Research report5-HT1B mRNA expression after chronic social stress
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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