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Social subordination increases risk for psychiatric disorders, while dominance increases resilience to these disorders. Fluoxetine, a selective serotonin (5HT) reuptake inhibitor whose actions are mediated in part by the 5HT1A receptor (5HT1AR), has sex- and social status-specific effects on socioemotional behavior and aggressive behavior. However, the impact of social status on these sex-specific effects remains unclear. The current study evaluated the impact of acute fluoxetine treatment and social status on dominance-related behaviors in female and male hamsters, and the impact of chronic fluoxetine treatment on socioemotional behavior and 5HT1AR binding potential (5HT1AR(BP)) in female rhesus macaques. We hypothesized that sex differences in the effects of fluoxetine on aggression in hamsters would be diminished in dominant and enhanced in subordinate males and that aggression in female hamsters would be enhanced in dominants and diminished in subordinates. In female rhesus macaques, we hypothesized that chronic fluoxetine would alter socioemotional behaviors and site-specific 5HT1AR(BP) in a status-dependent manner. Male (n=46) and female (n=56) hamsters were paired with conspecifics for three days to establish social rank. Hamsters received a single dose of 20mg/kg fluoxetine or vehicle two-hours prior to a test with a non-aggressive intruder. Female rhesus monkeys (n=14) housed were administered fluoxetine (2.8mg/kg/day) or vehicle injections chronically for 14-days, separated by a three-week washout period. On Day 15, positron emission tomography neuroimaging for 5HT1AR(BP) was conducted. Fluoxetine treatment decreased aggression in subordinate female monkeys and subordinate female hamsters but not in dominant females of either species. Fluoxetine decreased aggression in dominant but not in subordinate male hamsters. Fluoxetine also reduced and increased prefrontal 5HT1AR(BP) in dominant and subordinate females, respectively. Taken together, these results provide cross-species evidence that social status and sex impact how increased 5HT modulates agonistic behavior.

Most studies investigating the effects of acute administration of selective serotonin reuptake inhibitors (SSRI) on responses to social stress have been conducted with males. This is despite the fact that SSRIs remain the primary pharmacotherapy for social stress-related disorders for both sexes and that the prevalence of these disorders is twofold higher in women than in men. To determine whether acute treatment with the SSRI, fluoxetine, alters behavioral responses to social defeat stress in a sex- or social stress-dependent manner, male and female Syrian hamsters were subjected to one of three social defeat conditions: no defeat (placed into an empty resident aggressor (RA) cage), a single defeat by one RA for 15 minutes, or three consecutive defeats using different RAs for five minutes each. The day following social defeat, subjects were infused with either vehicle or fluoxetine (20 mg/kg, I.P.) two hours prior to a five minute social avoidance test. Overall, we found that fluoxetine increased social vigilance regardless of sex or defeat condition. We also found that fluoxetine affected social avoidance in a sex by stress intensity interaction, such that fluoxetine increased avoidance in no defeat males and in males defeated once but significantly increased avoidance in females only after three defeats. These data suggest that treatment with an SSRI could initially exacerbate the effects of social stress in both sexes. These data also emphasize the importance of including sex as a biological variable when investigating the efficacy of pharmacotherapy for stress-related disorders.

Syrian hamsters readily display territorial aggression. If they lose even a single agonistic encounter, however, hamsters show striking reductions in aggressive behavior and increases in submissive behavior, a distinct behavioral change that we have previously termed conditioned defeat. This acute social defeat stressor is primarily psychological and is effective in both males and females. Therefore, we maintain that this procedure presents an ideal model for studying behavioral and physiological responses to social stress. Here, we demonstrate that social avoidance following social defeat is a particularly useful dependent measure because of its sensitivity and stability between sexes and across the estrous cycle. In addition, we demonstrate that peripubertal hamsters exposed to a single, 15min social defeat exhibit significantly more social avoidance 24h later when compared with no-defeat controls. Later, defeated and non-defeated hamsters display similar agonistic behavior in adulthood indicating that the peripubertal defeat does not alter adult territorial aggression. After experiencing an additional social defeat in adulthood, however, the hamsters that experienced the pubertal defeat respond to the adult defeat with increased social avoidance when compared with hamsters that were defeated only in adulthood and with no-defeat controls. These data are the first to show that a single social defeat in puberty increases susceptibility to later social defeat in both males and females.

Histone acetylation has emerged as a critical factor regulating learning and memory both during and after exposure to stressful stimuli. There are drugs that we now know affect histone acetylation that are already in use in clinical populations. The current study uses these drugs to examine the consequences of acutely increasing or decreasing histone acetylation during exposure to social stress. Using an acute model of social defeat in Syrian hamsters, we systemically and site-specifically administered drugs that alter histone acetylation and measured subsequent behavior and immediate-early gene activity. We found that systemic administration of a histone deacetylase inhibitor enhances social stress-induced behavioral responses in males and females. We also found that systemic administration completely blocks defeat-induced neuronal activation, as measured by Fos-immunoreactivity, in the infralimbic cortex, but not in the amygdala, after a mild social defeat stressor. Lastly, we demonstrated that site-specific administration of histone deacetylase inhibitors in the infralimbic region of the prefrontal cortex, but not in the basolateral amygdala, mimics the systemic effect. Conversely, decreasing acetylation by inhibiting histone acetyltransferases in the infralimbic cortex reduces behavioral responses to defeat. This is the first demonstration that acute pharmacological manipulation of histone acetylation during social defeat alters subsequent behavioral responses in both males and females. These results reveal that even systemic administration of drugs that alter histone acetylation can significantly alter behavioral responses to social stress and highlight the importance of the infralimbic cortex in mediating this effect.

Dominance status in hamsters is driven by interactions between arginine-vasopressin V1a, oxytocin (OT), and serotonin 1A (5-HT1A) receptors. Activation of V1a and OT receptors in the anterior hypothalamus (AH) increases aggression in males, while decreasing aggression in females. In contrast, activation of 5-HT1A receptors in the AH decreases aggression in males and increases aggression in females. The mechanism underlying these differences is not known. The purpose of this study was to determine if dominance status and sex interact to regulate V1a, OT, and 5-HT1A receptor binding. Same-sex hamsters (N = 47) were paired 12 times across six days in five min sessions. Brains from paired and unpaired (non-social control) hamsters were collected immediately after the last interaction and processed for receptor binding using autoradiography. Differences in V1a, OT, and 5-HT1A receptor binding densities were observed in several brain regions as a function of social status and sex. For example, in the AH, there was an interaction between sex and social status, such that V1a binding in subordinate males was lower than in subordinate females and V1a receptor density in dominant males was higher than in dominant females. There was also an interaction in 5-HT1A receptor binding, such that social pairing increased 5-HT1A binding in the AH of males but decreased 5-HT1A binding in females compared with unpaired controls. These results indicate that dominance status and sex play important roles in shaping the binding profiles of key receptor subtypes across the neural circuitry that regulates social behavior.

Brain-derived neurotrophic factor (BDNF) is known to promote fear learning as well as avoidant behavioral responses to chronic social defeat stress, but, conversely, this peptide can also have antidepressant effects and can reduce depressant-like symptoms such as social avoidance. The purpose of this study was to use a variety of approaches to determine whether BDNF acting on tropomyosin receptor kinase B (TrkB) promotes or prevents avoidant phenotypes in hamsters and mice that have experienced acute social defeat stress. We utilized systemic and brain region-dependent manipulation of BDNF signaling before or immediately following social defeat stress in Syrian hamsters, TrkB(F616A) knock-in mice, and C57Bl/6J mice and measured the subsequent behavioral response to a novel opponent. Systemic TrkB receptor agonists reduced, and TrkB receptor antagonists enhanced, behavioral responses to social defeat in hamsters and mice. In the neural circuit that we have shown mediates defeat-induced behavioral responses, BDNF in the basolateral amygdala, but not the nucleus accumbens, also reduced social avoidant phenotypes. Conversely, knockdown in the basolateral amygdala of TrkB signaling in TrkB(F616A) mice enhanced defeat-induced social avoidance. These data demonstrate that systemic administration of BDNF-TrkB drugs at the time of social defeat alters the behavioral response to the defeat stressor. These drugs appear to act, at least in part, in the basolateral amygdala and not the nucleus accumbens. These findings were generalizable to two rodent species with very different social structures and, within mice, to a variety of strains providing converging evidence that BDNF-TrkB signaling reduces anxiety- and depression-like symptoms following short-term social stress.

Hamsters are an ideal animal model for a variety of biomedical research areas such as cancer, virology, circadian rhythms, and behavioural neuroscience. The use of hamsters has declined, however, most likely due to the dearth of genetic tools available for these animals. Our laboratory uses hamsters to study acute social stress, and we are beginning to investigate the genetic mechanisms subserving defeat-induced behavioural change. We have been limited, however, by the lack of genetic resources available for hamsters. In this study, we sequenced the brain transcriptome of male and female Syrian hamsters to generate the necessary resources to continue our research. We completed a de novo assembly and after assembly optimization, there were 113,329 transcripts representing 14,530 unique genes. This study is the first to characterize transcript expression in both female and male hamster brains and offers invaluable information to promote understanding of a host of important biomedical research questions for which hamsters are an excellent model.

It is widely held that social isolation produces higher rates of mortality and morbidity and has deleterious effects on an individual's sociality. Relatedly, it is widely observed that socially isolated adult rodents display significantly higher levels of aggression when placed in a social situation than do their conspecifics living in social groups. In the following study, we investigated the effects of social isolation on several neurochemical signals that play key roles in the regulation of social behavior in adults. More specifically, we examined the effects of social isolation on vasopressin (AVP) V1a, oxytocin (OT) and serotonin (5-HT)1a receptor binding within the neural circuit controlling social behavior. Male and female Syrian hamsters were housed individually or with two other hamsters for four weeks and were then tested with a same-sex nonaggressive intruder in a neutral arena for 5 min. Social isolation significantly increased aggression in both males and females and altered receptor binding in several brain regions in a sex-dependent manner. For example, V1a receptor binding was greater in socially isolated males in the anterior hypothalamus than it was in any other group. Taken together, these data provide substantial new support for the proposition that the social environment can have a significant impact on the structural and neurochemical mechanisms regulating social behavior and that the amount and type of social interactions can produce differential effects on the circuit regulating social behavior in a sex-dependent manner.

We have previously demonstrated that the basolateral amygdala (BLA) is a key component of a neural circuit mediating memory formation for emotionally relevant stimuli in an ethologically-based model of conditioned fear, termed conditioned defeat (CD). In this model, subjects are socially defeated by a larger, more aggressive hamster. Upon subsequent exposure to a smaller, non-aggressive intruder, the defeated animal will show high levels of submissive behaviors and fail to defend its territory. Here we examined whether the medial prefrontal cortex (mPFC), an area with extensive connections with the amygdala, is also a component of this circuit. Temporary inactivation of the mPFC using muscimol, a GABA(A) receptor agonist, significantly enhanced the acquisition but not expression of CD, while blockade of GABA(A) receptors in the mPFC using bicuculline, a GABA(A) antagonist, impaired acquisition of CD. Given these findings, we next sought to test whether plasticity related to the defeat experience occurs in the mPFC. We infused anisomycin, a protein synthesis inhibitor, in the mPFC but this treatment did not alter the acquisition of CD. In our final experiment, we demonstrated that bicuculline failed to alter the acquisition of CD. Together, these results demonstrate for the first time that while the mPFC is both necessary and sufficient for the acquisition of CD, it does not appear to mediate plasticity related to the defeat experience. In contrast, while plasticity underlying CD does appear to occur in the BLA, GABAergic receptor inhibition in the BLA is not sufficient to enhance CD. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Exposure to social stressors can cause profound changes in an individual's physiology and behavior. In Syrian hamsters, even a single social defeat results in conditioned defeat, which includes an abolishment of territorial aggression and the emergence of high levels of submissive behavior. The purpose of the current study was to determine whether the lateral septum (LS) is a component of the putative neural circuit underlying conditioned defeat. Experiment 1 explored the possibility that plasticity in the LS is necessary for the induction of conditioned defeat. Infusions of the protein synthesis inhibitor, anisomycin, prior to defeat training, however, failed to alter conditioned defeat during testing on the following day, suggesting that synaptic plasticity in the LS is not critical for defeat-induced suppression of aggression. Experiment 2 tested whether the LS is necessary for the expression of conditioned defeat. Infusions of the GABA(A) agonist muscimol into the LS prior to testing significantly increased aggression and decreased submission in previously defeated animals suggesting that the LS is an important component of the neural circuit mediating the expression of both aggression and submission in conditioned defeat. Experiment 3 examined whether the effects of muscimol on aggression were dependent on prior social defeat. Non-defeated animals receiving muscimol infusions prior to testing with a non-aggressive intruder displayed significantly more aggression than did hamsters receiving control injections. Thus, these data suggest that the activation of GABA(A) receptors in the LS increases aggression regardless of whether or not a hamster has previously experienced social defeat.

Male Syrian hamsters are naturally aggressive animals that reliably defend their home territory against intruding conspecifics. Hamsters that lose agonistic encounters subsequently exhibit a striking change in their agonistic behavior, however, expressing no aggression and instead becoming highly submissive, a behavioral change that we have termed conditioned defeat. We have generally employed an inescapable defeat training protocol when studying conditioned defeat. The purpose of the present study was to determine if conditioned defeat is an epiphenomenon of the inescapable defeat experience by comparing the behavior of hamsters exposed to inescapable versus escapable defeat. In the conditioned defeat model, defeated hamsters subsequently generalize their submission and social avoidance to a novel, non-aggressive opponent, suggesting that hamsters subjected to inescapable defeat may not form a specific memory of their aggressive opponent. Thus, a secondary purpose of the present study was to determine whether hamsters subjected to our defeat protocol have the ability to recognize a familiar opponent following defeat. Our results provide evidence that conditioned defeat is not solely a by-product of inescapable defeat because all experimental animals, regardless of the type of defeat, expressed conditioned defeat during testing. We also found that animals experiencing an inescapable defeat avoided a familiar aggressor significantly more than they did an unfamiliar aggressor, demonstrating that these animals have the ability to recognize their previous attacker. Thus, we maintain that a variety of social defeat models, and conditioned defeat in particular, represent generalizable and ethologically valid models with which to study the effects of social stress on physiology and behavior.

Reversible inactivation of the basolateral amygdala (BLA) disrupts the acquisition and expression of conditioned defeat (CD), an ethological model of conditioned fear, suggesting that the BLA may be a critical component of the neural circuit mediating behavioral plasticity associated with the experience of social defeat. We have also shown that this effect is N-methyl-d-aspartic acid (NMDA) receptor-dependent, because infusion of d,l-2-amino-5-phosphovalerate (APV) into the BLA also impairs the acquisition of CD. APV is a non-selective NMDA antagonist, however, thus it disrupts the entire heteromeric receptor complex, making it difficult to distinguish the relative contributions of either the NR2A or NR2B receptor subtypes on the acquisition of CD. There is ample evidence, however, that the NR2B subunit of the NMDA receptor in the amygdala is critical for mediating long-term potentiation and plasticity related to fear learning. The purpose of the present experiment was to determine whether infusion of ifenprodil, a selective antagonist of the NR2B subunit, into the BLA would block the acquisition (but not expression) of CD. In Experiment 1, infusion of ifenprodil immediately before defeat training significantly decreased submissive behaviors and restored territorial aggression when hamsters were later paired with a non-aggressive intruder (NAI). Conversely, infusion of ifenprodil immediately before CD testing failed to inhibit the expression of submissive behaviors in previously defeated hamsters. These results support the hypothesis that the BLA is a critical site for the plasticity underlying social defeat-induced changes in behavior.

Several neuroendocrine signals of the hypothalamic-pituitary-adrenal (HPA) axis are released following exposure to stressful events. It has long been proposed that the signals in this cascade each act to modify ongoing and future behavior. In this study we investigated whether blocking glucocorticoid synthesis, corticotropin-releasing factor (CRF)-1 receptors, or CRF-2 receptors during social defeat would alter subsequent behavioral responses. We used a conditioned defeat model in Syrian hamsters in which social defeat results in a dramatic shift from territorial aggression to increased submissive and defensive behavior in future social encounters. We found that intracerebroventricular administration of anti-sauvagine-30, a CRF-2 receptor antagonist, prior to social defeat training reduced the acquisition of conditioned defeat. In contrast, the acquisition of conditioned defeat was not altered by the CRF-1 receptor antagonist CP-154,526 or the glucocorticoid synthesis inhibitor metyrapone. Our results suggest that CRF, and perhaps related neuropeptides such as urocortins, act at CRF-2 receptors to promote the development of defeat-induced changes in social behavior, whereas signaling at CRF-1 and glucocorticoid receptors plays a negligible role in this process.

We examined the roles of the amygdala and hippocampus in the formation of emotionally relevant memories using an ethological model of conditioned fear termed conditioned defeat (CD). Temporary inactivation of the ventral, but not dorsal hippocampus (VH, DH, respectively) using muscimol disrupted the acquisition of CD, whereas pretraining VH infusions of anisomycin, a protein synthesis inhibitor, failed to block CD. To test for a functional connection between the VH and basolateral amygdala (BLA), we used a classic functional connectivity design wherein injections are made unilaterally in brain areas either on the same or opposite sides of the brain. A functional connection between the BLA and VH necessary for the acquisition of CD could not be found because unilateral inactivation of either BLA alone (but not either VH alone) was sufficient to disrupt CD. This finding suggested instead that there may be a critical functional connection between the left and right BLA. In our final experiment, we infused muscimol unilaterally in the BLA and assessed Fos immunoreactivity on the contralateral side following exposure to social defeat. Inactivation of either BLA significantly reduced defeat-induced Fos immunoreactivity in the contralateral BLA. These experiments demonstrate for the first time that whereas the VH is necessary for the acquisition of CD, it does not appear to mediate the plastic changes underlying CD. There also appears to be a critical interaction between the two BLAs such that bilateral activation of this brain area must occur in order to support fear learning in this model, a finding that is unprecedented to date.

Conditioned defeat is a model wherein hamsters that have previously experienced a single social defeat subsequently exhibit heightened levels of avoidance and submission in response to a smaller, non-aggressive intruder. While we have previously demonstrated the critical involvement of the basolateral and central nuclei of the amygdala in the acquisition and expression of conditioned defeat, the role of the medial amygdala has yet to be investigated. In Experiment 1, muscimol, a GABAA receptor agonist, was infused bilaterally into the MeA prior to initial defeat training. Experiment 2 examined the effects of muscimol injections given prior to subsequent testing with a non-aggressive intruder. Finally, in Experiment 3, anisomycin was used to block protein synthesis in the medial and basolateral amygdala to examine the involvement of these nuclei in memory consolidation related to conditioned defeat. Submissive behavior was significantly reduced in animals that received muscimol prior to initial defeat training as well as in animals injected prior to testing with the non-aggressive intruder, indicating that the MeA is necessary for the acquisition and expression of conditioned defeat. In Experiment 3, however, anisomycin reduced conditioned defeat only when administered into the BLA, and not when injected into the MeA. The results of the present series of experiments suggest that, while the MeA may serve an important gateway for sensory information that is crucial for conditioned defeat, it does not appear to play a role in the plasticity including this behavioral response to social defeat.

The cAMP-responsive element binding protein (CREB) is a transcription factor that regulates synaptic plasticity and memory formation. Studies that have used conditioned fear models have established that CREB is important for the acquisition and consolidation of fear learning. The authors demonstrate that overexpression of CREB within the basolateral amygdala (BLA) of animals that are exposed to social defeat enhances subsequent defeat-induced changes in social behavior. This effect is specific to the acquisition of defeat-induced behaviors; overexpression of CREB has no effect on the expression of these behaviors if the overexpression occurs after the initial defeat. These data demonstrate that CREB is important for regulating learning not only to explicit cues but also for mediating behavioral plasticity in ethologically relevant social contexts.

Many nontropical rodent species rely on photoperiod as a primary cue to coordinate seasonally appropriate changes in physiology and behavior. Among these changes, some species of rodents demonstrate increased aggression in short, "winter-like" compared with long "summer-like" day lengths. The precise neuroendocrine mechanisms mediating changes in aggression, however, remain largely unknown. The goal of the present study was to examine the effects of photoperiod and exogenous melatonin on resident-intruder aggression in male Syrian hamsters (Mesocricetus auratus). In Experiment 1, male Syrian hamsters were housed in long (LD 14:10) or short (LD 10:14) days for 10 weeks. In Experiment 2, hamsters were housed in long days and half of the animals were given daily subcutaneous melatonin injections (15 microg/day in 0.1 ml saline) 2 h before lights out for 10 consecutive days to simulate a short-day pattern of melatonin secretion, while the remaining animals received injections of the vehicle alone. Animals in both experiments were then tested using a resident-intruder model of aggression and the number of attacks, duration of attacks, and latency to initial attack were recorded. In Experiment 1, short-day hamsters underwent gonadal regression and displayed increased aggression compared with long-day animals. In Experiment 2, melatonin treatment also increased aggression compared with control hamsters without affecting circulating testosterone. Collectively, the results of the present study demonstrate that exposure to short days or short day-like patterns of melatonin increase aggression in male Syrian hamsters. In addition, these results suggest that photoperiodic changes in aggression provide an important, ecologically relevant model with which to study the neuroendocrine mechanisms underlying aggression in rodents.

Arginine-vasopressin (AVP) and oxytocin (OT) and their receptors are very similar in structure. As a result, at least some of the effects of these peptides may be the result of crosstalk between their canonical receptors. The present study investigated this hypothesis by determining whether the induction of flank marking, a form of social communication in Syrian hamsters, by OT is mediated by the OT receptor or the AVP V1a receptor. Intracerebroventricular (ICV) injections of OT or AVP induced flank marking in a dose-dependent manner although the effects of AVP were approximately 100 times greater than those of OT. Injections of highly selective V1a receptor agonists but not OT receptor agonists induced flank marking, and V1a receptor antagonists but not OT receptor antagonists significantly inhibited the ability of OT to induce flank marking. Lastly, injection of alpha-melanocyte-stimulating hormone (α-MSH), a peptide that stimulates OT but not AVP release, significantly increased odor-induced flank marking, and these effects were blocked by a V1a receptor antagonist. These data demonstrate that OT induces flank marking by activating AVP V1a and not OT receptors, suggesting that the V1a receptor should be considered to be an OT receptor as well as an AVP receptor.

Social defeat is a powerful experience that often leads to drastic physiological and behavioral changes in many animal species. An example of such a change is conditioned defeat in Syrian hamsters. The neurophysiological mechanisms that underlie such changes are not yet fully understood, however, there is evidence that the amygdala plays an essential role in behavioral and emotional responses to a variety of stressors. The goal of the present study was to determine whether GABAergic neurotransmission in the amygdala is a critical component of conditioned defeat in male Syrian hamsters. Experiment 1 examined whether infusion of the GABA(A) receptor agonist, muscimol (0.0, 4.4, 8.8 nmol), into the amygdala would block the acquisition of conditioned defeat. Experiment 2 examined whether infusion of muscimol into the amygdala prior to testing would block expression of conditioned defeat. Submissive behavior during testing was significantly reduced in animals receiving infusions of muscimol immediately prior to initial defeat training. Animals that received infusions of muscimol immediately prior to being tested with a non-aggressive intruder also displayed significantly less submissive behavior than did animals receiving vehicle control. These data indicate that infusion of muscimol into the amygdala can block the acquisition and expression of conditioned defeat, a finding that indicates that GABAergic neurotransmission within the amygdala is involved in the acquisition and expression of fear or stress-induced behavioral changes. This is the first evidence indicating that the neural circuits involved in Pavlovian fear conditioning are also involved in more ethologically-relevant models examining stress-related behavioral plasticity.

Stressors, both physical and psychological, can activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to a wide range of physiological responses including increased glucocorticoid release and suppression of immune function. The majority of studies published to date have focused on the effects of physical stressors (e.g., cold exposure, electric shock) on immunity. The present study examined the role of a stressor, social defeat, on humoral immune function of Syrian hamsters (Mesocricetus auratus). Specifically, adult male Syrian hamsters experienced social defeat (i.e., exposure to a dominant animal in that animal's home cage) that was either acute (i.e., a single exposure) or chronic (i.e., daily exposures across 5 days). A control group of animals was placed in a resident's home cage without the resident animal present and did not experience defeat. After the last encounter, blood samples were drawn and animals were subsequently injected with keyhole limpet hemocyanin (KLH). Blood samples were again taken 5 and 10 days postimmunization and serum was analyzed to determine serum cortisol and anti-KLH immunoglobulin G (IgG) concentrations. Cortisol concentrations were elevated in both acutely and chronically defeated hamsters compared with control animals. In contrast, serum IgG concentrations were significantly reduced in both groups of defeated hamsters compared with control animals. Collectively, these results demonstrate that both acute social defeat and chronic social defeat lead to activation of the HPA axis and suppression of humoral immune function. These data suggest that social defeat is an important, ecologically relevant model with which to examine stress-induced immune suppression in rodents.

Many nontropical rodent species display seasonal changes in both physiology and behavior that occur primarily in response to changes in photoperiod. Short-day reductions in reproduction are due, in part, to reductions in gonadal steroid hormones. In addition, gonadal steroids, primarily testosterone (T), have been implicated in aggression in many mammalian species. Some species, however, display increased aggression in short days despite basal circulating concentrations of T. The goal of the present studies was to test the effects of photoperiod on aggression in male Siberian hamsters (Phodopus sungorus) and to determine the role of T in mediating photoperiodic changes in aggression. In Experiment 1, hamsters were housed in long and short days for either 10 or 20 weeks and aggression was determined using a resident-intruder model. Hamsters housed in short days for 10 weeks underwent gonadal regression and displayed increased aggression compared to long-day-housed animals. Prolonged maintenance in short days (i.e., 20 weeks), however, led to gonadal recrudescence and reduced aggression. In Experiment 2, hamsters were housed in long and short days for 10 weeks. Half of the short-day-housed animals were implanted with capsules containing T whereas the remaining animals received empty capsules. In addition, half of the long-day-housed animals were castrated whereas the remaining animals received sham surgeries. Short-day control hamsters displayed increased aggression compared to either castrated or intact long-day-housed animals. Short-day-housed T treated hamsters, however, did not differ in aggression from long-day-housed animals. Collectively, these results confirm previous findings of increased aggression in short-day-housed hamsters and suggest that short-day-induced increases in aggression are inversely related to gonadal steroid hormones.

The purpose of the present study was to determine whether corticotropin-releasing factor (CRF) is involved in mediating the expression of conditioned defeat in male Syrian hamsters. The present study examined the effects of two different competitive CRF receptor antagonists on the expression of conditioned defeat. Specifically, Experiment 1 examined whether peripheral administration of CP-154,526, a specific non-peptide CRF 1 receptor antagonist, would reduce the expression of conditioned defeat. Experiment 2 examined whether d -Phe CRF (12–41) , a nonspecific CRF 1 /CRF 2 receptor antagonist, infused directly into the brain, would reduce the expression of conditioned defeat. The results revealed that i.p. injections of CP-154,526 did not reduce the expression of conditioned defeat, whereas i.c.v. injections of d -Phe CRF (12–41) successfully reduced the expression of conditioned defeat. The duration of submissive/defensive behaviors in hamsters that received the high dose of d -Phe CRF (12–41) was significantly less than that exhibited by animals that received a vehicle control. The present data suggest that central CRF may be involved in mediating the expression of conditioned defeat and other behavioral responses to stressful stimuli.

GABAergic drugs have profound effects on the regulation of circadian rhythms. The present study evaluated the effects of microinjections of GABAergic drugs into the suprachiasmatic region in hamsters on phase shifts induced by light and by microinjection of a cocktail containing vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI) and gastrin-releasing peptide (GRP). The phase-advancing effects of light at circadian time (CT) 19 were significantly reduced by microinjection of GABA(A) or GABA(B) agonists into the SCN, but were not altered by microinjection of GABA(A) or GABA(B) antagonists. Microinjection of a GABA(B) agonist also reduced the phase-delaying effects of light at CT 13.5-14 while a GABA(B) antagonist increased the phase delays caused by light. Neither GABA(B) drug altered the phase delays produced by microinjection of a peptide cocktail containing VIP, PHI, GRP. These data indicate that changes in GABA(A) or GABA(B) activity within the SCN can alter the phase-shifting effects of light on circadian rhythms and support a role for GABA in gating photic input to the circadian clock.

NEUROPEPTIDE Y (NPY) injected into the suprachiasmatic region 6 h before the onset of locomotor activity produces phase advances in circadian rhythms. The present study investigated whether the phase advances produced by NPY in Syrian hamsters are mediated by a Y 1 - or Y 2 -like NPY receptor by comparing the phase advancing effects of the Y 1 agonist, [Leu 31 ,Pro 34 ]NPY, and the Y 2 agonist, NPY(3-36), following their injection into the suprachiasmatic region. Microinjection of the Y 2 agonist produced phase advances that were significantly greater than those produced by the microinjection of the Y 1 agonist. These data support the hypothesis that the phase advancing effects of NPY in the suprachiasmatic region are mediated by a Y 2 -like NPY receptor, similar to results found in vitro.

Following exposure to a stressor, plasma prolactin (PRL) rises in most species. The purpose of the present study was to examine the effect of social conflict or of footshock stress on PRL responsiveness in male Syrian hamsters. Contrary to expectations, PRL was significantly lower in subordinate hamsters than in their dominant opponents or in controls following one, five, or nine exposures to social conflict. Similarly, PRL was reduced in hamsters subjected to a mild footshock stressor. By contrast, adrenocorticotropin, another stress-responsive hormone, was elevated following exposure to each of these stressors. We also demonstrate that PRL release is inhibited by dopamine as it is in other species by showing that there is a dose-dependent increase in PRL release following treatment with the dopamine receptor blocker, domperidone.

The role of gastrin releasing peptide (GRP) in phase shifting circadian rhythms was investigated. Microinjection of GRP into the suprachiasmatic region (SCN) region produced only small changes in the phase of free-running circadian activity rhythms in hamsters housed in constant darkness. However, co-administration of GRP with vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) produced significantly larger phase delays than GRP alone. These data support the hypothesis that GRP interacts with VIP and PHI within the SCN to induce phase shifts of circadian rhythms.

Microinjection of neuropeptide Y (NPY) into the suprachiasmatic nucleus of the hypothalamus (SCN) during the middle of the subjective day (i.e. circadian time 6) causes large phase advances in circadian rhythms. The present study demonstrates that microinjection of the γ-aminobutyric acid (GABA) antagonist, bicuculline, completely blocks NPY-induced phase advances. These data indicate that GABAA activity within the SCN may mediate the phase shifting effects of some stimuli on the circadian pacemaker.

Syrian hamsters are highly aggressive animals that reliably defend their home territory. After social defeat, however, hamsters no longer defend their home cage but instead display submissive and defensive behavior toward an intruder, a response that we have termed conditioned defeat. Plasma testosterone is significantly reduced in Syrian hamsters following repeated defeat suggesting that social defeat might also impair copulatory behavior. The present study aimed to determine whether copulatory behavior in male Syrian hamsters is suppressed following repeated social defeats and additionally whether exposure to a hormone-primed stimulus female after social defeat reduces the behavioral response to defeat. Hamsters were paired with an aggressive opponent for one or nine defeats using a resident-intruder model, while controls were placed into the empty cage of a resident aggressor. On the day after the last treatment, half of the hamsters were paired with a receptive female for 10 min. There were no significant differences in the copulatory behavior of defeated versus non-defeated hamsters, and the opportunity to copulate had no effect on subsequent conditioned defeat testing, as defeated animals displayed significantly more submissive behavior than did non-defeated animals. The current data suggest that conditioned defeat is not necessarily a maladaptive response to social stress, at least in terms of reproductive behavior, but may instead represent a viable behavioral strategy adopted by losing animals following social defeat. Further, these data indicate that conditioned defeat is relatively persistent and stable, as the opportunity to copulate does not reduce the subsequent display of submissive behavior.

The geniculohypothalamic tract (GHT) is a projection from the intergeniculate leaflet to the suprachiasmatic nucleus (SCN). The GHT exhibits neuropeptide Y (NPY) immunoreactivity and appears to communicate photic information to the SCN. Microinjection of NPY into the SCN has been found to phase shift circadian rhythms of hamsters housed in constant light in a manner similar to the phase shifts produced by pulses of darkness or triazolam injections. In the present study, NPY was injected into the SCN of Syrian hamsters housed in constant darkness and was found to produce phase shifts similar to those seen in hamsters housed in constant light. Microinjections were not followed by wheel running during the subjective day (the time when NPY microinjections are followed by significant phase advances). These data suggest that NPY produces phase shifts by some mechanism other than by inducing wheel running or by inhibiting the response of SCN neurons to light and supports a role for NPY in nonphotic shifting of the circadian clock.

Syrian hamsters readily form dominant-subordinate relationships under laboratory conditions. Winning or losing in agonistic encounters can have striking, long-term effects on social behavior, but the mechanisms underlying this experience-induced behavioral plasticity are unclear. The present study tested the hypothesis that changes in brain-derived neurotrophic factor (BDNF) may at least in part mediate this plasticity. Male hamsters were paired for 15-min using a resident-intruder model, and individuals were identified as winners or losers on the basis of their behavior. BDNF was examined with in situ hybridization 2 hours after treatment during the consolidation period of emotional learning. Losing animals had significantly more BDNF mRNA in the basolateral (BLA) and medial (MeA) nuclei of the amygdala when compared to winning animals as well as novel cage and home cage controls. Interestingly, winning animals had significantly more BDNF mRNA in the dentate gyrus of the dorsal hippocampus (DHPC DG) than did losing animals, novel and home cage controls. No conflict-related changes in BDNF mRNA were observed in several other regions including the bed nucleus of the stria terminalis and central amygdala. Next, we demonstrated that K252a, a Trk receptor antagonist, significantly reduced the acquisition of conditioned defeat when administered within the BLA. These data support a model in which BDNF-mediated plasticity within the BLA supports learning of submission or subordinate social status in losing animals, whereas BDNF-mediated plasticity within the hippocampus may instantiate aspects of winning such as control of a territory in dominant animals.

When Syrian hamsters (Mesocricetus auratus) are defeated by a larger, more aggressive hamster, they subsequently exhibit submissive and defensive behavior, instead of their usual aggressive and social behavior, even toward a smaller, non-aggressive opponent. This change in behavior is termed conditioned defeat, and we have found that the amygdala, bed nucleus of the stria terminalis, and ventral hippocampus, among others, are crucial brain areas for either the acquisition and/or expression of this behavioral response to social stress. In the present study, we tested the hypothesis that the nucleus accumbens is also a necessary component of the circuit mediating the acquisition and expression of conditioned defeat. We found that infusion of the GABA(A) agonist muscimol into the nucleus accumbens prior to defeat training failed to affect acquisition of conditioned defeat, but infusion prior to testing significantly decreased submissive behavior and significantly increased aggressive behavior directed toward the non-aggressive intruder. These data indicate that, unlike the basolateral complex of the amygdala, the nucleus accumbens is not a critical site for the plasticity underlying conditioned defeat acquisition, but it does appear to be an important component of the circuit mediating the expression of the behavioral changes that are produced in response to a previous social defeat. Of note, this is the first component of the putative "conditioned defeat neural circuit" wherein we have found that pharmacological manipulations are effective in restoring the territorial aggressive response in previously defeated hamsters.

Male Syrian hamsters were paired and allowed to interact with a conspecific for 15 min a day for 4 days. On the fifth day, the animals were again paired, but they were kept physically separated by a mesh partition that allowed visual, olfactory, and auditory contact between the animals. Controls were placed with conspecifics on each of the 5 testing days, but the partition between them was never removed. Hamsters that were submissive on days 1–4 exhibited elevated plasma adrenocorticotropin-like immunoreactivity (ACTH-LI), beta-endorphin-like immunoreactivity (B-EP-LI), and cortisol on day 5 even though no fighting occurred on that day. Dominant hamsters did not differ from controls. These data support the hypothesis that there is an important psychological component to the pituitary-adrenocortical response in defeated hamsters.

Serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) have been implicated in stress-induced changes in behavior. Previous research indicates that stressful stimuli activate 5-HT neurons in select subregions of the DRN. Uncontrollable stress is thought to sensitize 5-HT neurons in the DRN and allow for an exaggerated 5-HT response to future stimuli. In the current study, we tested the hypothesis that following aggressive encounters, losing male Syrian hamsters would exhibit increased c-Fos immunoreactivity in 5-HT DRN neurons compared to winners or controls. In addition, we tested the hypothesis that losers would have decreased 5-HT1A mRNA levels in the DRN compared to winners or controls. We found that a single 15-min aggressive encounter increased c-Fos expression in 5-HT and non-5-HT neurons in losers compared to winners and controls. The increased c-Fos expression in losers was restricted to ventral regions of the rostral DRN. We also found that four 5-min aggressive encounters reduced total 5-HT1A mRNA levels in the DRN in losers compared to winners and controls, and that differences in mRNA levels were not restricted to specific DRN subregions. These results suggest that social defeat activates neurons in select subregions of the DRN and reduces message for DRN 5-HT1A autoreceptors. Our results support the hypothesis that social stress can activate 5-HT neurons in the DRN, reduce 5-HT1A autoreceptor-mediated inhibition, and lead to hyperactivity of 5-HT neurons.

The purpose of the present study was to characterize the hormonal response of dominant and submissive male hamsters to acute and repeated exposure to social conflict. We found that submissive, but not dominant, males exhibited elevated plasma levels of adrenocorticotropin (ACTH), cortisol, and beta-endorphin (beta-EP) following one exposure to an agonistic encounter. After five exposures to a dominant opponent, submissive males showed smaller, but still significant, elevations in these plasma hormones. After nine exposures, submissive hamsters showed significant elevations only in plasma ACTH and beta-EP. Plasma testosterone was significantly suppressed in submissive males that fought nine times. We conclude that hamsters are a useful species with which to study the neuroendocrine correlates of social behavior.

When Syrian hamsters (Mesocricetus auratus) are defeated by a larger, more aggressive opponent, they subsequently produce more defensive and submissive behaviors and less chemosensory investigation and aggression, even when they are paired with a smaller, non-aggressive intruder. This persistent change in the behavior of defeated animals has been termed conditioned defeat. In the present study, we tested the hypothesis that the bed nucleus of the stria terminalis (BNST) is important for the acquisition and expression of conditioned defeat. We found that the GABA(A) receptor agonist muscimol infused into the BNST immediately prior to initial defeat training failed to disrupt the acquisition of conditioned defeat, while muscimol infused prior to testing caused a significant reduction in submissive/defensive behaviors and an increase in investigatory behaviors of the non-aggressive intruder. These results indicate that (1) the BNST, unlike the amygdala, does not appear to be critically involved in the consolidation process related to the memory of social defeat and (2) the BNST may be an important site for the execution of fear behaviors associated with social defeat. Considering the high degree of connectivity between the BNST and the amygdala, these findings provide further insight into the neural circuitry governing conditioned defeat and support the view of a functional dissociation between the amygdala and the BNST in the modulation of conditioned fear in an ethologically relevant model.

We have reported that there is a sex difference in the behavioral response to social defeat in hamsters. While previously defeated male hamsters fail to display normal territorial aggression and instead produce submissive/defensive behavior, a phenomenon that we have termed conditioned defeat (CD), only a small portion of previously defeated females exhibit CD. In Experiment 1, we tested the hypothesis that CD varies over the estrous cycle and found that previously defeated female hamsters tested on diestrus 2 and proestrus were more likely to exhibit CD than were females tested on diestrus 1 and estrus. In Experiment 2, we found that regardless of hormonal status, non-defeated females displayed normal territorial aggression, indicating that the behavioral changes observed in Experiment 1 were not due to a cyclic variation in submissive behavior independent of a previous defeat encounter. In Experiment 3, we found that females tested 4 days after defeat responded similarly to those tested 1 day after defeat suggesting that the hormonal status of females on the day of testing is a more important determinant of the behavioral response to defeat than is the hormonal status on the day of defeat training. Finally, in Experiment 4, we monitored anxiety-like behaviors in diestrous 1 and proestrous females in an open field arena and found that there was no effect of cycle on any of the observed behavioral measures, suggesting that the observed differences in CD are not the result of differences in generalized anxiety-like behaviors across the estrous cycle.

Obesity is a world-wide epidemic, and many factors, including stress, have been linked to this growing trend. After social stress (i.e., defeat), subordinate laboratory rats and most laboratory mice become hypophagic and, subsequently, lose body mass; the opposite is true of subordinate Syrian hamsters. After social defeat, Syrian hamsters become hyperphagic and gain body mass compared with nonstressed controls. It is unknown whether this increase in body mass and food intake is limited to subordinate hamsters. In experiment 1, we asked, do dominant hamsters increase food intake, body mass, and adiposity after an agonistic encounter? Subordinate hamsters increased food intake and body mass compared with nonstressed controls. Although there was no difference in food intake or absolute body mass between dominant and nonstressed control animals, cumulative body mass gain was significantly higher in dominant than in nonstressed control animals. Total carcass lipid and white adipose tissue (WAT) (i.e., retroperitoneal and epididymal WAT) masses were significantly increased in subordinate, but not dominant, hamsters compared with nonstressed controls. In experiment 2, we asked, does footshock stress increase food intake, body mass, and adiposity. Hamsters exposed to defeat, but not footshock stress, increased food intake relative to nonstressed controls. In animals exposed to defeat or footshock stress, body mass, as well as mesenteric WAT mass, increased compared with nonstressed controls. Collectively, these data demonstrate that social and nonsocial stressors increase body and lipid mass in male hamsters, suggesting that this species may prove useful for studying the physiology of stress-induced obesity in some humans.

In Syrian hamsters (Mesocricetus auratus), social defeat produces a prolonged change in subsequent agonistic behavior termed conditioned defeat. This stress-induced change in behavior is marked by increased submissive and defensive behavior toward a novel, nonaggressive opponent and a complete loss of normal territorial aggression. Corticotropin-releasing factor (CRF) has been shown to affect serotonergic neurons in the dorsal raphe nucleus (DRN) and to modulate learned helplessness via a CRF type-2 receptor (CRF-R2) mechanism.In this study, we tested the hypothesis that a nonselective CRF receptor antagonist (experiment 1: 250 or 500 ng D: -Phe CRF in 200 nl saline), or a selective CRF-R2 antagonist (experiment 2: 500 ng anti-Svg-30 in 200 nl saline), injected into the DRN would reduce the acquisition of conditioned defeat in male hamsters. We also tested similar hypotheses for the expression of conditioned defeat (experiments 3 and 4).Infusion of D: -Phe CRF into the DRN significantly reduced both the acquisition and expression of conditioned defeat compared to vehicle controls, whereas infusion of anti-Svg-30 into the DRN reduced expression but not acquisition. In particular, CRF antagonism in the DRN decreased fleeing from novel opponents but did not reinstate normal territorial aggression after social defeat.Our results suggest that the increased flight associated with conditioned defeat is modulated by CRF-R2 activation within the DRN. Overall, social defeat is an ethologically relevant stressor that appears to activate at least some of the same neural substrates that have been implicated in the control of learned helplessness.

Overeating and increases in body and fat mass are the most common responses to day-to-day stress in humans, whereas stressed laboratory rats and mice respond oppositely. Group housing of Syrian hamsters increases body mass, adiposity, and food intake, perhaps due to social confrontation-induced stress. In experiment 1 we asked, Does repeated social defeat increase food intake, body mass, and white adipose tissue (WAT) mass in Syrian hamsters? Male hamsters subjected to the resident-intruder social interaction model and defeated intermittently 15 times over 34 days for 7-min sessions significantly increased their food intake, body mass, and most WAT masses compared with nondefeated controls. Defeat significantly increased terminal adrenal norepinephrine, but not epinephrine, content. In experiment 2 we asked, Are 15 intermittent resident-intruder interactions necessary to increase body mass and food intake? Body mass and food intake of subordinate hamsters defeated only once were similar to those of nondefeated controls, but four or eight defeats similarly and significantly increased these responses. In experiment 3 we asked, Do intermittent defeats increase adiposity and food intake more than consecutive defeats? Four intermittent or consecutive defeats similarly and significantly increased food intake and body mass compared with nondefeated controls, but only intermittent defeats significantly increased all WAT masses. Consecutive defeats significantly increased mesenteric and inguinal WAT masses. Plasma leptin, but not insulin, concentrations were similarly and significantly increased compared with nondefeated controls. Collectively, social defeat, a natural stressor, significantly increased food intake, body mass, and adiposity in Syrian hamsters and may prove useful in determining mechanisms underlying human stress-induced obesity.

In Syrian hamsters (Mesocricetus auratus), social defeat produces a subsequent increase in submissive and defensive behavior and a loss of normal territorial aggression, which the authors have called conditioned defeat. In this study, the authors investigated the effect of blocking corticotropin-releasing factor (CRF) Type I and Type II receptors on conditioned defeat. Intracerebroventricular infusion of the CRF-sub-2 receptor antagonist antisauvagine-30 prior to testing significantly reduced conditioned defeat compared with vehicle controls, whereas the CRF-sub-1 receptor antagonist CP-154,526 had no effect. Also, infusion of antisauvagine-30 into the bed nucleus of the stria terminalis (BNST) 15 min, but not immediately, prior to testing reduced conditioned defeat in a dose-dependent manner. The authors' results provide evidence that CRF-sub-2 receptors in the BNST, but not CRF-sub-1 receptors, are an important component in the neural circuitry regulating conditioned defeat.

The present study investigated the hypothesis that social isolation increases aggression by increasing the number of V1a vasopressin receptors in the anterior hypothalamus (AH). Male hamsters were randomly assigned to a group that was allowed to interact with a small nonaggressive hamster three times each week for 3 weeks (socially experienced) or to a group that did not interact socially with other hamsters (social isolates). On the final day of the experiment, hamsters in both groups were placed in a neutral arena with a small, nonaggressive intruder, and agonistic behavior was scored for 10 min. In social isolates, the duration of aggression and the number of attacks were significantly greater than in socially experienced hamsters. There were no significant between-group differences in the latency to the onset of aggression, the number of flank marks or in the duration of defensive/submissive, social or nonsocial behavior. The amount of V1a receptor binding was significantly greater in the AH, the paraventricular nucleus of the hypothalamus and the lateral hypothalamus in the social isolates than in the socially experienced hamsters. The amount of V1a receptor binding was significantly greater in the central amygdala of socially experienced hamsters than in socially isolated hamsters. Serum concentrations of testosterone were significantly higher in the socially experienced hamsters than in social isolates. These data support the hypothesis that social isolation increases aggression by increasing the number of V1a vasopressin receptors in the AH.

Arginine vasopressin (AVP) regulates aggression in male Syrian hamsters. In this study, we used radioligand receptor autoradiography to examine whether changes in agonistic behavior following acute and repeated social defeat are accompanied by changes in AVP V1a receptor binding. Social defeat produced high levels of submissive behavior and a loss of territorial aggression when hamsters were subsequently tested with a novel intruder, and repeated agonistic encounters produced similar behavioral changes in subordinates. AVP V1a receptor binding was not reduced by acute social defeat but was affected by repeated agonistic encounters. Dominants had significantly more AVP V1a receptor binding in lateral portions of the ventromedial hypothalamus (VMHL) than did their subordinate opponents, but subordinates were no different from controls. In contrast, receptor binding did not differ in most other brain regions examined. The changes in receptor binding appear to be independent of testosterone levels, as testosterone levels did not differ among dominants, subordinates, and controls. Our results suggest that changes in AVP V1a receptors do not account for the changes in agonistic behavior produced by acute social defeat but AVP V1a binding in the VMHL correlates with, and may modulate, the behavioral changes that occur following repeated experiences of victory.

The authors investigated whether corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST) is a critical component of the neural circuitry mediating conditioned defeat. In this model, hamsters that have experienced social defeat subsequently display only submissive-defensive agonistic behavior instead of territorial aggression. Conditioned defeat was significantly reduced following infusion of the CRF receptor antagonist D-Phe CRF((12-41)) into the BNST but not into the CeA. In another experiment, hamsters given unilateral lesions of the CeA and infusions of D-Phe CRF((12-41)) into the contralateral BNST displayed significantly less submissive behavior than did controls. These data suggest that CRF acts within a neural circuit that includes the amygdala and the BNST to modulate agonistic behavior following social defeat.

There are striking differences in the behavioral response to social defeat between male and female Syrian hamsters. Whereas males exhibit a prolonged behavioral response to defeat (i.e., conditioned defeat), many females remain aggressive or show only a transient submissive response following defeat. The current study tested the hypothesis that sex steroids underlie this differential behavioral responsivity to social defeat. Female hamsters were ovariectomized and implanted with Silastic capsules containing estradiol (E(2)), testosterone (T), progesterone (P), dihydrotestosterone (DHT), or a blank capsule (no hormone replacement). After a 3-week recovery period, each subject was placed inside the home cage of a larger, more aggressive female for four 5-min defeat trials. The following day, each animal was tested for conditioned defeat by testing it in its own home cage in the presence of a smaller, non-aggressive intruder. Submissive, aggressive, social, and nonsocial behaviors were subsequently scored. Hamsters receiving E(2) or T displayed significantly lower levels of submissive behavior than did animals receiving P, DHT, or no hormone replacement. There were no significant differences in aggressive behavior among groups. These data suggest that gonadal hormones can influence submissive behavior in female hamsters. Collectively, these results suggest that the sex differences observed in conditioned defeat may, in part, be explained by sex differences in circulating gonadal hormones.

A brief exposure to social defeat in male Syrian hamsters (Mesocricetus auratus) leads to profound changes in the subsequent agonistic behavior exhibited by the defeated animals. Following defeat in the home cage of an aggressive conspecific, male hamsters will subsequently fail to defend their home territory even if the intruder is a smaller, nonaggressive male. This phenomenon has been called conditioned defeat. In Experiment 1, we examined the duration of conditioned defeat by repeatedly testing (every 3-5 days) defeated hamsters with a nonaggressive intruder. We found that conditioned defeat occurs in all defeated male hamsters and persists for a prolonged period of time (at least 33 days) in the majority of male hamsters tested despite the fact that these animals are never attacked by the nonaggressive intruders. In Experiment 2, we examined whether conditioned defeat could be induced in female Syrian hamsters. While conditioned defeat occurred in some females, they displayed only low levels of submissive/defensive behavior and, in contrast to males, the conditioned defeat response did not persist beyond the first test. These results suggest that in male hamsters conditioned defeat is a profound, persistent behavioral change characterized by a total absence of territorial aggression and by the frequent display of submissive and defensive behaviors. Conversely, social defeat in female hamsters does not appear to induce long-term behavioral changes. Finally, in Experiment 3, we determined that plasma adrenocorticotropin-like immunoreactivity increases in females following social defeat in a manner similar to that seen in males, suggesting that the disparate behavioral reactions of males and females are not due to sex differences in the release of, or response to, plasma adrenocorticotropin.

Circadian rhythms of physiology and behavior in mammals are driven by a circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus. The majority of neurons in the suprachiasmatic nucleus are GABAergic, and activation of GABA receptors in the suprachiasmatic nucleus can induce phase shifts of the circadian pacemaker both in vivo and in vitro. GABA also modulates the phase shifts induced by light in vivo, and photic information is thought to be conveyed to the suprachiasmatic nucleus by glutamate. In the present study, we examined the interactions between GABA receptor agonists, glutamate agonists, and light in hamsters in vivo. The GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen were microinjected into the suprachiasmatic nucleus at circadian time 13.5 (early subjective night), followed immediately by a microinjection of N-methyl-D-aspartate (NMDA). Both muscimol and baclofen significantly reduced the phase shifting effects of NMDA. Further, coadministration of tetrodotoxin with baclofen did not alter the inhibition of NMDA by baclofen, suggesting a postsynaptic mechanism for the inhibition of NMDA-induced phase shifts by baclofen. Finally, the phase shifting effects of microinjection of muscimol into the suprachiasmatic nucleus during the subjective day were blocked by a subsequent light pulse. These data suggest that GABA regulates the phase of the circadian clock through both pre- and postsynaptic mechanisms.

The present study examined the effect of endomorphin-1 (EM1), an endogenous opioid with a high affinity for the mu opiate receptor, on conditioned defeat. Conditioned defeat is a phenomenon in which hamsters that have been defeated subsequently fail to exhibit normal territorial aggression and instead display submissive/defensive behaviors even when paired with a non-aggressive intruder. In experiment 1, animals were placed in the home cage of a larger resident for 15 min and were defeated. After 24 h, animals received a 3-microl injection of EM1 (0.0, 0.3, 3.0, or 10 nmol) into the left lateral cerebral ventricle 5 min before a smaller non-aggressive intruder was placed in the home cage of the experimental animal. In experiment 2, animals were infused with EM1 immediately after the initial defeat and were paired with a non-aggressive intruder 24 h later as in experiment 1. EM1 reduced the duration of submissive/defensive behavior in experiment 1 (P0.05) but not in experiment 2 (P0.05). These data support the hypothesis that the highly selective mu receptor agonist endomorphin-1 modulates the expression of conditioned defeat, but provides no support for the hypothesis that endomorphin-1 modulates the consolidation of conditioned defeat.

During the middle of the subjective day, circadian activity rhythms in Syrian hamsters can be phase advanced by a variety of stimuli including microinjection of neuropeptide Y (NPY) or muscimol into the suprachiasmatic nucleus (SCN). It is not known, however, if these treatments shift activity rhythms by acting directly on pacemaker cells within the SCN. In the present study NPY and muscimol were microinjected with either tetrodotoxin or saline in order to determine whether classical synaptic transmission within the SCN is necessary for the phase advances produced by NPY or muscimol. Blockade of sodium-dependent action potentials within the SCN prevented NPY- but not muscimol-induced phase advances. These data, along with our previous finding that bicuculline blocks NPY-induced phase advances, suggest that NPY requires sodium-dependent action potentials within GABAergic neurons in order to phase-shift the circadian pacemaker.

This study investigated the effects of (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaline hydrobromide (8-OH-DPAT) on circadian rhythms in Syrian hamsters. Systemic administration of 8-OH-DPAT (0.75 mg in 150 microl saline) at circadian time 7 produced phase advances in the circadian activity rhythm. These 8-OH-DPAT-induced phase advances were blocked by microinjection of bicuculline (166 ng, 200 nl) into the suprachiasmatic nucleus, suggesting that GABAergic activity in the suprachiasmatic nucleus mediates the phase shifts produced by systemic injections of 8-OH-DPAT. Microinjection of 8-OH-DPAT (1 microg, 200 nl) or serotonin (0.7 microg, 200 nl) directly into the suprachiasmatic nucleus did not induce phase shifts at circadian time 7, suggesting that the phase shifting effects of systemic injection of 8-OH-DPAT are mediated outside the suprachiasmatic nucleus. To examine possible sites of action of 8-OH-DPAT, 8-OH-DPAT (0.5 microg (100 nl) or 1.0 microg (200 nl)) was microinjected into the intergeniculate leaflet, dorsal raphe nuclei, and the median raphe nucleus at circadian time 7. Significant phase advances were observed after microinjection into the dorsal raphe and median raphe but not the intergeniculate leaflet. These results support the hypothesis that systemic injection of serotonergic agonists can alter circadian rhythms via action in the midbrain raphe nucleus, and that the phase shifts induced by microinjection of 8-OH-DPAT into the raphe nuclei are mediated by a neurotransmitter other than serotonin within the suprachiasmatic nucleus.

The present study investigated the effects of gamma-amino butyric acid (GABA)A-active drugs on the ability of light or coadministration of vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), and gastrin-releasing peptide (GRP) to phase delay hamster activity rhythms. Microinjection of the GABAA agonist, muscimol, significantly (p < .01) reduced the phase-delaying effect of light administered at circadian time (CT) 13.5. By contrast, microinjection of the GABAA antagonist, bicuculline, significantly (p < .01) increased the phase-delaying effect of light administered at CT 13.5. Microinjection of muscimol or bicuculline into the suprachiasmatic nucleus (SCN) produced little or no effect on circadian phase when no light pulses were provided. Coadministration of muscimol with VIP/PHI/GRP significantly (p < .01) reduced the phase-delaying effect of VIP/PHI/GRP, whereas administration of bicuculline with VIP/PHI/ GRP significantly (p A activity within the SCN can modulate the phase-delaying effects of light and VIP/PHI/GRP during the early portion of subjective night.