Elsevier

Behavioural Brain Research

Volume 224, Issue 2, 31 October 2011, Pages 350-357
Behavioural Brain Research

Research report
5-HT1B mRNA expression after chronic social stress

https://doi.org/10.1016/j.bbr.2011.06.016Get rights and content

Abstract

Chronic stress contributes to vulnerability for depression and drug addiction. The function of the serotonergic system has been found to be modified by chronic stress and these changes may play an important role in stress-related relapses to drug craving. The 5-HT1B receptor is expressed in nucleus accumbens (NAc) projection neurons and modulates drug reward mechanisms and there is evidence suggesting that stress alters the regulation and function of these receptors. To examine the role of these receptors in integrating the effects of stress on reward mechanisms, we examined whether chronic or acute social defeat stress (SDS) regulates 5-HT1B mRNA in dorsal and ventral striatum, regions that are critical for integrating the effects of environmental stressors on reward motivated behavior. In addition, 5-HT1B mRNA regulation in response to another acute stressor, inescapable tailshock, was measured. Our results indicate that intermittent and daily SDS procedures attenuated body weight gain, induced adrenal hypertrophy, and reduced the preference for saccharin, a sweet solution preferred by normal rats. There was a trend for daily, but not intermittent SDS to increase 5-HT1B receptor mRNA levels in nucleus accumbens. Therefore, in the next experiment, we examined daily SDS in greater detail and found that it increased 5-HT1B receptor mRNA expression in rostral nucleus accumbens shell, an area especially associated with reward functions. Neither acute SDS, nor acute tailshock stress had a significant impact on 5-HT1B mRNA expression in the striatum. Since increased 5-HT1B receptor expression in nucleus accumbens shell neurons can facilitate cocaine and alcohol reward mechanisms, this adaptation in endogenous 5-HT1B mRNA may be involved in the SDS-associated increase in vulnerability for developing addiction.

Highlights

► Chronic social defeat induces hedonic deficits. ► Chronic social defeat upregulates 5-HT1B receptor mRNA expression in the NAcSh. ► 5-HT1B mRNA is regulated by stress along a rostral–caudal gradient.

Introduction

Certain types of chronic stress can exacerbate the course of mood disorders [1] and contribute to the vulnerability to initiate drug abuse or trigger relapse [2], [3]. Altered hedonic response to natural rewards is a core feature of both mood disorders and drug addiction, and may be an important interface between stress response and reward mechanisms in the brain [4]. The mesocorticolimbic reward pathway is critical in assessing reward (but see [5]), and plasticity in this circuit may contribute to stress-induced anhedonia as well as adaptations related to drug use [4]. Hedonic deficits induced by chronic stress can be detected in the form of decreased preference for a sweet solution [6], [7]; this index of anhedonia can be reversed by antidepressant treatment [8], [9], [10].

The mesocorticolimbic circuit for assessing and responding to reward includes the nucleus accumbens (NAc) in the ventral striatum, the dorsal striatum, the ventral tegmental area (VTA) and the medial prefrontal cortex. These regions have also been implicated in certain types of stress, the symptomatology of depression [4], and drug abuse [11]; manipulations of the NAc can produce both pro-depressive and antidepressant effects [4], [12], [13]. Serotonin is a key modulator of stress responses and reward function [14], [15], and several lines of evidence implicate the serotonin-1B (5-HT1B) receptor in NAc neurons as an important mediator of drug and stress adaptations in reward-related behavior. In the NAc shell (NAcSh), 5-HT1B receptors are expressed in medium spiny neurons and are located on axon terminals in targets such as the VTA where they inhibit GABA release [16], [17], [18]. These projections to VTA provide inhibitory feedback that reduces subsequent release of dopamine from VTA projections back to NAc [19], [20]; therefore, activation of these 5-HT1B receptors disinhibits dopaminergic function. Available evidence suggests that acute cocaine exposure (both contingent and noncontingent) regulates 5-HT1B mRNA in these neurons, and increased 5-HT1B expression in these neurons enhances a variety of behavioral responses to cocaine, alcohol, and amphetamine [21], [22], [23], [24]. There is also evidence that stress regulates these 5-HT1B receptors, but the evidence is less clear [22], [25], [26].

Given the link between hedonic state, reward, stress, and serotonin, it is possible that 5-HT1B receptors in the mesocorticolimbic reward pathway are critical modulators of hedonic state that are regulated by stress and drug experiences and in turn modulate hedonic and drug reward mechanisms. To begin to tease apart the different aspects of these relationships, we have examined the impact of two well-established stress models in rats, social defeat and inescapable tail shock, on 5-HT1B mRNA expression and hedonic behavior. Therefore, we wanted to examine the effect of stress in the absence of cocaine exposure to assess its role in regulating 5-HT1B mRNA expression in the striatum. We used the social defeat model as a chronic and acute stressor, as it is a well-established and reliable method of examining the effects of chronic stress on hedonic and drug addiction mechanisms. For example, it induces anhedonic behavior in the sucrose preference test [7], increases sensitization to psychostimulants, and escalates cocaine self-administration [27], [28]. Additionally, we used acute inescapable tail shock because it has been shown to be a reliable and reproducible method of eliciting stress-induced anhedonia (i.e., decreased consumption of sucrose solution) [29], increases immediate early gene expression in serotonergic neurons [30], and has been shown to facilitate drug–induced dopamine efflux in NAcSh [31]. Our over-riding hypothesis is that stress exposure increases 5-HT1B mRNA expression in the ventral striatum as a compensatory adaptation to hedonic challenges, but that this increases the rewarding effects of drugs and thereby accelerates the progression of addiction. The hypothesis for the current set of studies is that chronic stress increases expression of 5-HT1B mRNA in the ventral striatum. We will investigate 5-HT1B mRNA regulation along the full extent of the striatum. Our rationale for a rostral–caudal investigation is supported by previous studies that have shown that activating GABA receptors along the rostral–caudal gradient of the NAc elicits behavioral outcomes, in terms of hedonic response [32]. Studies investigating behavioral drug response have also implicated rostral–caudal differences in drug mechanisms [33], [34], [35].

Section snippets

Subjects

Male Sprague Dawley rats (250–275 g) were two months old at the time of delivery into the animal facility and were used in experiments after a one week acclimation period. Male (375–425 g) and female (8 weeks old) Long–Evans rats were used as stimulus animals (i.e. resident pairs) only; no dependent measures were collected from these animals. All rats were procured from Harlan Laboratories (Indianapolis, IN). Experimental animals (Sprague Dawley) were individually housed; resident stimulus

Experiment 1

The purpose of this experiment was to determine the impact of social defeat stress frequency on hedonic state and the expression of 5-HT1B receptors in the mesolimbic reward pathway. Both chronic and intermittent social defeat decreased the rate of body weight gain (Fig. 2), consistent with other chronic stress paradigms [42], [43], [44]. There was a main effect of group (F2,208 = 4.46, p < 0.05), day (F10,208 = 332.38, p < 0.001), and an interaction between group and day (F20,208 = 2.75, p < 0.001) on

Discussion

Social defeat is a potent and ethologically relevant stressor that can interfere with normal hedonic state and increase susceptibility to the rewarding effects of drugs of abuse [6]. Since previous data from this and other laboratories suggest that certain types of stressors, such as needle poke, social stress, and cocaine withdrawal may modulate 5-HT1B receptor expression in NAc [22], [25], [26], and activation of 5-HT1B receptors in the mesocorticolimbic circuit increases the rewarding

Acknowledgements

This work was supported by grants from NIDA 5F32DA026265 (ARF) and 5R01DA016432 (JFN).

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