stahl, 1994, Celada et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

A genetic rat model of depression, Flinders sensitive line, has a lower density of 5-HT1A receptors, but a higher density of 5-HT1B receptors, compared to control rats

Nishi

Kanemaru

Dikšić

2009

Neurochemistry International

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Deficiencies in brain serotonergic neurotransmission, which is in part associated with the alteration of brain serotonin (5-HT) receptors, have been proposed as part of a neurochemical imbalance in affective disorders, including depression. The drugs used for the treatment of these disorders generally act through and/or on the serotonergic system. Different animal models of depression have provided researchers with tools to obtain a better understanding of drug actions and possibilities to obtain insight into the neurochemical bases of these disorders. The measurements of the 5-HT 1A and 5-HT 1B receptor densities in a rat model of depression, Flinders Sensitive Line (FSL) rats, and comparisons with Sprague-Dawley (SPD) and Flinders Resistant Line (FRL) rats, are reported here. The receptor sites were quantified by autoradiography in more than twenty-five distinct brain regions known to have relatively large densities of respective sites. Some brain regions (e.g., dental gyrus, septal nucleus) were divided into several parts, according to previously known subdivisions, because of a substantial heterogeneity of these receptors. The densities in the FSL rats ("depressed" rats) were compared statistically to those in the SPD rats. In addition, comparisons were made to the densities in the FRL rats (rats not showing depressive symptoms). Comparisons were performed with the SPD and FRL rats because both of these strains have been used as control animals in studies of FSL rats. The results show that the densities of 5-HT 1A receptors are not significantly different between the FSL and SPD rats, but they are significantly different from the FRL rats. 5-HT 1A receptor density is significantly higher in the FRL rats than the SPD rats. The 5-HT 1B receptors were significantly greater in the FSL rats than in either the SPD or FRL rats. In addition, the FRL rats have 5-HT 1B receptor densities significantly lower in many brain regions than the SPD rats. The data presented here, in addition to previously reported differences in regional synthesis between these strains and the effect of acute citalopram on synthesis, suggest that SPD rats are likely a more appropriate control than FRL rats, when studies of FSL rats are performed with drugs acting directly or indirectly on, or through, the brain serotonergic system. However, comparisons, particularly of neurochemical and/ or biological parameters in FRL rats, may reveal new insight into the alterations of 5-HT neurotransmission in this animal model of depression and possibly human depression, as well as the elevation of symptoms with treatments. The data also suggest that there could be a different fraction 3Correspondence to:

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Cortical 5-HT1A receptor downregulation by antidepressants in rat brain

Cited by 25 publications

References 33 publications

In vivo Effect of Antidepressants on [3H]paroxetine Binding to Serotonin Transporters in Rat Brain

In vivo Effect of Antidepressants on [3H]paroxetine Binding to Serotonin Transporters in Rat Brain

A final common pathway for depression? Progress toward a general conceptual framework

A genetic rat model of depression, Flinders sensitive line, has a lower density of 5-HT1A receptors, but a higher density of 5-HT1B receptors, compared to control rats

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