Elsevier

Brain Research

Volume 976, Issue 1, 20 June 2003, Pages 22-29
Brain Research

Research report
The effects of antidepressant treatment on serotonergic and dopaminergic systems in Fawn–Hooded rats: a quantitative autoradiography study

https://doi.org/10.1016/S0006-8993(03)02598-8Get rights and content

Abstract

Fawn–Hooded (FH) rats exhibit a phenotype including depressive behaviour and high alcohol preference, and as such tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) reduce alcohol consumption in this rat strain [Psychiatr. Genet. 12 (2002) 1–16]. However, the neurochemical effects of these antidepressants on monoamine systems in the brain, especially in mesolimbic areas have not been studied in FH rats. Therefore, the present study investigated neurochemical effects of subchronic treatment (10 days) with desipramine (DMI) and sertraline on several neurochemical markers of serotonin and dopamine systems. Binding to these markers including dopamine transporters (DATs), 5-HT transporters (SERTs), 5-HT1A- and 5-HT2A-receptors in rat brain sections was performed by quantitative autoradiography. The findings from the present study revealed that DMI and sertraline exhibited differential effects on SERTs and DATs in FH rat brain. For example, DMI caused a dramatic up-regulation of DATs whereas sertraline had no effect on DAT binding. In addition, both antidepressants showed some common and some differential effects on the binding to 5-HT1A- and 5-HT2A-receptors dependent upon region. These data demonstrate that DMI and sertraline differentially effect serotonergic and dopaminergic systems in mesolimbic regions in FH rats, suggesting that there may be different neurochemical mechanisms underlying their efficacy to reduce ethanol consumption in this animal model.

Introduction

Antidepressants such as tricyclic antidepressants (TCAs) and selective serotonin re-uptake inhibitors (SSRIs) have been used to reduce ethanol consumption in animals [23] and certain groups of human alcoholics [27]. However, the neurochemical mechanism(s) of action in this respect, for example, whether, and how neurotransmitter systems in mesolimbic regions are affected by antidepressants, remain to be fully elucidated. Similar to many abused drugs, ethanol may be consumed due to its reinforcing effect on the brain mesolimbic dopamine system via influencing endogenous neurotransmitter systems [16]. Neuroanatomically, the mesolimbic system mainly contains dopaminergic afferents innervating the nucleus accumbens (NAcc) from the ventral tegmental area (VTA) [16], which can be regulated or modulated by many neurotransmitters such as serotonin (5-HT) and endogenous opioids [5], [8] or affected by exogenous agents such as abused drugs including cocaine or ethanol [11], [40]. Therefore, the efficacy of antidepressants in treatment of ethanol consumption in human alcoholics or animal models suggests a possible influence of antidepressants on the mesolimbic system.

Emerging evidence suggests that alteration of neurotransmitter systems in mesolimbic areas is found in both depression and alcoholism [21] and the efficacy of antidepressants in both situations may support this hypothesis. For example, Fawn–Hooded (FH) rats, a strain of rat characterized with a phenotype of depression and high alcohol preference [34], have neurochemical alterations of the 5-HT system such as an increased density of serotonin transporters (SERTs) in some mesolimbic regions compared to alcohol non-preferring rats [7], [9]. In addition, volitional consumption of ethanol by FH rats could be attenuated by pharmacological intervention with antidepressants [33]. As such, we hypothesize that antidepressants in vivo may affect either mesolimbic dopaminergic or serotonergic transmission directly (interaction) or indirectly (adaptation). Therefore, desipramine (DMI), a TCA and sertraline, an SSRI were selected in the present study. A neurochemical study of dopaminergic and serotonergic markers in brain regions of rats was performed in FH rats subjected to 10 days drug treatment with DMI, sertraline or vehicle. By quantitative autoradiographic analysis, the distribution and densities of dopamine transporters (DATs), 5-HT transporters (SERTs), 5-HT1A- and 5-HT2A-receptors in reward-related areas were investigated.

Section snippets

Materials

All experiments described herein were performed in accordance with the Prevention of Cruelty to Animals Act 1986 under the guidance of the Code of Practice for the Care and Use of Animals for Experimental Purposes in Australia.

Male FH rats (300–400 g) were bred at Central Animal Services, Monash University, the parental stocks came from the University of North Carolina, Chapel Hill, NC (USA). All rats were housed in groups of three or four in a temperature-controlled room (22±1 °C) that was

Effects of antidepressants on SERT density

Representative autoradiograms show the binding of [3H]citalopram at the level of the NAcc in brain sections of FH rats treated with DMI (Fig. 1, panel A2) or vehicle (Fig. 1, panel A1). Binding of [3H]citalopram to numerous regions was significantly elevated by DMI treatment (Table 1), for example, by +30% in the caudate-putamen (CPu), +18% in frontal and parietal cortex [Cx (FP)] and +15% in the anterior medial forebrain bundle (mfba), respectively. However, in the present study, all brain

Discussion

The present study represents the first characterisation of the effects of antidepressant treatment on several neurochemical markers of serotonin and dopamine systems in reward-related brain nuclei of FH rats. Not surprisingly, DMI and sertraline displayed different neurochemical effects in mesolimbic regions. For example, [3H]citalopram binding to SERTs was undetectable in all tested brain regions in sertraline-treated rats confirming a complete blockade of SERTs under the present treatment

Acknowledgments

This study was part of F.C.’s Ph.D. work supported by Monash Graduate Scholarship, Australia and the Australia Brewers’ Foundation. A.J.L. is a Senior Research Fellow of National Health & Medical Research Council, Australia. Fawn–Hooded rat parental stocks were kindly supplied from Dr. Amir H. Rezvani at Duke University Medical Center, North Carolina, USA. Sertraline was a gift from Pfizer.

References (41)

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