Swim Stress Research Articles

Daily administration of Sake Lees (Sake Kasu) reduced psychophysical stress-induced hyperalgesia and Fos responses in the lumbar spinal dorsal horn evoked by noxious stimulation to the hindpaw in the rats.

We tested whether Sake Lees (SL) had inhibitory effects on hyperalgesia in the hindpaw under psychophysical stress conditions. Male rats were subjected to repeated forced swim stress treatments (FST) from Day -3 to Day -1. Intraperiotoneal administration of SL which contained low concentration of ethanol (SLX) was conducted after each FST. On Day 0, formalin-evoked licking behaviors and Fos responses in the lumbar spinal cord (DH) and several areas within the rostral ventromedial medulla (RVM) were quantified as nociceptive responses. FST-induced hyperalgesia in the hindpaw was prevented by repeated SL and SLX treatments. Fos expression was significantly increased in DH and some areas within the RVM under FST, which was prevented by repeated SL or SLX. These findings indicated that daily administration of SL had the potential to alleviate stress-induced hyperalgesia.

Unexpected effects of metyrapone on corticosteroid receptor interaction with the genome and subsequent gene transcription in the hippocampus of male rats.

Glucocorticoid hormones (GCs) play a pivotal role in many stress-related biological processes. In the hippocampus, GCs act through mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) to modify gene transcription. The involvement of GCs in biological processes has been investigated using the corticosterone (CORT)-synthesis blocker metyrapone. How metyrapone affects the action of GC at the genomic level still remains unclear. Therefore, we investigated the effects of this enzyme blocker on plasma CORT levels and hippocampal MR and GR binding to GC responsive elements (GREs) within the GC target genes Fkbp5 (FK506-binding protein 5), Per1 (Period 1) and Sgk1 (Serum- and glucocorticoid-activated kinase 1), as well as the transcriptional responses of these genes under control and acute stress conditions in rats. For comparison, we also investigated these endpoints in rats that had undergone adrenalectomy (ADX). Although metyrapone had no effect on baseline levels of CORT, the drug increased MR and GR to GRE binding within the GC target genes and the transcriptional activity of these genes. As expected, acute forced swim (FS) stress strongly increased plasma CORT levels, hippocampal MR and GR to GRE binding within Fkbp5, Per1 and Sgk1, and the transcriptional activity (mainly hnRNA levels) of these genes. Metyrapone attenuated, but did not abolish, these effects of stress on plasma CORT and MR and GR to GRE binding. The drug effects on FS-induced transcriptional activity were gene-dependent with a reduction seen in Fkbp5 hnRNA (but not Fkbp5 mRNA), an enhancement in Per1 hnRNA (but not Per1 mRNA), and no effect on both Sgk1 hnRNA and mRNA levels. ADX however completely abrogated the effects of FS on plasma CORT, as well as hippocampal MR and GR to GRE binding and transcriptional responses. Thus, in contrast to ADX, metyrapone produced inconsistent effects on GC-sensitive genomic endpoints that question its suitability as a tool in neuroendocrine and other research.

Pharmacological In vivo test to evaluate the antidepressant activity of polyherbal formulation

The antidepressant effects of the polyherbal formulation (PF) (contain four extracts of medicinal plants namely: Nyctanthes arbortristis, Hippophae salcifolia, Ocimum tenuiflorum and Withania somnifera ) was examined by evaluating the extent of reduction of behavioural alterations and neurotransmitter in the rats stressed by forced swim test (FST). In the present study, compared with the model control group (FST), the altered behavioural parameters were attenuated significantly (P < 0.05) in the group treated with the PF (100, 200 and 400 mg•kg−1), comparable with the standard drug treated group, Sertraline (10mg•kg−1). The PF and Sertraline significantly (P < 0.05) increased the level of the neurotransmitter such as serotonin, dopamine, acetylcholine and noradrenalin whereas decreased the level of monoamine oxidase along with oxidant in the brain of the stressed rats. PF and Sertraline were also involved in the reduced oxidant and generated antioxidant in the stressed rats. The results indicated that polyherbal formulation exhibited significant antidepressant activity, as indicated by its ability to decrease force swim stress, induced immobility time in rats as well as restoring the biogenic amines to normal level that were altered by the swim induced stress in whole rat brain. Therefore, PF can be a potential candidate for treatment of depression as well as a potent antidepressant. However, further studies are required to substantiate the same.

Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice

Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8 to 10. Pain and depressive-like behavior were measured over 14 days, and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females vs males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. Although low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.

D1- and D2-like receptors in the dentate gyrus region of the hippocampus are involved in the reinstatement induced by a subthreshold dose of morphine and forced swim stress in extinguished morphine-CPP in rats.

Addiction to opioids is an important global problem. Published research has indicated the powerful rewarding effects of drug use, which in the case of opiates like morphine may lead to drug addiction and maladaptive decision making with negative social consequences. In-depth comprehension of the role of responsible mechanisms in addiction can lead us to better and more effective treatments for drug dependence. Continuing previous work in our laboratory, in this study we aimed to investigate the role of dopamine D1- and D2-like receptors in the dentate gyrus (DG) on the reinstatement of drug-seeking behavior induced by the combination of forced swim stress and a subthreshold dose of morphine on extinguished morphine-conditioned place preference in rats. The rats were bilaterally implanted with 2 separate cannulas into the DG region. After the extinction phase of morphine-conditioned place preference, the animals received different doses (0.5, 2, and 4 μg per 0.5 μL vehicle/side) of SCH-23390 or sulpiride on the reinstatement day and were tested for the combination of forced swim stress and a subthreshold dose of morphine in discrete groups. Our findings indicated that D1- and D2-like receptor antagonists attenuated the reinstatement induced by the combination of FSS and the subthreshold dose of morphine. The reduction was more robust in groups of animals that received sulpiride as compared with SCH-23390. Our results showed a role for DG dopamine receptors in relapse to drugs of abuse, the activity of which may be induced by exposure to a stressor like forced swim stress. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

P.127 Alterations in the central opioid system following acute swim stress and olfactory bulbectomy in the rat

As a classic neurotransmitter in the brain, norepinephrine (NE) also is an important modulator to other neuronal systems. Using primary cultures from rat ventral mesencephalon (VM) and dopaminergic cell line MN9D, the present study examined the neuroprotective effects of NE and its effects on the expression of tyrosine hydroxylase (TH). The results showed that NE protected both VM cultures and MN9D cells against 6-hydroxydopamine-caused apoptosis, with possible involvement of adrenal receptors. In addition, treatment with NE upregulated TH protein levels in dose- and time-dependent manner. Further experiments to investigate the potential mechanisms underlying this NE-induced upregulation of TH demonstrated a marked increase in protein levels of the brain-derived neurotrophic factor (BDNF) and the phosphorylated extracellular signal-regulated protein kinase 1 and 2 (pERK1/2) in VM cultures treated with NE. In MN9D cells, a significantly increase of TH and pERK1/2 protein levels were observed after their transfection with BDNF cDNA or exposure to BDNF peptides. Treatment of VM cultures with K252a, an antagonist of the tropomyosin-related kinase B, blocked the upregulatory effects of NE on TH, BDNF and pERK1/2. Administration of MEK1 & MEK2 inhibitors also reversed NE-induced upregulation of TH and pERK1/2. Moreover, ChIP assay showed that treatment with NE or BDNF increased H4 acetylation in the TH promoter. These results suggest that the neuroprotection and modulation of NE on dopaminergic neurons are mediated via BDNF and MAPK/ERK pathways, as well as through epigenetic histone modification, which may have implications for the improvement of therapeutic strategies for Parkinson's disease.

Adolescent forced swim stress increases social anxiety-like behaviors and alters kappa opioid receptor function in the basolateral amygdala of male rats

Adolescence is a developmental period marked by robust neural alterations and heightened vulnerability to stress, a factor that is highly associated with increased risk for emotional processing deficits, such as anxiety. Stress-induced upregulation of the dynorphin/kappa opioid receptor (DYN/KOP) system is thought to, in part, underlie the negative affect associated with stress. The basolateral amygdala (BLA) is a key structure involved in anxiety, and neuromodulatory systems, such as the DYN/KOP system, can 1) regulate BLA neural activity in an age-dependent manner in stress-naïve animals and 2) underlie stress-induced anxiety in adults. However, the role of the DYN/KOP system in modulating stress-induced anxiety in adolescents is unknown. To test this, we examined the impact of an acute, 2-day forced swim stress (FSS – 10 min each day) on adolescent (~postnatal day (P) 35) and adult Sprague-Dawley rats (~P70), followed by behavioral, molecular and electrophysiological assessment 24 h following FSS. Adolescent males, but not adult males or females of either age, demonstrated social anxiety-like behavioral alterations indexed via significantly reduced social investigation and preference when tested 24 h following FSS. Conversely, adult males exhibited increased social preference. While there were no FSS-induced changes in expression of genes related to the DYN/KOP system in the BLA, these behavioral alterations were associated with alterations in BLA KOP function. Specifically, while GABA transmission in BLA pyramidal neurons from non-stressed adolescent males responded variably (potentiated, suppressed, or was unchanged) to the KOP agonist, U69593, U69593 significantly inhibited BLA GABA transmission in the majority of neurons from stressed adolescent males, consistent with the observed anxiogenic phenotype in stressed adolescent males. This is the first study to demonstrate stress-induced alterations in BLA KOP function that may contribute to stress-induced social anxiety in adolescent males. Importantly, these findings provide evidence for potential KOP-dependent mechanisms that may contribute to pathophysiological interactions with subsequent stress challenges.

Lasting Impact of Chronic Adolescent Stress and Glucocorticoid Receptor Selective Modulation in Male and Female Rats

Adolescent animals are vulnerable to the effects of stress on brain development. We hypothesized that long-term effects of adolescent chronic stress are mediated by glucocorticoid receptor (GR) signaling. We used a specific GR modulator (CORT108297) to pharmacologically disrupt GR signaling in adolescent rats during exposure to chronic variable stress (CVS). Male and female rats received 30 mg/kg of drug during a 2-week CVS protocol starting at PND46. Emotional reactivity (open field) and coping behaviors (forced swim test (FST)) were then tested in adulthood, 5 weeks after the end of the CVS protocol. Blood samples were collected two days before FST and serial samples after the onset of the swim test to determine baseline and stress response levels of HPA hormones respectively.Our results support differential behavioral, physiological and stress circuit reactivity to adolescent chronic stress exposure in males and females, with variable involvement of GR signaling. In response to adolescent stress, males had heightened reactivity to novelty and exhibited marked reduction in neuronal excitation following swim stress in adulthood, whereas females developed a passive coping strategy in the FST and enhanced HPA axis stress reactivity. Only the latter effect was attenuated by treatment with the GR modulator C108297. In summary, our data suggest that adolescent stress differentially affects emotional behavior and circuit development in males and females, and that GR manipulation during stress can reverse at least some of these effects.

Comparative Effectiveness of Agmatine and Choline Treatment in Rats with Cognitive Impairment Induced by AlCl3 and Forced Swim Stress

Endogenous agmatine has a significant role in learning and memory processes as a neurotransmitter. Various studies described the physiological role of endogenous agmatine in learning and memory of multiple cognitive tasks suggesting elevated levels of agmatine during the learning process in the rat brain. Dietary intake of choline showed correlation with cognitive functions in human subjects and treatment with choline supplements validated the ability to diminish learning and cognitive impairment dementias. 36 Albino rats were equally divided into three groups previously: a) control-water, b) Test I - AlCl3 (100 mg/Kg body weight), and c) Test II - Forced swim stress (FSS) for 14 days. On the next day of AlCl3 and FSS last administration, animals were allocated into further three groups and received the following treatments: a. water was given orally to the control group, b. Agmatine (100 mg/Kg Body Weight) group, and c. Choline (100 mg/Kg Body Weight) group for the next 14 days. Behaviors were assessed in Light/Dark Box, Open Field, Novel Object Recognition Test (NOR), T Maze Test, and Morris Water Maze Test. Animals administered with agmatine demonstrated increased time spent in bright areas of light/dark box and square crossed while improved spatial memory in Morris water maze and T maze test and enhanced discrimination of novel object in NOR were observed in learning and memory paradigms along with choline. The present study determines that agmatine at the dose of (100 mg/kg body weight) attenuates memory and cognitive impairment in comparison with choline supplements.

Quantitative analysis of Gria1, Gria2, Dlg1 and Dlg4 expression levels in hippocampus following forced swim stress in mice

AMPA receptors and interacting proteins are importantly involved in mediating stress-dependent plasticity. Previously we reported that GluA1-containing AMPA receptors and their interaction with PDZ-proteins are required for the experience-dependent expression of behavioral despair in the forced swim test. However, it is unclear if the expression of GluA1-containing AMPA receptors is affected by this type of behavior. Here we investigated in wild type mice, whether hippocampal gene or protein levels of GluA1 or associated PDZ proteins is altered following forced swim stress. We show that expression of Dlg4 (the gene coding for PSD-95) was strongly reduced after two days of forced swimming. In contrast, levels of Dlg1, Gria1, and Gria2 (coding for SAP97, GluA1, and GluA2 respectively) were not affected after one or two days of forced swimming. The changes in gene expression largely did not translate to the protein level. These findings indicate a limited acute effect of forced swim stress on the expression of the investigated targets and suggest that the acute involvement of GluA1-containing AMPA receptors tor forced swim behavior is a result of non-genomic mechanisms.

Gastro-protective potentials of Spirulina: role of vitamin B12.

Gastric ulcer is a chronic health problem world over. Spirulina is known to contain significant amounts of vitamin B12 hence Spirulina was evaluated for gastroprotective properties against gastric ulcerations. Spirulina biomass (SB) and Spirulina extract (SE) were evaluated in swim stress induced gastric ulcers in adult male albino rats. Both SB and SE inhibited 45% and 60% of ulcers formation induced by swim stress respectively. Gastroprotection has been elucidated to be due to inhibition of (a) upregulated H+, K+-ATPase activity that induced ulcer condition; (b) lipid peroxidation and (c) altered antioxidant enzyme levels. The data highlighted the importance of vitamin B12 in protecting the gut against gastric ulcerations and suggested that both Spirulina biomass and Spirulina extract contain bioavailable B12. Spirulina based product/food can be used as alternatives to gastroprotective agents that are known to cause acidity themselves upon long term use.

Swimming modifies the effect of noise stress on the HPG axis of male rats.

Few studies have examined the effect of noise pollution on the hypothalamic-pituitary-gonadal (HPG) axis. In this study, the effects of noise pollution and swimming on the HPG hormone axis of male rats were investigated. Forty male Sprague Dawley rats were assigned to four groups of equal size, including control (C), swimming (S), noise (N), and noise with swimming (NS). Serum levels of GnRH, LH, FSH, and testosterone were measured through blood samples taken 48h following the last session of treatment. The main treatment programs of voluntary swimming and noise stress were performed 5days per week over 7weeks. Serum levels of GnRH, LH, FSH, and testosterone decreased after exposure to the noise compared with the S and C groups, while in the S group, all hormone levels were higher than those in the C and N groups. Hormone levels of the SN group were higher than those in the N group but lower than those in the C group. Long-term exposure to noise is known to have a negative impact on male sex hormones, while submaximal swimming exercise is likely to reduce these effects and improve HPG axis hormones.

English

English

Dopamine D2L Receptor Deficiency Causes Stress Vulnerability through 5-HT1A Receptor Dysfunction in Serotonergic Neurons.

Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knock-out (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT efflux in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was upregulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR-activated G-protein-activated inwardly rectifying potassium conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.SIGNIFICANCE STATEMENT Etiologies of mental disorders are multifactorial, e.g., interactions between genetic and environmental factors. In this study, using a mouse model, we showed that genetic depletion of an isoform of dopamine D2 receptor, D2LR, causes stress vulnerability associated with dysfunction of serotonin 1A receptor, 5-HT1AR in serotonergic neurons. The D2LR/5-HT1AR inhibitory G-protein-coupled heteromer may function as a negative feedback regulator to suppress psychosocial stress.

Tualang honey and DHA-rich fish oil reduce the production of pro-inflammatory cytokines in the rat brain following exposure to chronic stress.

ObjectivesThe aim of the present study was to investigate the effects of Tualang honey (TH), DHA-rich fish oil, and their combination on the concentrations of selected pro-inflammatory cytokines in rat brains following exposure to chronic stress.MethodsFifty male Sprague–Dawley rats were divided into (i) control, (ii) stress-exposed, (iii) stress-exposed and treated with TH (1 g/kg body weight twice daily via oral gavage), (iv) stress-exposed and treated with DHA-rich fish oil (450 mg/kg body weight twice daily via oral gavage), and (v) stress-exposed and treated with a combination of TH and DHA-rich fish oil. The chronic stress regimen consisted of a combination of restraint stress and a swim stress test for 28 days. The concentrations of selected pro-inflammatory cytokines in brain homogenates (TNF-α, IL6, and IFN-γ) were measured by ELISA.ResultsThe concentrations of TNF-α, IL6, and IFN-γ in brain homogenates from the DHA, TH, and TH + DHA-treated groups were significantly lower compared to the control and stress-only-exposed groups (p < 0.05), but no difference was observed between treatment groups.ConclusionConsumption of DHA-rich fish oil and TH can be effective in lowering pro-inflammatory cytokine levels in the brains of rats under chronic stress conditions. However, consuming these agents together does not provide additional benefits compared to taking them separately.

Coping with the forced swim stressor

Coping with the forced swim stressor

Jeju ground water containing vanadium induces normal T cell development and immune activation in chronically stressed mice.

Containing high concentration of vanadium served by the volcanic bedrock, Jeju ground water has long been known for various implicit health benefits including immune-promotion. Exposure to stress has been reported to be associated with immunosuppression such as reducing lymphocyte population or antibody production due to stress hormones. In this study, we aimed at evaluating the effects of Jeju ground water on chronically stressed mice. C57BL/6 mice were subjected to various stressors such as restraint stress, water swimming stress, heat stress, acoustic stress, and Jeju ground water was supplied for 28days with two different concentrations, S1 (vanadium 15-20μg/l, pH 8.3) and S2 (vanadium 20-25μg/l, pH 8.5). Treatment with Jeju ground water increased CD4+CD8- or CD4-CD8+ single-positive thymocytes. It also increased the proliferation of splenocytes and the populations of CD4+ T cells, CD45R/B220+ B cells, CD11b+ macrophages or Gr-1+ granulocytes in spleen. In addition, the production of IgG was increased in chronically stressed mice by treatment with Jeju ground water. These results suggest vanadium-rich Jeju ground water may be helpful in T cell development in thymus and immune cell proliferation and its function in spleen against chronic stress.

Anandamide modulation of circadian- and stress-dependent effects on rat short-term memory

The endocannabinoid system plays a key role in the control of emotional responses to environmental challenges. CB1 receptors are highly expressed within cortico-limbic brain areas, where they modulate stress effects on memory processes. Glucocorticoid and endocannabinoid release is influenced by circadian rhythm. Here, we investigated how different stress intensities immediately after encoding influence rat short-term memory in an object recognition task, whether the effects depend on circadian rhythm and if exogenous augmentation of anandamide levels could restore any observed impairment. Two separate cohorts of male adult Sprague-Dawley rats were tested at two different times of the day, morning (inactivity phase) or afternoon (before the onset of the activity phase) in an object recognition task. The anandamide hydrolysis inhibitor URB597 was intraperitoneally administered immediately after the training trial. Rats were thereafter subjected to a forced swim stress under low or high stress conditions and tested 1 h after training. Control rats underwent the same experimental procedure except for the forced swim stress (no stress). We further investigated whether URB597 administration might modulate corticosterone release in rats subjected to the different stress conditions, both in the morning or afternoon. The low stressor elevated plasma corticosterone levels and impaired 1 h recognition memory performance when animals were tested in the morning. Exposure to the higher stress condition elevated plasma corticosterone levels and impaired memory performance, independently of the testing time. These findings show that stress impairing effects on short-term recognition memory are dependent on the intensity of stress and circadian rhythm. URB597 (0.3 mg kg−1) rescued the altered memory performance and decreased corticosterone levels in all the impaired groups yet leaving memory unaltered in the non-impaired groups.

Piracetam potentiates neuronal and behavioral effects of ketamine

Introduction: Ketamine has a fast, but short-term antidepressant effect. To support the therapeutic effect, repeated administrations of the drug are needed, which causes cognitive disorders. The drugs with cerebroprotective action can potentially intensify the main and weaken the side effects of drugs. Materials and methods: The impact of ketamine (5 and 20 μM), piracetam (100 μM), and their combinations on the synaptic transmission was studied on hippocampal slices in the CA1 area of rat hippocampus by means of electrophysiological methods. In behavioral experiments were aimed at studying an impact of the used drugs on the predictors which mark depressant behavior of rats: the duration of immobilization in a forced swimming test and preference for the consumption of sucrose solution (comparably with water). The behavioral experiments were performed on intact rats and rats with behavioral depression induced by chronic swimming stress. Results and discussion: Ketamine (5 and 20 μM) potentiates synaptic transmission in the radial layer of the CA1 hippocampal area. At a smaller concentration, ketamine potentiates synaptic transmission only due to the postsynaptic action, and at a greater concentration – with help of post- and presynaptic action. Piracetam (100 µM), like ketamine at a concentration of 5 μM stimulated synaptic transmission, but to a lesser degree. Ketamine at a concentration 5 μM under combined effect with piracetam induced the same effect as that at a concentration of 20 μM without piracetam, only due to a postsynaptic action. Ketamine at doses of 5 and 20 mg/kg one hour after a single systemic administration resulted in the reduced immobilization duration, but not predictors of preference for consuming a sweet solution; piracetam at a dose of 100 mg/kg under these conditions had no impact on the parameters of the rats’ behavior. The studied behavior parameters in cases of behavioral depression also changed after a single administration of ketamine at the doses of 5 and 20 mg/kg. Piracetam significantly stimulated an antidepressant action of ketamine under these circumstances. Conclusion: Piracetam potentiates a ketamine-induced enhancement of the synaptic transmission at the radial layer of the CA1 hippocampal area when investigating at the brain slices. Piracetam stimulates an antidepressant action of a single dose of ketamine in cases of behavioral depression, though it has no antidepressant effect when administered at a single dose.

Individual Vulnerability to Stress Is Associated With Increased Demand for Intravenous Heroin Self-administration in Rats.

Opioid use is a widespread epidemic, and traumatic stress exposure is a critical risk factor in opioid use and relapse. There is a significant gap in our understanding of how stress contributes to heroin use, and there are limited studies investigating individual differences underlying stress reactivity and subsequent stress-induced heroin self-administration. We hypothesized that greater individual vulnerability to stress would predict higher demand for heroin self-administration in a within-subjects rodent model of stress and heroin use comorbidity. Male rats were exposed to inescapable intermittent swim stress (ISS) and individual biological (corticosterone) or behavioral [open field, social exploration, and forced swim tests (FSTs)] measures were assessed before and after the stress episode. Individual demand for self-administered heroin (0.05 mg/kg/infusion; 12-h sessions) was assessed using a behavioral economics approach followed by extinction and reinstatement tests triggered by stress re-exposure, non-contingent cue presentations, and yohimbine (0, 1.0, or 2.5 mg/kg). We found that behavioral, biological, and a combination of behavioral and biological markers sampled prior to and after the stress episode that occurred weeks before the access to heroin self-administration predicted the magnitude of individual demand for heroin. Non-contingent presentation of cues, that were previously associated with heroin, reinstated heroin seeking in extinction. For the first time, we show that individual biological response to an ecologically relevant stressor in combination with associated behavioral markers can be used to predict subsequent economic demand for heroin.