The neural link between ostensibly aversive stress experiences and intensely rewarding drug taking remains to be delineated. Epidemiological data associate stress and the abuse of various drugs, and experimental data identify the conditions that determine how episodic social stress intensifies the motivation for cocaine and the actual self-administration of cocaine. Two types of social stress have been the focus of experimental study in Long-Evans rats, since they engender divergent changes in drug- or sugar-rewarded behavior and in neuroadaptation. Episodic social defeat stress consists of four brief confrontations between the experimental rat and an aggressive resident rat of the Long-Evans strain over the course of 10 days. Subordination stress involves the continuous exposure to an aggressive resident for five weeks, while living in a protective cage within the resident’s home cage with brief daily confrontations. These stress experiences result in 1) increased intravenous cocaine self-administration under a fixed ratio schedule with prolonged binge-like access in episodically defeated intruder rats, but suppressed cocaine intake by continuously subordinate rats; 2) deteriorated sugar preference and intake and decreased exploratory behavior in subordinate, but not intermittently defeated, rats; 3) a sensitized dopamine (DA) response in the n. accumbens via in vivo microdialysis and increased tegmental BDNF in episodically defeated rats, whereas the continuously subordinate rats show suppression of the DA and BDNF responses. These divergent neuroadaptations to social stress may represent the substrates for the intensification of cocaine “bingeing” relative to the anhedonia-like deterioration of reward processes during subordination stress.
Social defeat stress is an ethologically salient stressor which activates dopaminergic areas and, when experienced repeatedly, has long-term effects on dopaminergic function and related behavior. The mechanism for these long-lasting consequences remains unclear. A potential candidate for mediating these effects is brain-derived neurotrophic factor (BDNF), a neurotrophin involved in synaptic plasticity and displaying alterations in dopaminergic regions in response to various types of stress. In this study, we sought to determine whether repeated social defeat stress altered BDNF mRNA and protein expression in dopaminergic brain regions either immediately after the last stress exposure or four weeks later. Male Sprague-Dawley rats were subjected to social defeat stress consisting of brief confrontation with an aggressive male rat every third day for 10 days; control rats were handled according to the same schedule. Animals were euthanized either 2 h or 28 days after the last stress or handling episode. Our results show that 2 h after stress, BDNF protein and mRNA expression increased in the medial prefrontal cortex. At this time-point, BDNF mRNA increased in the amygdala and protein expression increased in the substantia nigra. Twenty-eight days after stress, BDNF protein and mRNA expression were elevated in the medial amygdala and ventral tegmental area. Given the role of BDNF in neural plasticity, BDNF alterations that are long-lasting may be significant for neural adaptations to social stress. The dynamic nature of BDNF expression in dopaminergic brain regions in response to repeated social stress may therefore have implications for lasting neurochemical and behavioral changes related to dopaminergic function.
KeywordsMesolimbic; ventral tegmental area; prefrontal cortex; amygdala; dopamine; neurotrophin Social defeat stress is an ethologically salient stressor which provides a relevant model to investigate the etiology of stress-related disorders in humans (Koolhaas et al., 1997;Koolhaas et al., 1999 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. is sufficient to alter behaviors such as exploratory activity and sensitivity to other stressors for several weeks (Koolhaas et al., 1999).
NIH Public AccessVarious types of stressors can dramatically alter neurochemistry specifically within the mesocorticolimbic dopamine circuit (Fadda et al., 1978;Dunn and File, 1983;Deutch et al., 1985;Louilot et al., 1986;Abercrombie et al., 1989;Imperato et al., 1992;Tidey and Miczek, 1996;Nikulina et al., 1998Nikulina et al., , 2001Bland et al., 2005;, which mediates general rewa...
Social stress can engender behavioral and neural sensitization and this process appears to enhance the transition to compulsive drug abuse. Exposures to brief social defeat stress in rats have significant consequences on cocaine-reinforced behavior and on the level of functional activation within regions of the mesocorticolimbic dopamine system. The objectives of the current study were to examine the enduring consequences of brief episodes of social defeat stress on cocaine bingeing (during 24 h of continuous access) and on the emergence of neural adaptations as revealed by zif268 immediate early gene expression. Adult, male Long-Evans rats were subjected to four 25 min episodes of social defeat (once every 72 h). After 2 months, cocaine binges or zif268 mRNA gene expression were studied after confirming behavioral cross-sensitization to stimulant challenge. Sensitization to social defeat increased cocaine intake during a 24 h binge, effectively abolishing the typical circadian pattern of intake. Furthermore, 60 days after exposure to the sensitizing regimen of social defeat, levels of functional activation, measured by zif268 mRNA expression, in the central and medial amygdala were increased, while levels of activation in the medial prefrontal cortex were decreased. Persistent stress-induced levels of zif268 in the central and medial amygdala were attenuated by an injection of amphetamine (1.0 mg/kg). Divergent changes in zif268 within the amygdala and cortex 2 months after social defeat stress indicate the vulnerability of distinct cellular populations in networks that modulate the behavioral actions of psychomotor stimulants.
Zolmitriptan proved to be an effective and behaviorally specific anti-aggressive agent in situations that engender moderate and alcohol-heightened levels of aggression. These effects are potentially due to activation of post-synaptic 5-HT1BD receptors.
Intermittent social defeat stress exposure augments behavioral response to psychostimulants in a process termed cross-sensitization. Brain-derived neurotrophic factor (BDNF) mediates synaptic plasticity and cellular responses to stress and drugs of abuse. We previously showed that repeated social defeat stress persistently alters BDNF and activates ΔFosB expression in mesocorticolimbic regions. Here, we hypothesized that social defeat stress would increase ΔFosB expression in BDNF-containing mesocorticolimbic neurons at a time when cross-sensitization is evident. Because the ventral tegmental area (VTA) is critical for cross-sensitization, we similarly hypothesized that repeated social defeat stress would induce ΔFosB in neurons of mesocorticolimbic terminal regions that innervate the VTA. We induced social defeat stress in rats by short confrontations with an aggressive resident rat every third day for 10 days. Control rats were handled according to the same schedule. Defeated rats exhibited sensitized locomotor response to amphetamine (1.0 mg/kg, i.p.) 10 days after termination of stress exposure. Separate rats, which underwent stress procedures without amphetamine challenge, were used for histological assessments. Rats received intra-VTA infusion of the retrograde tracer, Fluorogold, and brain tissue was collected 10 days after stress or handling for immunhistochemistry. Stress exposure increased BDNF immunoreactivity in anterior cingulate, prelimbic and infralimbic regions of the prefrontal cortex, medial amygdala, nucleus accumbens and VTA; ΔFosB labeling in anterior cingulate cortex and nucleus accumbens; and ΔFosB/BDNF co-expression in prelimbic cortex, nucleus accumbens and medial amygdala. Infralimbic ΔFosB-labeling was enhanced by stress in neurons innervating the VTA. Increased ΔFosB/BDNF co-expression and persistent functional activation of corticolimbic neurons after stress may contribute to mechanisms underlying cross-sensitization to psychostimulants.
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