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A reduction in the rewarding properties of social interactions is frequently a key contributor to neuropsychiatric disorders. Although much remains to be learned about the neural mechanisms governing social reward, numerous studies have found that oxytocin can enhance the salience of rewarding social interactions. As a result, oxytocin has been suggested as a pharmacotherapy for disorders characterized by a dampening of social motivation. However, exogenous oxytocin does not cross the blood-brain barrier effectively, which has led to the investigation of alternative approaches to induce central oxytocin release, such as pharmaceuticals targeting melanocortins. Although oxytocin treatment is widely viewed to increase social reward, there is also recent evidence that high concentrations of oxytocin can decrease social reward. In the present study we tested the hypothesis that alpha-melanocyte-stimulating hormone (αMSH) influences the rewarding properties of social interactions by acting on oxytocin receptors. Male and female Syrian hamsters were given intracerebroventricular infusions of saline, αMSH, or a cocktail containing αMSH and an oxytocin receptor antagonist during social conditioning with a same-sex hamster and then tested for a conditioned place preference. αMSH decreased preference for the socially-paired chamber compared to saline treatment, and administration of the oxytocin antagonist concurrent with αMSH administration returned subjects' preference to control levels. Importantly, αMSH treatments did not affect any measures of body composition or the specific social behaviors displayed during conditioning. These data suggest that melanocortin-targeting drugs should be administered carefully to avoid the possibility of decreasing the rewarding properties of social interactions.

The suprachiasmatic nucleus (SCN) contains a pacemaker that generates circadian rhythms and entrains them with the 24-h light-dark cycle (LD). The SCN is composed of 16,000 to 20,000 heterogeneous neurons in bilaterally paired nuclei. γ-amino butyric acid (GABA) is the primary neurochemical signal within the SCN and plays a key role in regulating circadian function. While GABA is the primary inhibitory neurotransmitter in the brain, there is now evidence that GABA can also exert excitatory effects in the adult brain. Cation chloride cotransporters determine the effects of GABA on chloride equilibrium, thereby determining whether GABA produces hyperpolarizing or depolarizing actions following activation of GABAA receptors. The activity of Na-K-2Cl cotransporter1 (NKCC1), the most prevalent chloride influx cotransporter isoform in the brain, plays a critical role in determining whether GABA has depolarizing effects. In the present study, we tested the hypothesis that NKCC1 protein expression in the SCN is regulated by environmental lighting and displays daily and circadian changes in the intact circadian system of the Syrian hamster. In hamsters housed in constant light (LL), the overall NKCC1 immunoreactivity (NKCC1-ir) in the SCN was significantly greater than in hamsters housed in LD or constant darkness (DD), although NKCC1 protein levels in the SCN were not different between hamsters housed in LD and DD. In hamsters housed in LD cycles, no differences in NKCC1-ir within the SCN were observed over the 24-h cycle. NKCC1 protein in the SCN was found to vary significantly over the circadian cycle in hamsters housed in free-running conditions. Overall, NKCC1 protein was greater in the ventral SCN than in the dorsal SCN, although no significant differences were observed across lighting conditions or time of day in either subregion. These data support the hypothesis that NKCC1 protein expression can be regulated by environmental lighting and circadian mechanisms within the SCN.

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.

Oxytocin (OT) and arginine vasopressin (AVP), as well as synthetic ligands targeting their receptors (OTR, V1aR), are used in a wide variety of research contexts, although their pharmacological properties are determined in only a few species. Syrian hamsters (Mesocricetus auratus) have a long history of use as a behavioural and biomedical model for the study of OT and AVP and, more recently, hamsters have been used to investigate behavioural consequences of OT-mediated activation of V1aR. We aimed to determine the binding affinities of OT, AVP and the selective V1aR antagonist, Manning compound, for OTR and V1aR in hamster brains. We performed saturation binding assays to determine the Kd values for the selective OTR and V1aR radioligands, [125 I]ornithine vasotocin analogue and [125 I]linear vasopressin antagonist. We then performed competition binding assays to determine Ki values for OT, AVP and Manning compound at both the OTR and V1aR. We found that OT and AVP each had the highest affinity for their canonical receptors (OT-OTR Ki = 4.28 [95% confidence interval (CI) = 2.9-6.3] nmol L-1 ; AVP-V1ar Ki = 4.70 [95% CI = 1.5-14.1] nmol L-1 ) and had the lowest affinity for their non-canonical ligands (OT-V1aR = 495.2 [95% CI = 198.5-1276] nmol L-1 ; AVP-OTR Ki = 36.1 [95% CI = 12.4-97.0] nmol L-1 ). Manning compound had the highest affinity for the V1aR (MC-V1aR Ki = 6.87 [95% CI = 4.0-11.9] nmol L-1 ; MC-OTR Ki = 213.8 [95% CI = 117.3-392.7] nmol L-1 ), although Manning compound was not as selective for the V1aR in hamsters as has been reported for the receptor in rats. When comparing these data with previously published work, we found that the promiscuity of the V1aR in hamsters with respect to OT and AVP binding is more similar to the promiscuity of the human V1aR than to the rat V1aR receptor. Moreover, the selectivity of OT at hamster receptors is more similar to the selectivity of OT at human receptors than the selectivity of OT at rat receptors. These data highlight the importance of determining the pharmacological properties of behaviourally relevant compounds in diverse model species.

The rewarding properties of social interactions play a critical role in the development and maintenance of social relationships, and deficits in social reward are associated with various psychiatric disorders. In the present study, we used a novel Operant Social Preference (OSP) task to investigate the reinforcing properties of social interactions under conditions of high or low reward value, and high or low behavioral effort in male Syrian hamsters. Further, we investigated the role of oxytocin (OT) in a key structure of the mesolimbic reward system, the ventral tegmental area (VTA), in mediating the reinforcing properties of social interaction. Adult male hamsters were placed in a three-chambered apparatus, and allowed access to either a social chamber containing an unrestrained conspecific or a non-social chamber, by pushing through a one-way entry, vertical-swing door. Increasing the duration of social interaction (reward value) decreased the frequency of entering the social interaction chambers, whereas decreasing the duration of social interaction conversely increased the frequency of entries. Moreover, increasing behavioral effort required to access social interaction decreased the frequency of entries, especially under conditions when the duration of social interaction was only 5 s. OT injected into the VTA decreased the frequency of entering social interaction chambers in a manner similar to that observed when duration was increased, whereas injection of an OT receptor antagonist in the VTA increased the frequency of seeking social interaction. Taken together, these data support the hypothesis that activation of OT receptors in the VTA are critical for the reinforcing properties of social interactions. Furthermore, social interactions may exhibit duration and cost dependent reinforcing effects on behavior similar to those observed with food and drugs of abuse.

Changes in photoperiod length are transduced into neuroendocrine signals by melatonin (MEL) secreted by the pineal gland triggering seasonally adaptive responses in many animal species. Siberian hamsters, transferred from a long-day ‘summer-like’ photoperiod (LD) to a short-day ‘winter-like’ photoperiod (SD), exhibit a naturally-occurring reversal in obesity. Photoperiod-induced changes in adiposity are mediated by the duration of MEL secretion and can be mimicked by exogenously administered MEL into animals housed in LD. Evidence suggests that MEL increases the sympathetic nervous system (SNS) drive to white adipose tissue (WAT). Here, we investigated whether MEL-driven seasonally adaptive losses in body fat are associated with WAT lipolysis and browning. Hamsters were subcutaneously administered vehicle (LD + VEH) or 0.4 mg/kg MEL (LD + MEL) daily for 10 weeks while animals housed in SD served as a positive control. MEL and SD exposure significantly decreased the retroperitoneal (RWAT), inguinal (IWAT), epididymal (EWAT) WAT, food intake and caused testicular regression compared with the LD + VEH group. MEL/SD induced lipolysis in the IWAT and EWAT, browning of the RWAT, IWAT, and EWAT, and increased UCP1 expression in the IBAT. Additionally, MEL/SD significantly increased the number of shared MEL receptor 1a and dopamine beta-hydroxylase-immunoreactive neurons in discrete brain sites, notably the paraventricular hypothalamic nucleus, dorsomedial hypothalamic nucleus, arcuate nucleus, locus coeruleus and dorsal motor nucleus of vagus. Collectively, these findings support our hypothesis that SD-exposed Siberian hamsters undergo adaptive decreases in body adiposity due to SNS-stimulated lipid mobilization and generalized WAT browning.

Understanding the neurobiological mechanisms mediating dominance and competitive aggression is essential to understanding the development and treatment of various psychiatric disorders. Previous research suggests that these mechanisms are both sexually differentiated and influenced substantially by social experience. In numerous species, GABA(A) receptors in the lateral septum have been shown to play a significant role in aggression in males. However, very little is known about the role of these GABA(A) receptors in female aggression, the role of social experience on GABA(A) receptor mediated aggression, or the roles of different GABA(A) subtypes in regulating aggression. Thus, in the following set of experiments we determined the role of social experience in modulating GABA(A) receptor induced aggression in both male and female Syrian hamsters, with a particular focus on the GABA(A) receptor subtype mediating these effects. Activation of GABA(A) receptors in the dorsal lateral septum increased aggression in both males and females. Social housing, however, significantly decreased the ability of GABA(A) receptor activation to induce aggression in males but not females. No significant differences were observed in the effects of GABA(A) receptor activation in dominant and subordinate group housed hamsters. Finally, examination of potential GABA(A) receptor subtype specificity revealed that social housing decreased the ratio of extrasynaptic to synaptic subunit GABA(A) receptor mRNA expression in the anterior dorsal lateral septum. While activation of extrasynaptic, but not synaptic GABA(A) receptors in the dorsal lateral septum increased aggression. These data suggest that social experience can have profound effects on the neuronal mechanisms mediating aggression, especially in males, and that δ extrasynaptic GABA(A) receptors may be an important therapeutic target in disorders characterized by high levels of aggression.

Social recognition is a fundamental requirement for all forms of social relationships. A majority of studies investigating the neural mechanisms underlying social recognition in rodents have investigated relatively neutral social stimuli such as juveniles or ovariectomized females over short time intervals (e.g., 2h). The present study developed a new testing model to study social recognition among adult males using a potent social stimulus. Flank gland odors are used extensively in social communication in Syrian hamsters and convey important information such as dominance status. We found that the recognition of flank gland odors after a 3min exposure lasted for at least 24h, substantially longer than the recognition of other social cues in rats and mice. Intracerebroventricular injections of OT and AVP prolonged the recognition of flank gland odor for up to 48h. Selective OTR but not V1aR agonists, mimicked these enhancing effects of OT and AVP. Similarly, selective OTR but not V1aR antagonists blocked recognition of the odors after 20min. In contrast, the recognition of non-social stimuli was not blocked by either the OTR or the V1aR antagonists. Our findings suggest both OT and AVP enhance social recognition via acting on OTRs and not V1aRs and that the recognition enhancing effects of OT and AVP are limited to social stimuli.

Social reward is critical for social relationships, and yet we know little about the characteristics of social interactions that are rewarding or the neural mechanisms underlying that reward. Here, we investigate the sex-dependent role of oxytocin receptors within the ventral tegmental area (VTA) in mediating the magnitude and valence of social reward. Operant and classical conditioning tests were used to measure social reward associated with same-sex social interactions. The effects of oxytocin, selective oxytocin receptor agonists, antagonists, and vehicle injected into the VTA on social reward was determined in male and female Syrian hamsters. The colocalization of FOS and oxytocin in sites that project to the VTA following social interaction was also determined. Females find same-sex social interactions more rewarding than males and activation of oxytocin receptors in the VTA is critical for social reward in females, as well as males. These studies provide support for the hypothesis that there is an inverted U relationship between the duration of social interaction and social reward, mediated by oxytocin; and that in females the dose-response relationship is initiated at lower doses compared with males. Same-sex social interaction is more rewarding in females than in males, and an inverted U relationship mediated by oxytocin may have a critical role in assigning positive and negative valence to social stimuli. Understanding these sex differences in social reward processing may be essential for understanding the sex differences in the prevalence of many psychiatric disorders and the development of gender-specific treatments of neuropsychiatric disorders.

Over 90% of neurons within the suprachiasmatic nucleus (SCN) express γ-aminobutyric acid (GABA). Although GABA is primarily an inhibitory neurotransmitter, in vitro studies suggest that the activation of GABAA receptors (GABAAR) elicits excitation in the adult SCN. The ratio of excitatory to inhibitory responses to GABA depends on the balance of chloride influx by Na+-K+-Cl– cotransporter 1 (NKCC1) and chloride efflux by K+-Cl– cotransporters (KCCs). Excitatory responses to GABA can be blocked by inhibition of the inward chloride cotransporter, NKCC1, with the loop diuretic bumetanide. Here we investigated the role of NKCC1 activity in phase shifting the circadian pacemaker in response to photic and nonphotic signals in male Syrian hamsters housed in constant darkness. In the early subjective night (CT 13.5), injection of bumetanide into the SCN reduced light-induced phase delays. However, during the late subjective night (CT 19), bumetanide administration did not alter light-induced phase advances. Injection of bumetanide during the subjective day (CT 6) did not alter the phase of free-running circadian rhythms but attenuated phase advances induced by injection of the GABAAR agonist muscimol into the SCN. These data support the hypothesis that the excitatory effects of endogenously released GABA contribute to the ability of light to induce phase delays, thereby contributing to the most important function of the circadian system, its entrainment with the day-night cycle. Further, the finding that bumetanide inhibits the phase-advancing effects of muscimol during the subjective day supports the hypothesis that the excitatory responses to GABA also contribute to the ability of nonphotic stimuli to phase shift the circadian pacemaker.

The suprachiasmatic nucleus (SCN) contains a circadian clock that generates endogenous rhythmicity and entrains that rhythmicity with the day-night cycle. The neurochemical events that transduce photic input within the SCN and mediate entrainment by resetting the molecular clock have yet to be defined. Because GABA is contained in nearly all SCN neurons we tested the hypothesis that GABA serves as this signal in studies employing Syrian hamsters (Mesocricetus auratus). Activation of GABAA receptors was found to be necessary and sufficient for light to induce phase delays of the clock. Remarkably, the sustained activation of GABAA receptors for more than three consecutive hours was necessary to phase delay the clock. The duration of GABAA receptor activation required to induce phase delays would not have been predicted by either the prevalent theory of circadian entrainment or by expectations regarding the duration of ionotropic receptor activation necessary to produce functional responses. Taken together, these data identify a novel neurochemical mechanism essential for phase delaying the “master” circadian clock within the SCN as well as identifying an unprecedented action of an amino acid neurotransmitter involving the sustained activation of ionotropic receptors.

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.

Social reward plays a fundamental role in shaping human and animal behavior. The rewarding nature of many forms of social behavior including sexual behavior, parental behavior, and social play has been revealed using well-established procedures such as the conditioned place preference test. Many motivated social behaviors are regulated by the nonapeptides oxytocin (OT) and arginine vasopressin (AVP) through their actions in multiple brain structures. Interestingly, there are few data on whether OT or AVP might contribute to the rewarding properties of social interaction by their actions within brain structures that play a key role in reward mechanisms such as the ventral tegmental area (VTA). The goal of the present study was to investigate the role of OT and AVP in the VTA in regulating the reward-like properties of social interactions. Social interactions between two male hamsters reduced a spontaneous place avoidance in hamsters injected with saline control. Interestingly, however, OT and AVP injected into the VTA induced a significant two-fold reduction in place avoidance for the social interaction chamber when compared to control injections of vehicle. Finally, because OT and AVP can act on each other’s receptors to influence social behavior, we also injected highly selective OTR and V1aR agonists and antagonists to determine whether OT or AVP V1a receptors were responsible for mediating the effects of these neuropeptides on social reward. Our results not only demonstrated that OT and AVP activate OTRs and not V1aRs to mediate social reward, they also demonstrated that the activation of OT receptors in the VTA is essential for the expression of the rewarding properties of social interactions.

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.

Seasonal changes in the length of the daily photoperiod induce significant changes in social behavior. Hamsters housed in winter-like short photoperiods (SP) can express significantly higher levels of aggression than hamsters housed in long photoperiods (LP) that mimic summer. The mechanisms responsible for increasing aggressiveness in SP-exposed female hamsters are not well understood but may involve seasonal changes in the endocrine system. In experiment 1, the effects of SP exposure on the circulating levels of three adrenal hormones were determined. Short photoperiod exposure was found to significantly depress the circulating levels of cortisol and the adrenal androgen dehydropiandrosterone (DHEA) but significantly increased the circulating levels of the sulfated form of DHEA, DHEAS. Experiment 2 examined the effects of gonadal hormones on several different measures of aggression including its intensity in females housed in both long and short photoperiod. Exposure to SP resulted in high levels of aggression regardless of the endocrine state of the animal or the measure used to quantify aggression. In contrast, administration of estradiol to hamsters housed in LP significantly reduced aggression. The data of the present study support the hypothesis that SP-housed females are more aggressive than LP-housed females because SP exposure renders females insensitive to the aggression-reducing effects of ovarian hormones.

Microinjection of arginine vasopressin (Avp) into the rostral hypothalamus of Syrian hamsters induces a form of scent marking known as flank marking. The ability of Avp to stimulate flank marking is mediated by the vasopressin 1a receptor (Avpr1a). In hamsters housed in long 'summer-like' photoperiods, the amount of flank marking and the number of Avpr1a receptors in the rostral hypothalamus are regulated by testosterone. However, hamsters housed in short 'winter-like' photoperiods for 6-8 weeks continue to flank mark at high levels despite significant reductions in the circulating levels of testosterone. In the present study, we compared the effects of gonadal steroids on Avp-induced flank marking and Avpr1 a binding and affinity in hamsters housed in short photoperiods and those housed in long photoperiods. In long-photoperiod-housed hamsters, castration significantly reduced the amount of Avp-induced flank marking; however, in short-photoperiod-housed hamsters there were no significant differences between gonadally regressed and castrated hamsters. Surprisingly, Avpr1a receptor binding, but not affinity, in the medial preoptic area and the medial preoptic nucleus was significantly reduced in long-photoperiod-housed castrates as well as short-photoperiod-housed gonadally regressed and castrated hamsters, compared with long-photoperiod-housed gonadally intact hamsters. These data demonstrate that in short photoperiods Avp-induced flank marking is independent of gonadal hormones, despite gonadal steroid-dependent reductions in Avpr1a binding.

Activation of γ-aminobutyric acid (GABA)A receptors in the suprachiasmatic nucleus (SCN) resets the circadian clock during the day and inhibits the ability of light to reset the clock at night. Light in turn acts during the day to inhibit the phase-resetting effects of GABA. Some evidence suggests that Period mRNA changes in the SCN are responsible for these interactions between light and GABA. Here, the hypothesis that light and the GABAA receptor interact by altering the expression of Period 1 and/or Period 2 mRNA in the SCN is tested. The GABAA agonist muscimol was injected near the SCN just prior to a light pulse, during the mid-subjective day and the early and late subjective night. Changes in Period 1 and Period 2 mRNA were measured in the SCN by in situ hybridization. Light-induced Period 1 mRNA was inhibited by GABAA receptor activation in the early and late subjective night, while Period 2 mRNA was only inhibited during the late night. During the subjective day, light had no effect on the ability of muscimol to suppress Period 1 mRNA hybridization signal. Thus, light and GABA A receptor activation inhibit each other's ability to induce behavioral phase shifts throughout the subjective day and night. However, only in the late night are these behavioral effects correlated with changes in Period gene expression. Together, our data support the hypothesis that the interacting effects of light and GABA are the result of the opposing actions of these stimuli on Period mRNA, but only during the subjective night.

The circadian clock in the suprachiasmatic nucleus (SCN) is synchronized by the 24 h, light : dark cycle, and is reset by photic and non-photic cues. The acute effects of light in the SCN include the increase of mRNA levels of the circadian clock gene Per1 and a dramatic reduction of pineal melatonin. Neuropeptide Y (NPY), which appears to mediate the phase-resetting effects of non-photic stimuli, prevents the ability of light, and stimuli that mimic light, to phase shift the circadian clock when injected into the SCN. The purpose of the present study was to determine if NPY inhibits the ability of light to suppress pineal melatonin. Surprisingly, NPY injected into the SCN of hamsters mimicked the effects of light by suppressing pineal melatonin levels. To confirm that NPY inhibited the effects of light on the induction of Per1 mRNA levels, Per1 mRNA levels in the SCN were measured in these same animals. NPY significantly reduced Per1 mRNA levels induced by the light pulse. The suppression of melatonin by NPY appears to be mediated by the same subtype of NPY receptors in the SCN that mediate the modulation of phase shifts. Injection of Y5 receptor agonists mimicked the effects of NPY on pineal melatonin, while injection of a Y2 agonist did not. Thus, these data are the first to demonstrate the paradoxical effects of NPY within the SCN. NPY mimics the effects of light on pineal melatonin and inhibits the effects of light on the induction of Per1 mRNA.

Circadian rhythms are reset by light during the night or by nonphotic stimuli during the day. Neuropeptide Y (NPY), which appears to mediate at least some nonphotic phase shifts by its actions in the suprachiasmatic nucleus (SCN), induces phase advances during the day and inhibits light-induced phase advances during the night. In this study, we used a highly selective Y5-like agonist to test whether activation of NPY Y5 receptors is sufficient to mimic NPY during the day and late night in Syrian hamsters. We also tested whether NPY in the early night reduces light-induced phase delays in a dose-dependent manner. Microinjection of a selective Y5 receptor agonist, (Ala31, Aib32)-NPY, into the SCN significantly inhibited light-induced phase advances during the late night, but did not induce phase advances during the day. In addition, concentrations of NPY ranging from 0.23 to 23 mM did not attenuate light-induced phase delays in the early night. These results suggest that activation of Y5-like receptors is sufficient to inhibit light-induced phase advances during the late night but is not sufficient to induce phase advances during the day. Furthermore, this study provided no evidence that NPY can inhibit light-induced phase shifts early in the night.

Syrian hamsters are photoperiodic and become sexually quiescent when exposed to short "winter-like" photoperiods. In short photoperiods, male hamsters display significantly higher levels of aggression than males housed in long photoperiods. Arginine-vasopressin (AVP) within the anterior hypothalamus (AH) has been reported to modulate aggression in hamsters housed in long photoperiods. Previous studies have shown that AVP can facilitate aggression and its effects appear to be mediated by AVP V(1a) receptors (V(1a)R). In the present study, we investigated whether the increased levels of aggression observed after exposure to short photoperiod were the result of an increased responsiveness to AVP within the AH. Injections of AVP into the AH significantly increased aggression in hamsters housed in a long photoperiod, but had no effect in hamsters housed in a short photoperiod. In addition, injection of a V(1a)R antagonist into the AH significantly inhibited aggression in hamsters housed in long photoperiod, but had no effect in hamsters housed in a short photoperiod. These findings indicate that AVP within the AH increases aggression in hamsters housed in long photoperiods, but not in hamsters housed in short photoperiods.

Light resets the circadian clock in the suprachiasmatic nucleus (SCN) during the night and inhibits the ability of non-photic stimuli, such as injection of muscimol, to reset the clock during the day. Since activation of NMDA receptors appears to mediate the effects of light in the SCN, we investigated whether there are day-night differences in the SCN responses to NMDA. During the night, microinjection of NMDA mimicked the ability of light to induce phase delays, and these effects were not inhibited by blocking Na + -dependent action potentials with tetrodotoxin (TTX). During the day, NMDA mimicked the ability of light to inhibit muscimol-induced phase advances; however, this was inhibited by TTX. These data suggest that Na + -dependent action potentials within the SCN are required for NMDA to mimic the effects of light during the day but not during the night.

One brain region that has been implicated in the regulation of lordosis is the medial preoptic-anterior hypothalamic continuum (MPOA-AH). Previous studies have suggested that this zone may be part of the circuit mediating the effects of serotonin (5-HT) on sexual receptivity. In the present experiments, we investigated the role of 5-HT 1a/7 and 5-HT 2 receptor subtypes in the MPOA-AH in the control of lordosis. In two experiments, either 5-HT 1a/7 or 5-HT 2 agonists were injected unilaterally into the MPOA-AH of ovariectomized, hormonally primed female hamsters. In the first experiment, microinjections of the 5-HT 1a/7 agonist 8-hydroxy-2,9-(di- n -propylamino)tetralin resulted in an attenuation of the lordosis posture by causing a decrease in the mean lordosis duration and an increase in the number of lordosis episodes over the entire testing period. In the second experiment, microinjections of the 5-HT 2b/2c agonist m -chlorophenylpiperazine did not result in any changes in sexual receptivity. However, microinjections of the 5-HT 2 agonist (2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl facilitated lordosis by increasing the mean lordosis duration and decreasing the number of lordosis episodes in the first 5 min of the testing period. These data indicate that serotonin may act in the MPOA-AH via 5-HT 1a/7 receptors to attenuate and 5-HT 2 receptors to facilitate sexual receptivity.

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.

Historically, research on the neuroendocrinology of aggression has been dominated by the paradigm that the brain receives sex steroid hormones, such as testosterone (T), from the gonads, and then these gonadal hormones modulate behaviorally relevant neural circuits. While this paradigm has been extremely useful for advancing the field, recent studies reveal important alternatives. For example, most vertebrate species are seasonal breeders, and many species show aggression outside of the breeding season, when the gonads are regressed and circulating levels of gonadal steroids are relatively low. Studies in diverse avian and mammalian species suggest that adrenal dehydroepiandrosterone (DHEA), an androgen precursor and prohormone, is important for the expression of aggression when gonadal T synthesis is low. Circulating DHEA can be converted into active sex steroids within the brain. In addition, the brain can synthesize sex steroids de novo from cholesterol, thereby uncoupling brain steroid levels from circulating steroid levels. These alternative mechanisms to provide sex steroids to specific neural circuits may have evolved to avoid the costs of high circulating T levels during the non-breeding season. Physiological indicators of season (e.g., melatonin) may allow animals to switch from one neuroendocrine mechanism to another across the year. DHEA and neurosteroids are likely to be important for the control of multiple behaviors in many species, including humans. These studies yield fundamental insights into the regulation of DHEA secretion, the mechanisms by which DHEA affects behavior, and the brain regions and neural processes that are modulated by DHEA. It is clear that the brain is an important site of DHEA synthesis and action. This article is part of a Special Issue entitled 'Essential role of DHEA'.

Recently, endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 ; EM1), an endogenous peptide that has high affinity and selectivity for the μ-opiate receptor, has been shown to modulate emotional behavior in mice and social behavior in Syrian hamsters. Endomorphin-1 (EM1) is present throughout the central nervous system in rats, mice, and guinea pigs; however, the distribution of EM1 in hamsters has not been described. The purpose of the present study was to investigate the distribution of EM1-like immunoreactivity (EM1L-IR) in the limbic system of Syrian hamsters using immunocytochemistry. Perikarya containing EM1L-IR were present in the anterior area, dorsomedial, ventromedial, periventricular, posterior, and arcuate nuclei of the hypothalamus. Fibers expressing EM1L-IR were present in the nucleus accumbens, caudate putamen, septum, bed nucleus of the stria terminalis, amygdaloid complex, and hypothalamus. The distribution of EM1 suggests a potential endogenous role for this peptide in major processes modulated by opiates, including affective states and social behavior.

Male sexual behavior is mediated in part by androgens, but in several species, mating is also influenced by estradiol formed locally in the brain by the aromatization of testosterone. The role of testosterone aromatization in the copulatory behavior of male Syrian hamsters is unclear because prior studies are equivocal. Therefore, the present study tested whether blocking the conversion of testosterone to estradiol would inhibit male hamster sexual behavior. Chronic systemic administration of the nonsteroidal aromatase inhibitor Fadrozole (2.0 mg/kg/day) for 5 or 8 weeks did not significantly increase mount latency or reduce mount frequency, intromission frequency, ejaculation frequency, or anogenital investigation relative to levels shown by surgical controls. However, Fadrozole effectively inhibited aromatase activity, as evidenced by the suppression of estrogen-dependent progesterone receptor immunoreactivity in the male hamster brain. The JZB39 anti-progesterone receptor antibody labeled significantly more neurons in brains of sham-treated hamsters than in brains of Fadrozole-treated hamsters. These data suggest that aromatization of testosterone to estradiol is not necessary for normal mating behavior in Syrian hamsters.

In Syrian hamsters, vasopressin (AVP) in the medial preoptic-anterior hypothalamus (MPOA-AH) controls a form of scent marking called flank marking. Another neurochemical signal that may interact with AVP to control flank marking is glutamate. We tested the hypothesis that glutamate interacts with AVP in the MPOA-AH to regulate flank marking. On day 1, AVP was microinjected into the MPOA-AH. On day 2, AVP was microinjected as a cocktail combining either AP-5, a NMDA antagonist, or GAMS, a non-NMDA antagonist or propranolol, a β norepinephrine antagonist. On day 3, AVP alone was microinjected. Hamsters engaged in high levels of marking in response to AVP alone or to a combination of AVP and propranolol. In contrast, the frequency of marking was significantly reduced in response to a combination of either AVP and AP-5 or AVP and GAMS. These data support the hypothesis that stimulation of flank marking by AVP within the MPOA-AH requires the activity of glutamate.

In Syrian hamsters ( Mesocricetus autatus ) arginine-vasopressin (AVP) within the medial preoptic-anterior hypothalamus (MPOA-AH) plays a critical role in the control of a hormone-dependent behavior called flank marking. The present study investigated whether ovarian hormones influence flank marking by altering the response of the MPOA-AH to AVP. The amount of flank marking stimulated by microinjection of AVP (9 μ M in 200 nl saline) into the MPOA-AH varied significantly over the 4 days of the estrous cycle with the lowest levels of flank marking observed on estrus. A second experiment demonstrated that administration of progesterone significantly reduced AVP-stimulated flank marking in estradiol-treated ovariectomized hamsters. These data support the hypothesis that the changing levels of estradiol and progesterone during the estrous cycle influence flank marking by altering the sensitivity or response of the MPOA-AH to AVP.

Oxytocin (OXT) has been implicated in the control of a variety of social and reproductive behaviors in several species. The purpose of the present study was to test the hypothesis that OXT activity within the medial preoptic-anterior hypothalamus (MPOA-AH) and the ventromedial hypothalamus (VMH) plays a critical role in the expression of sexual receptivity in Syrian hamsters. The first 2 experiments investigated whether OXT would stimulate sexual receptivity in female hamsters in a dose-dependent manner. A 3rd experiment investigated whether sexual receptivity would be inhibited when endogenous OXT activity was blocked. Microinjection of OXT into the MPOA-AH or the VMH induced sexual receptivity in a dose-dependent manner in ovariectomized (OVX) hamsters primed with estradiol. Microinjection of a selective OXT antagonist, d(CH2)5[Tyr(Me)2Thr4,Tyr-NH29] ornithine vasotocin into the MPOA-AH or the VMH significantly reduced the levels of sexual receptivity exhibited by OVX hamsters administered estradiol and progesterone. These findings support the hypothesis that OXT activity in the MPOA-AH and the VMH plays an important role in the regulation of sexual receptivity in hamsters.

Arginine vasopressin (AVP) plays an important role in the control of a gonadal hormone-dependent communicative behavior in the Syrian hamster (Mesocricetus auratus) called flank marking. Previous studies have shown that gonadal hormones alter the amount of flank marking stimulated by the microinjection of AVP into the medial preoptic area-anterior hypothalamus (MPOA-AH). The purpose of the present study was to determine if testicular hormones alter the amount of flank marking stimulated by the microinjection of AVP into two other sites involved in the control of flank marking, the lateral septum-bed nucleus of the stria terminalis (LS-BNST) and the central gray. The data of the present study indicate that testicular hormones may influence the amount of AVP-stimulated marking in the central gray and LS-BNST; however, these effects are subtle and appear to occur primarily at high concentrations of AVP. When taken together with previous studies, these data indicate that gonadal hormones have greater effects on AVP-stimulated marking in the MPOA-AH than in the LS-BNST or central gray.

Arginine-vasopressin (AVP) activation of V1a AVP receptors in the medial preoptic area-anterior hypothalamus (MPOA-AH) plays a critical role in the control of a form of social communication called flank marking. The ability of AVP and V1a receptors in the MPOA-AH to regulate flank marking is modulated by a number of factors including galanin (GAL), serotonin (5-HT) and gonadal hormones. More recent studies suggest that there may be seasonal differences in the number or type of AVP receptors in the MPOA-AH controlling flank marking or in the modulation of these mechanisms by GAL or 5-HT. The purpose of the present study was to examine how exposure to "summer-like" and "winter-like" photoperiods alters the neural mechanisms regulating flank marking. These studies confirmed that V1a AVP receptors, but not V1b AVP receptors play a significant role in controlling flank marking in the MPOA-AH in both LP and SP-housed hamsters. These studies also found that there were no significant differences between hamsters housed in LP and SP in the ability of serotonin 5-HT1a/7 and 5-HT1b receptor agonists injected into the MPOA-AH to inhibit odor-induced flank marking. Finally, these studies found that GAL could significantly inhibit the ability of AVP to stimulate flank marking in SP-housed hamsters and that there were no differences between hamsters housed in LP and SP in the ability of a GAL antagonist to inhibit AVP-induced flank marking. The present study confirms that V1a receptors are critical for AVP regulation of flank marking and that photoperiodic mechanisms do not alter the modulation of flank marking by GAL or 5-HT in the MPOA-AH.

In Syrian hamsters (Mesocricetus auratus), precopulatory behaviors such as vaginal scent marking are essential for attracting a suitable mate. Vaginal marking is dependent on forebrain areas implicated in the neural regulation of reproductive behaviors in rodents, including the medial preoptic/anterior hypothalamus (MPOA-AH). Within MPOA-AH, the neuropeptide oxytocin (OT) acts to facilitate copulation (lordosis), as well as ultrasonic vocalizations towards males. It is not known, however, if OT in this area also facilitates vaginal marking. In the present study, a specific oxytocin receptor antagonist (OTA) was injected into MPOA-AH of intact female Syrian hamsters to determine if oxytocin receptor-dependent signaling is critical for the normal expression of vaginal marking elicited by male, female, and clean odors. OTA injections significantly inhibited vaginal marking in response to male odors compared with vehicle injections. There was no effect of OTA on marking in response to either female or clean odors. When injected into the bed nucleus of the stria terminalis (BNST), a nearby region to MPOA-AH, OTA was equally effective in decreasing marking. Finally, the effects of OTA appear to be specific to vaginal marking, as OTA injections in MPOA-AH or BNST did not alter general locomotor activity, flank marking, or social odor investigation. Considered together, these results suggest that OT in MPOA-AH and/or BNST normally facilitates male odor-induced vaginal marking, providing further evidence that OT generally supports prosocial interactions among conspecifics.

The mammalian circadian clock can be entrained by photic and nonphotic environmental time cues. gamma-aminobutyric acid (GABA) is a nonphotic stimulus that induces phase advances in the circadian clock during the middle of the subjective day. Several nonphotic stimuli suppress Period 1- and Period 2 mRNA expression in the suprachiasmatic nucleus (SCN); however, the effect of GABA on Period mRNA is unknown. In the present study we demonstrate that microinjection of the GABA(A) receptor agonist muscimol into the SCN region suppresses the expression of Period 1 mRNA in the hamster. A significant suppression of Period 2 mRNA following microinjection of muscimol was not observed in free-running conditions. However, Period 2 mRNA was significantly reduced following muscimol treatment when animals were maintained under a light cycle and transferred to constant darkness 42 h prior to treatment. An additional study investigated the maximum behavioural phase advance inducible by GABA(A) receptor activation.Together, these data indicate that, like other nonphotic stimuli, GABA suppresses Period 1- and Period 2 mRNA in the SCN.

Glutamate is the primary excitatory transmitter in the hypothalamus. It conveys photic information to the suprachiasmatic nucleus of the hypothalamus, thereby entraining the circadian clock to environmental light cycles. While ionotropic glutamate receptors have been implicated in the transduction of photic information in suprachiasmatic nucleus cells, there is evidence that metabotropic glutamate receptors play a significant modulatory role. We investigated the effects of the metabotropic glutamate agonist (±)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD) on light-evoked phase responses in Syrian hamsters at three phase points: circadian time 6, a time when light has no effect on the circadian timing system; circadian time 13.5, when light evokes the maximum phase delay; and circadian time 19, the maximum phase advance. We found that ACPD significantly increased the light-evoked phase shift at circadian time 13.5, and had no effect at other phase points tested. These data support a role for metabotropic glutamate receptors in the circadian photic signal transduction system.

Adolescence is a period during which many social behaviors emerge. One such behavior, flank marking, is a testosterone-modulated scent marking behavior that communicates dominance status between adult male Syrian hamsters. Testosterone modulates flank-marking behavior by altering neural transmission of vasopressin within a forebrain circuit. This study tested whether testicular hormones secreted during adolescence play purely a transient activational role in the display of flank-marking behavior, or whether adolescent steroid hormone secretions also cause long-term organizational changes in vasopressin binding within brain regions underlying flank-marking behavior. We tested this hypothesis by manipulating whether testicular secretions were present during adolescent development and then tested for flank-marking behavior and vasopressin receptor binding within the flank-marking neural circuit in young adulthood. Specifically, males were gonadectomized immediately before or after adolescence, replaced with testosterone 6 weeks following gonadectomy in young adulthood, and behavior tested 1 week later. Adult testosterone treatment activated flank-marking behavior only in males that were exposed to testicular hormones during adolescence. In addition, males exposed to testicular hormones during adolescence exhibited significantly less vasopressin receptor binding within the lateral septum than males deprived of adolescent hormones, suggesting that hormone-dependent remodeling of synapses normally occurs in the lateral septum during adolescence. These data highlight the importance of gonadal steroid hormone exposure during adolescence for the organization of neural circuits and social behavior.

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 daily light:dark cycle synchronizes the circadian timing system by resetting the phase of the circadian pacemaker on a daily basis. Light acutely increases mRNA levels of the clock genes Per1 and Per2 in the suprachiasmatic nucleus (SCN), the site of the primary circadian pacemaker in mammals. Light is conveyed to the SCN through the retinohypothalamic tract (RHT), an efferent projection from retinal ganglion cells that releases the excitatory amino acid (EAA) neurotransmitter glutamate in the SCN. EAA receptor activation in the SCN is critical for the ability of light to phase-shift the circadian pacemaker. In a previous study, we demonstrated that EAA receptor activation is necessary and sufficient for light to acutely increase Per1 mRNA levels in the SCN. In the current study, we determined whether EAA receptor activation in the SCN is necessary for the ability of light to increase Per2 mRNA levels in the SCN in Syrian hamsters. The NMDA receptor antagonist AP5 and the AMPA/kainate receptor antagonist DNQX inhibited the ability of light and NMDA to acutely increase Per2 mRNA levels in the SCN. In hamsters injected with DNQX, Per1 and Per2 mRNA levels remained slightly elevated in the ventrolateral SCN, suggesting that AMPA/kainate receptor activation in this region is not critical for the effects of light on the circadian pacemaker.

The suprachiasmatic nucleus (SCN) of the anterior hypothalamus contains a light-entrainable circadian pacemaker. Neurons in the SCN are part of a circuit that conveys light information from retinal efferents to the pineal gland. Light presented during the night acutely increases mRNA levels of the circadian clock genes Per1 and Per2 in the SCN, and acutely suppresses melatonin levels in the pineal gland. The present study investigated whether the ability of light to increase Per1 and Per2 mRNA levels and suppress pineal melatonin levels requires sodium-dependent action potentials in the SCN. Per1 and Per2 mRNA levels in the SCN and pineal melatonin levels were measured in Syrian hamsters injected with tetrodotoxin (TTX) prior to light exposure or injection of N-methyl-d-aspartate (NMDA). TTX inhibited the ability of light to increase Per1 and Per2 mRNA levels and suppress pineal melatonin levels. TTX did not, however, influence the ability of NMDA to increase Per1 and Per2 mRNA levels, though it did inhibit the ability of NMDA to suppress pineal melatonin levels. These results demonstrate that action potentials in the SCN are not necessary for NMDA receptor activation to increase Per1 and Per2 mRNA levels, but are necessary for NMDA receptor activation to decrease pineal melatonin levels. Taken together, these data support the hypothesis that the mechanism through which light information is conveyed to the pacemaker in the SCN is separate from and independent of the mechanism through which light information is conveyed to the SCN cells whose efferents suppress pineal melatonin levels.

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.

The hypocretins are peptides synthesized in neurons of the hypothalamus. Recent studies have suggested a role for these peptides in the regulation of sleep, feeding, and endocrine regulation. The distribution of hypocretin-immunoreactive cell bodies and fibers has been extensively described in rats, but not in other species. This study was designed to examine the distribution of hypocretin immunoreactivity in Syrian hamsters, as important differences in neuropeptide distribution between rats and hamsters have previously been demonstrated. Immunoreactive cell bodies were found primarily in the lateral hypothalamic area and the perifornical area, although a few hypocretin-positive cells were also located in the dorsomedial hypothalamus and the retrochiasmatic area. Fibers were distributed throughout the brain in a pattern similar to that seen in rats. The densest projections were found in the paraventricular nucleus of the thalamus, locus coeruleus, dorsal raphe, and lateroanterior hypothalamus. The innervation of the anterior hypothalamus may be of particular interest as similar cluster of immunoreactivity does not appear to be present in rats. Moderate levels of immunoreactivity could be seen throughout the hypothalamus, the lateral septum, bed nucleus of the stria terminalis, A5 noradrenergic area, and the midline thalamic nuclei. Hypocretin-immunoreactive fibers are present in all lamina of the spinal cord, with the greatest axon densities in lamina 1 and 10. The widespread distribution of hypocretin suggests its involvement in a wide variety of physiological and behavioral processes. Our results in hamsters indicate that the organization of the hypocretin system is strongly conserved across species, suggesting an important role for the peptide and its projections.

Although there is substantial evidence that glutamate mimics the effects of light on the mammalian circadian clockin vitro, it has been reported that microinjection of glutamate into the suprachiasmatic nucleus of the hypothalamus (SCN) regionin vivodoes not result in a pattern of phase shifts that mimic those caused by light pulses. The present study was designed to test the hypothesis that microinjection of NMDA into the SCN would induce light-like phase shifts of the circadian clock through activation of the NMDA receptor. Hamsters housed in constant darkness received microinjections of NMDA through guide cannulas aimed at the SCN region at various times throughout the circadian cycle. Wheel running was monitored as a measure of circadian phase. Microinjection of NMDA resulted in circadian phase shifts, the size and direction of which were dependent on the time of injection. The resulting phase–response curve closely resembled that of light. The circadian response showed a clear dose-dependence at circadian time (CT) 13.5 but not at CT19. Both phase delays and advances induced by NMDA were blocked by coinjection of the NMDA antagonist 2-amino-5-phosphopentanoic acid but were slightly attenuated by the non-NMDA antagonist 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione disodium. The ability of NMDA to induce phase shifts was not altered by coinjection with tetrodotoxin. These data are consistent with the hypothesis that activation of NMDA receptors is a critical step in the transmission of photic information to the SCN.

Recent studies of hamsters have documented the facilitation of lordosis and other sociosexual responses by injections of oxytocin (OXT) into the medial preoptic area-anterior hypothalamus (MPOA-AH). These data suggest the regulation of social interaction and bonds by OXT. In turn, this suggests that OXT could act in the MPOA-AH to control other behaviors involved in the initiation or maintenance of social contact, including the ultrasonic vocalizations that female hamsters use to alert and attract potential mates. To test this possibility, we compared the ultrasound rates of 11 naturally estrous hamsters before and after injections of OXT (200 ng/200 nl of saline) or saline (200 nl) into the MPOA-AH. The data revealed a clear facilitation of ultrasound rate 30 min after OXT treatment. This result suggests the modulation of ultrasound rate by endogenous OXT acting within the MPOA-AH. It extends the range of social behaviors sensitive to control by OXT and supports the possibility that OXT acts within the MPOA-AH to facilitate a variety of behaviors involved in the establishment or maintenance of the social interactions required for successful reproduction. At the same time, these data extend earlier observations linking ultrasound production to the MPOA-AH, and begin to describe the peptidergic mechanisms controlling this form of reproductive behavior.

Although there is considerable data that glutamate is the primary transducer of photic information to the circadian clock in the suprachiasmatic nucleus (SCN), the ability of glutamate to mimic the phase-shifting effects of light has yet to be demonstrated in vivo. In the present study, microinjections of the glutamate agonist NMDA directly into the SCN of Syrian hamsters induced significant phase delays at circadian time (CT) 13.5 and phase advances at CT 19. These results support the hypothesis that glutamate is the primary neurotransmitter responsible for the transduction of photic information to the SCN.

In Syrian hamsters, vasopressin (AVP) controls a form of scent marking called flank marking. Microinjection and lesion studies have identified several components of the neural circuit controlling this behavior. Microinjection of AVP into the medial preoptic-anterior hypothalamus (MPOA-AH), lateral septal nucleus (LS), bed nucleus of stria terminalis (BNST), and periaqueductal gray (PAG) stimulates an intense bout of flank marking. Lesions of areas such as the MPOA-AH and the LS inhibit flank marking. Other studies employing Fos immunocytochemistry suggest that the central amygdala (Ce) might be a component of this neural circuit. The purpose of the present study was to assess the significance of the Ce in regulation of AVP-induced flank marking. In Expt. 1A, the Ce of hamsters were either lesioned with ibotenic acid or sham-lesioned. In Expt. 1B, the Ce of hamsters were either lesioned electrolytically or sham-lesioned. All lesions were made bilaterally. One week later, hamsters were microinjected with AVP into the MPOA-AH and immediately tested for flank marking. In Expt. 2, the hamsters were microinjected with AVP into the Ce and were immediately tested for flank marking. Ibotenic lesions of the Ce reduced flank marking and electrolytic lesions completely inhibited flank marking in response to AVP microinjected into the MPOA-AH. Sham-lesions or lesions placed in other areas of the amygdala resulted in intense bouts of AVP-induced flank marking and flank grooming. No flank marking or flank grooming was observed in response to AVP microinjected into the Ce. These data indicate that the Ce plays a critical role in AVP-induced flank marking, although flank marking is not induced by AVP within the Ce itself.

Vasopressin (AVP) within the medial preoptic-anterior hypothalamic continuum (MPOA-AH) plays an essential role in the control of flank marking in Syrian hamsters. Sex differences are found in the scent marking of many mammalian species, including hamsters. The first two experiments tested the hypothesis that sex differences in flank marking are the result of sex differences in the availability of AVP for release in several CNS sites. No support for this hypothesis was provided because neither immunohistochemical analysis nor radioimmunoassay of tissue punches revealed sex differences in AVP immunoreactivity in the MPOA-AH or other sites likely to be involved in flank marking. The third experiment, which tested the hypothesis that sex differences in flank marking are the result of sex differences in the sensitivity or response of the MPOA-AH to AVP, found no sex differences in the amount of flank marking stimulated by microinjection of AVP in the MPOA-AH. These data provide no support for the hypothesis that sex differences in vasopressinergic activity are responsible for sex differences in flank marking.