Modulation of value representation by social context in the primate orbitofrontal cortex

Primates depend for their survival on their ability to understand their social environment, and their behavior is often shaped by social circumstances. We report that the orbitofrontal cortex, a brain region involved in motivation and reward, is tuned to social information. Macaque monkeys worked to collect rewards for themselves and two monkey partners. Behaviorally, monkeys discriminated between cues signaling large and small [corrected] rewards, and between cues signaling rewards to self only and reward to both self and another monkey, with a preference for the former over the latter in both instances. Single neurons recorded during this task encoded the meaning of visual cues that predicted the magnitude of future rewards, as well as the motivational value of rewards obtained in a social context. Furthermore, neuronal activity was found to track momentary social preferences and partner's identity and social rank. The orbitofrontal cortex thus contains key neuronal mechanisms for the evaluation of social information.     

Oxytocin blunts social vigilance in the rhesus macaque

Exogenous application of the neuromodulatory hormone oxytocin (OT) promotes prosocial behavior and can improve social function. It is unclear, however, whether OT promotes prosocial behavior per se, or whether it facilitates social interaction by reducing a state of vigilance toward potential social threats. To disambiguate these two possibilities, we exogenously delivered OT to male rhesus macaques, which have a characteristic pattern of species-typical social vigilance, and examined their performance in three social attention tasks. We first determined that, in the absence of competing task demands or goals, OT increased attention to faces and eyes, as in humans. By contrast, OT reduced species typical social vigilance for unfamiliar, dominant, and emotional faces in two additional tasks. OT eliminated the emergence of a typical state of vigilance when dominant face images were available during a social image choice task. Moreover, OT improved performance on a reward-guided saccade task, despite salient social distractors: OT reduced the interference of unfamiliar faces, particularly emotional ones, when these faces were task irrelevant. Together, these results demonstrate that OT suppresses vigilance toward potential social threats in the rhesus macaque. We hypothesize that a basic role for OT in regulating social vigilance may have facilitated the evolution of prosocial behaviors in humans.     

Mirroring of attention by neurons in macaque parietal cortex

Macaques, like humans, rapidly orient their attention in the direction other individuals are looking. Both cortical and subcortical pathways have been proposed as neural mediators of social gaze following, but neither pathway has been characterized electrophysiologically in behaving animals. To address this gap, we recorded the activity of single neurons in the lateral intraparietal area (LIP) of rhesus macaques to determine whether and how this area might contribute to gaze following. A subset of LIP neurons mirrored observed attention by firing both when the subject looked in the preferred direction of the neuron, and when observed monkeys looked in the preferred direction of the neuron, despite the irrelevance of the monkey images to the task. Importantly, the timing of these modulations matched the time course of gaze-following behavior. A second population of neurons was suppressed by social gaze cues, possibly subserving task demands by maintaining fixation on the observed face. These observations suggest that LIP contributes to sharing of observed attention and link mirror representations in parietal cortex to a well studied imitative behavior.     

Five-month-old infants' identification of the sources of vocalizations

Humans speak, monkeys grunt, and ducks quack. How do we come to know which vocalizations animals produce? Here we explore this question by asking whether young infants expect humans, but not other animals, to produce speech, and further, whether infants have similarly restricted expectations about the sources of vocalizations produced by other species. Five-month-old infants matched speech, but not human nonspeech vocalizations, specifically to humans, looking longer at static human faces when human speech was played than when either rhesus monkey or duck calls were played. They also matched monkey calls to monkey faces, looking longer at static rhesus monkey faces when rhesus monkey calls were played than when either human speech or duck calls were played. However, infants failed to match duck vocalizations to duck faces, even though infants likely have more experience with ducks than monkeys. Results show that by 5 months of age, human infants generate expectations about the sources of some vocalizations, mapping human faces to speech and rhesus faces to rhesus calls. Infants'' matching capacity does not appear to be based on a simple associative mechanism or restricted to their specific experiences. We discuss these findings in terms of how infants may achieve such competence, as well as its specificity and relevance to acquiring language.     

Oxytocin modulates fMRI responses to facial expression in macaques

Increasing evidence has shown that oxytocin (OT), a mammalian hormone, modifies the way social stimuli are perceived and the way they affect behavior. Thus, OT may serve as a treatment for psychiatric disorders, many of which are characterized by dysfunctional social behavior. To explore the neural mechanisms mediating the effects of OT in macaque monkeys, we investigated whether OT would modulate functional magnetic resonance imaging (fMRI) responses in face-responsive regions (faces vs. blank screen) evoked by the perception of various facial expressions (neutral, fearful, aggressive, and appeasing). In the placebo condition, we found significantly increased activation for emotional (mainly fearful and appeasing) faces compared with neutral faces across the face-responsive regions. OT selectively, and differentially, altered fMRI responses to emotional expressions, significantly reducing responses to both fearful and aggressive faces in face-responsive regions while leaving responses to appeasing as well as neutral faces unchanged. We also found that OT administration selectively reduced functional coupling between the amygdala and areas in the occipital and inferior temporal cortex during the viewing of fearful and aggressive faces, but not during the viewing of neutral or appeasing faces. Taken together, our results indicate homologies between monkeys and humans in the neural circuits mediating the effects of OT. Thus, the monkey may be an ideal animal model to explore the development of OT-based pharmacological strategies for treating patients with dysfunctional social behavior.In the last decade, oxytocin (OT), a mammalian hormone, has become one of the most studied peptides of the neuroendocrine system. In humans, accumulating evidence has demonstrated that OT affects a wide range of social behavior and cognition, including perception, recognition and memory of social stimuli (1–5), socially reinforced learning (6), and more complex sociocognitive behaviors [e.g., trust (7, 8), cooperation (9), generosity (10), and empathy (6, but see ref. 11)]. Therefore, it has been proposed that OT may serve as a treatment for various disorders with dysfunctional social behavior, such as autism spectrum disorders, antisocial personality disorder, and schizophrenia (for review, see ref. 12). A recent study found that OT enhances brain activity for socially meaningful stimuli but attenuates activity for nonsocially meaningful stimuli in children with autism spectrum disorders (13). Although these studies suggest very promising prospects of OT for clinical use, the neural mechanisms underlying OT’s modulatory effects remain elusive. To understand these mechanisms, it is important to investigate the effect of OT on brain activity, especially in regions involved in social behavior and cognition.Functional magnetic resonance imaging (fMRI) has been the major approach to investigating altered brain activation patterns in response to OT in humans. OT may affect the perception of social stimuli, and thus mediate subsequent social information processing (e.g., learning and memory, etc.) (14). Many fMRI studies have examined the effects of OT on brain activity during the perception of social stimuli to probe the brain regions that underlie OT’s modulatory effects. Emotional stimuli, which are crucial for social communication and interaction, have been mainly used. For example, Kirsch et al. showed that OT reduces activation in response to fear-inducing stimuli in the amygdala, a key brain region involved in emotional regulation (15). Subsequently, a series of studies examined the effects of OT on responses to facial expressions (3, 16), to conditioned facial expressions (17), and to threatening scenes (18). These studies showed that activity evoked by emotional stimuli, especially negative stimuli (e.g., fearful faces, but see refs. 3 and 16 for happy faces), is systematically altered within an interconnected network of brain regions after OT administration.Because of the limitation of experimental approaches with human subjects, animal models are essential not only for investigating the neural mechanisms underlying the effects of OT but also for exploring OT-based therapeutic strategies for individuals with dysfunctional social behavior. Given the similarities between monkeys and humans in the neural circuitry underlying social cognition (19), the rhesus macaque could be an ideal animal model to examine the effects of OT. To date, only a few studies have investigated the behavioral consequences of OT administration in monkeys (20–25). Consistent with the human literature, these studies have found that intranasal administration of OT affects social behavior and cognition in monkeys, including vicarious as well as self-reinforcement (20), social vigilance (22), socially reinforced learning (26), and attention to facial features and expressions (21, 24). However, how OT exerts its effects on brain activity in monkeys remains unclear. To explore the neural mechanisms mediating the effects of OT in macaque monkeys, in the present study, we investigated whether OT would modulate fMRI responses evoked by the perception of facial expressions, an effect mainly studied in humans thus far.We scanned monkeys while they viewed images of monkey faces with four different expressions: neutral, fearful, aggressive, and appeasing. Scanning was conducting under two different conditions: placebo control (saline) and intranasal OT. We predicted that in the placebo condition, emotional faces (especially fearful) would evoke enhanced activation compared with neutral faces, that is, they would show a valence effect; that, as in humans, OT administration would reduce this valence effect in monkeys; and that OT administration would alter functional coupling among those brain regions showing a valence effect.     

Neural mechanisms of social decision-making in the primate amygdala

Social decisions require evaluation of costs and benefits to oneself and others. Long associated with emotion and vigilance, the amygdala has recently been implicated in both decision-making and social behavior. The amygdala signals reward and punishment, as well as facial expressions and the gaze of others. Amygdala damage impairs social interactions, and the social neuropeptide oxytocin (OT) influences human social decisions, in part, by altering amygdala function. Here we show in monkeys playing a modified dictator game, in which one individual can donate or withhold rewards from another, that basolateral amygdala (BLA) neurons signaled social preferences both across trials and across days. BLA neurons mirrored the value of rewards delivered to self and others when monkeys were free to choose but not when the computer made choices for them. We also found that focal infusion of OT unilaterally into BLA weakly but significantly increased both the frequency of prosocial decisions and attention to recipients for context-specific prosocial decisions, endorsing the hypothesis that OT regulates social behavior, in part, via amygdala neuromodulation. Our findings demonstrate both neurophysiological and neuroendocrinological connections between primate amygdala and social decisions.How we treat others impacts not only their well-being but our own. Human society depends on cooperation, charity, and altruism, as well as institutions to regulate selfish biases. In humans, these behaviors involve perspective-taking, empathy, and theory of mind (1, 2), and the rudiments of these capacities appear to mediate complex social behavior in animals (3). Recent research has sketched a rough outline of the neural circuits that contribute to complex social behavior (4, 5). These comprise a set of domain-general brain areas, including the ventromedial prefrontal cortex and ventral striatum, that process information about reward and punishment and contribute to decision-making, and a set of specialized areas, including the temporoparietal junction and medial prefrontal cortex, that process specifically social information (4, 6). How social and nonsocial signals in these circuits are integrated to mediate decisions with respect to others remains imperfectly understood, in part, due to the indirect nature of hemodynamic signals measured in human neuroimaging experiments that constitute the bulk of this research. Recent advances in the development of neurophysiological and neuropharmacological models of social decision-making, however, permit more direct inquiry into the neural mechanisms mediating other-regarding behavior (7–11).The amygdala, especially the basolateral division (BLA), has been implicated in both decision-making and social perception, inviting the possibility that it contributes to decision-making with respect to others (12–17). This set of nuclei is well known for contributions to emotional experience and expression, especially fear. More recent studies demonstrate activity in BLA tracks the value of rewards and punishments (18), predicts risky financial decisions (19), reflects internal motivational goals (20), and correlates with vigilance and attention (21). BLA also signals social information, such as facial expressions and the direction of gaze, and has been implicated in theory of mind and emotional empathy (22–26). Notably, oxytocin (OT), a neurohypophysial hormone that modulates many social behaviors (27), appears to do so via the amygdala in humans and nonhuman primates (28–30). Intranasal OT reliably modulates hemodynamic activity in the amygdala in healthy humans (28, 29, 31), children with autism (32), and rhesus macaques (30). These changes in amygdala activity are related to social cognition. These observations invite the hypothesis that BLA directly mediates decision-making with respect to others (24). How neurons in BLA respond during social decisions, however, remains unknown.Here, we examine this hypothesis using a modified dictator game, which we previously used to probe social information signaling by neurons in the anterior cingulate and orbitofrontal cortices (7) and the impact of inhaling OT on social decision-making (33). We previously reported that the preference to allocate reward to the other monkey is enhanced by greater familiarity between the two animals, and is abolished if the recipient is replaced with a juice collection bottle (34). We also reported that reward withholding is reduced when actor monkeys are dominant toward recipients, and the variability and the degree of preferences often depend on the identity of the recipients (34). We show, to our knowledge for the first time, that BLA neurons respond during social decisions, these responses signal the value of rewards chosen for self and others using a similar coding scheme, and these signals are correlated with social preferences. We further show that unilateral infusion of OT into BLA increases both the frequency of prosocial decisions and attention paid to the recipients of prosocial decisions. Together, these findings directly implicate the amygdala in social decision-making and constrain models of its computational role in the decision process.     

Medial prefrontal cortex and striatum mediate the influence of social comparison on the decision process

We compared private and social decision making to investigate the neural underpinnings of the effect of social comparison on risky choices. We measured brain activity using functional MRI while participants chose between two lotteries: in the private condition, they observed the outcome of the unchosen lottery, and in the social condition, the outcome of the lottery chosen by another person. The striatum, a reward-related brain structure, showed higher activity when participants won more than their counterpart (social gains) compared with winning in isolation and lower activity when they won less than their counterpart (social loss) compared with private loss. The medial prefrontal cortex, implicated in social reasoning, was more activated by social gains than all other events. Sensitivity to social gains influenced both brain activity and behavior during subsequent choices. Specifically, striatal activity associated with social gains predicted medial prefrontal cortex activity during social choices, and experienced social gains induced more risky and competitive behavior in later trials. These results show that interplay between reward and social reasoning networks mediates the influence of social comparison on the decision process.     

Interspecies radioimmunoassay for the major structural proteins of primate type-D retroviruses.

A competition radioimmunoassay has been developed in which type-D retroviruses from three primate species compete. The assay utilizes the major structural protein (36,000 daltons) of the endogenous squirrel monkey retrovirus and antisera directed against the major structural protein (27,000 daltons) of the Mason-Pfizer monkey virus isolated from rhesus monkeys. Purified preparations of both viruses grown in heterologous cells, as well as extracts of heterologous cells infected with squirrel monkey retrovirus or Mason-Pfizer monkey virus, compete completely in the assay. Addition of an endogenous virus of the langur monkey also results in complete blocking. No blocking in the assay is observed with type-C baboon viruses, woolly monkey virus, and gibbon virus. Various other type-C and type-B viruses also showed no reactivity. An interspecies assay has thus been developed that recognizes the type-D retroviruses from both Old World monkey (rhesus and langur) and New World monkey (squirrel) species.     

Comparison of plasma oxytocin and catecholamine concentrations with uterine activity in pregnant rhesus monkeys

Pregnant rhesus monkeys exhibit diurnal changes in uterine activity (UA), with episodes of increased UA during the early hours of darkness. The estrogenic environment during late pregnancy serves a permissive role in the maintenance of nocturnal UA episodes and may involve myometrial interactions with oxytocin (OT) and/or alpha-adrenergic stimuli. In the present study we have used chronically catheterized pregnant rhesus monkeys to measure diurnal changes in maternal plasma OT, epinephrine, norepinephrine, and dopamine. We also determined the effects of infusing an OT antagonist (ORF 22164) and the alpha-adrenergic antagonist phentolamine on nocturnal UA episodes. Animals were exposed to a 16-h light, 8-h dark photo-period, with the hours of darkness between 2300-0700 h. Maternal plasma samples were collected at 3-h intervals for 36 h and analyzed by RIA for OT and by high performance liquid chromatography for catecholamines. Plasma OT was correlated with UA in animals that displayed nocturnal UA episodes (r = 0.76; P less than 0.01). Maximal OT concentrations occurred at 2400 h in these animals; plasma OT was higher during the hours of darkness compared to levels during the light phase (10.4 +/- 1.9 and 3.0 +/- 0.3 pmol/L, respectively; n = 4). Some animals did not display nocturnal episodes of increased UA and showed no increase in OT concentrations during the hours of darkness. Maternal plasma catecholamine concentrations were not correlated with nocturnal UA and were maximal during the light phase. Nocturnal UA was abolished within 30 min of infusion of the OT antagonist, but phentolamine infusions had no effect on nocturnal UA. We conclude that 1) changes in maternal plasma catecholamine concentrations are not involved in the generation of nocturnal UA; 2) the presence of episodes of increased UA at night results from increased maternal plasma OT concentrations; and 3) the absence of nocturnal UA in some animals can be explained by a reduced level of OT secretion.     

Monkeys benefit from reciprocity without the cognitive burden

The debate about the origins of human prosociality has focused on the presence or absence of similar tendencies in other species, and, recently, attention has turned to the underlying mechanisms. We investigated whether direct reciprocity could promote prosocial behavior in brown capuchin monkeys (Cebus apella). Twelve capuchins tested in pairs could choose between two tokens, with one being “prosocial” in that it rewarded both individuals (i.e., 1/1), and the other being “selfish” in that it rewarded the chooser only (i.e., 1/0). Each monkey’s choices with a familiar partner from their own group was compared with choices when paired with a partner from a different group. Capuchins were spontaneously prosocial, selecting the prosocial option at the same rate regardless of whether they were paired with an in-group or out-group partner. This indicates that interaction outside of the experimental setting played no role. When the paradigm was changed, such that both partners alternated making choices, prosocial preference significantly increased, leading to mutualistic payoffs. As no contingency could be detected between an individual’s choice and their partner’s previous choice, and choices occurred in rapid succession, reciprocity seemed of a relatively vague nature akin to mutualism. Having the partner receive a better reward than the chooser (i.e., 1/2) during the alternating condition increased the payoffs of mutual prosociality, and prosocial choice increased accordingly. The outcome of several controls made it hard to explain these results on the basis of reward distribution or learned preferences, and rather suggested that joint action promotes prosociality, resulting in so-called attitudinal reciprocity.     

Expression and regulation of plasminogen activators,plasminogen activator inhibitor type-1, and steroidogenic acute regulatory protein in the rhesus monkey corpus luteum

The corpus luteum (CL) is a transient endocrine organ that secretes progesterone to support early pregnancy. Using primate materials obtained from rhesus monkeys, we have in this study investigated the expression and regulation of the plasminogen activators (PAs) and PA inhibitor type 1 (PAI-1) during CL development and regression. Adult (5-7 yr old) female rhesus monkeys were treated with pregnant mare serum gonadotropin/human chorionic gonadotropin to induce ovulation and follicular luteinization. At various luteal developmental stages, CL or whole ovaries were obtained for preparing luteal cells, Northern blot, in situ hybridization, and immunohistochemistry. We demonstrated that luteal cells from the rhesus monkey were able to produce both tissue type PA (tPA) and urokinase type PA, as well as the physiological PAI-1. During luteal development in the monkey, urokinase type PA was the major PA species taking part in the active angiogenesis and tissue remodeling processes in the forming CL. However, the mRNA as well as the enzymatic activity levels of tPA increased dramatically in monkey CL with the advent of luteolysis. This change of tPA levels was in a temporal coordination with the regulation of PAI-1 expression, resulting in an increased tPA activity at the initiation of luteolysis. Therefore, we suggest that tPA might be a luteolytic factor to the monkey CL. A PAI-1 modulated tPA activity might be important for the initiation of luteolysis in the monkey. In addition, we have also demonstrated that the expression of steroidogenic acute regulatory protein in the monkey CL was in accordance with the changes of progesterone production, suggesting that steroidogenic acute regulatory protein expression may be considered as a reliable marker for CL function in primates.     

Histologic identification and immunochemical studies of prolactin and growth hormone in the primate pituitary gland

The two acidophilic cell types were tinctorially differentiated in rhesus monkey pituitaries as well as in pituitaries of other species of monkeys and apes and were identified by immunofluorescence as the prolactin and the growth hormone (GH) cells. The number of prolactin cells was significantly greater in adult than in juvenile rhesus monkeys. During late pregnancy and lactation, these cells appeared to occupy 60–80% of the entire anterior lobe of the rhesus monkey. The concentration of prolactin and CH was measured by radioimmunoassay in pituitary extracts (PE) from pools of juvenile male, juvenile female, adult male and adult female rhesus monkey pituitaries. More prolactin was present in PEs from adult than from juvenile animals, with the highest concentration being present in adult females. A similar relationship was observed with GH. The qualitative immunologic relationship between ovine prolactin and prolactin in the rhesus monkey PEs, and between human GH and GH in the PEs, was established using agar gel diffusion. The two prolactin hormones were partially related immunochemically, while the two GHs were shown to be immunochemically identical. In intact juvenile female rhesus monkeys given estradiol benzoate, the concentrations of pituitary and serum prolactin were elevated over that of the controls, while the concentration of pituitary GH was decreased. An increase in the number of prolactin cells was also observed in the steroid-treated animals. These observations demonstrate further that prolactin and GH reside in separate cells in the primate pituitary and that the concentration of these two hormones varies depending upon age, sex, or stage of the reproductive cycle of the animal.     

Development of a circadian variation of plasma oxytocin concentration in the late gestation rhesus monkey

The 24-h pattern of oxytocin (OT) concentrations in maternal plasma was investigated serially from 112-168 days gestation in four chair-restrained pregnant rhesus monkeys. No change in the mean daily plasma OT concentration was observed with advancing gestational age; there was a change in the pattern of plasma OT secretion throughout the period, however. About 21 days from delivery (150.8 +/- 1.8 days gestational age), plasma OT levels showed occasional fluctuations, distributed throughout the day. About 8 days from delivery (163.2 +/- 2.4 days gestational age), a clear circadian pattern of OT was detected, with an acrophase at 2200 h. These results suggest that there is a relationship between the pattern of OT secretion and advancing pregnancy. This may account partially for the increase in uterine activity known to occur in term rhesus monkeys.     

Influence of social rank on the development of long-term ethanol drinking trajectories in cynomolgus monkeys

Background

Chronic stress contribute to the development of alcohol use disorder (AUD). However, characterizing the role of chronic social stressors in the development of problematic drinking trajectories in humans is complicated by practical and ethical constraints. Group-housed nonhuman primates develop social dominance hierarchies that represent a continuum of social experiences from enrichment in higher-ranked (dominant) monkeys to chronic social stress in lower-ranked (subordinate) individuals. This framework provides a translationally relevant model of chronic social stress that can be used to characterize its effects on vulnerability to AUD.

Methods

Twelve male cynomolgus monkeys living in three social groups with established social dominance hierarchies were provided access to ethanol and water for 22 h/day, 4–5 days/week, for 1 year. Ethanol-free periods (2- or 3-day “weekends” or longer periods up to 10 days) were spent in social groups to maintain the stability of the social hierarchies. Observational studies conducted 6 months into the year of drinking assessed signs of ethanol withdrawal. After 1 year, monkeys were individually housed 24 h/day, 7 days/week for four consecutive weeks to examine the effect of eliminating the “weekends” spent socially housed.

Results

Subordinate monkeys had significantly higher mean daily ethanol intakes than dominant monkeys across 1 year of open access. Subordinates also had higher intakes on the first day back drinking following ethanol-free periods of 9–10 days. Moreover, during the last 4 weeks of open access, intakes on the first drinking day after an ethanol-free weekend increased significantly in subordinate monkeys. This effect diminished when all monkeys were individually housed for 4 weeks, indicating that the increased intake in subordinates was driven by the social environment.

Conclusions

These data demonstrate that social subordination, which is associated with chronic social stress, results in increased vulnerability to the development and maintenance of heavy drinking trajectories.     

Operant matching is a generic outcome of synaptic plasticity based on the covariance between reward and neural activity

The probability of choosing an alternative in a long sequence of repeated choices is proportional to the total reward derived from that alternative, a phenomenon known as Herrnstein's matching law. This behavior is remarkably conserved across species and experimental conditions, but its underlying neural mechanisms still are unknown. Here, we propose a neural explanation of this empirical law of behavior. We hypothesize that there are forms of synaptic plasticity driven by the covariance between reward and neural activity and prove mathematically that matching is a generic outcome of such plasticity. Two hypothetical types of synaptic plasticity, embedded in decision-making neural network models, are shown to yield matching behavior in numerical simulations, in accord with our general theorem. We show how this class of models can be tested experimentally by making reward not only contingent on the choices of the subject but also directly contingent on fluctuations in neural activity. Maximization is shown to be a generic outcome of synaptic plasticity driven by the sum of the covariances between reward and all past neural activities.     

Ethanol reinforcement in nondeprived mice: effects of abstinence and naltrexone

BACKGROUND: Operant experiments which indicate that ethanol can serve as a reinforcer to maintain lever responding during limited periods of access have not been conducted on non-food-deprived mice, as they have for rats and monkeys. Furthermore, there are no reports of the effects of chronic ethanol and subsequent abstinence on ethanol reward in mice. Finally, although naltrexone reduces responding for ethanol in food-deprived mice, the effects of the drug on ethanol reward for non-food-deprived mice have not been reported. METHODS: In three experiments, lever responding for ethanol (10-12%) was established in C57BL/6 (B6) mice by using either sucrose or saccharin fading procedures commonly used for rats. Experiment 1 examined both appetitive and consummatory responses while sucrose was faded from the ethanol solutions. Experiment 2 examined lever responding and ethanol intake (1) during saccharin fading; (2) when reinforcement schedules, reward availability, and primary conditioned reinforcers were manipulated; and (3) when mice were allowed chronic ethanol consumption followed by forced abstinence. Experiment 3 examined the effects of low doses of naltrexone on ethanol reward. RESULTS: Lever responding for ethanol can be established in non-food-deprived mice with the sucrose and saccharin fading procedures commonly used for rats. Lever responses increased with decreases in the reinforcer and increases in schedule demand, which indicated the reward value of the ethanol solution. Removal of ethanol from the solution reduced consumption with no change in the appetitive, instrumental response, which indicated that the two responses were under control of different stimuli, perhaps mediated by different neural mechanisms. Forced abstinence after chronic ethanol exposure increased responding for the drug, which suggested increased reward value. Naltrexone reduced responding as previously reported for food-deprived B6 mice. CONCLUSIONS: Ethanol appears to serve as a reinforcer for non-food-deprived or non-water-deprived B6 mice. Its reinforcing effects are increased by forced abstinence after chronic exposure and are decreased by naltrexone.     

Maternal separation produces lasting changes in cortisol and behavior in rhesus monkeys

Maternal separation (MS), which can lead to hypothalamic pituitary adrenal axis dysfunction and behavioral abnormalities in rhesus monkeys, is frequently used to model early adversity. Whether this deleterious effect on monkeys is reversible by later experience is unknown. In this study, we assessed the basal hair cortisol in rhesus monkeys after 1.5 and 3 y of normal social life following an early separation. These results showed that peer-reared monkeys had significantly lower basal hair cortisol levels than the mother-reared monkeys at both years examined. The plasma cortisol was assessed in the monkeys after 1.5 y of normal social life, and the results indicated that the peak in the peer-reared cortisol response to acute stressors was substantially delayed. In addition, after 3 y of normal social life, abnormal behavioral patterns were identified in the peer-reared monkeys. They showed decreases in locomotion and initiated sitting together, as well as increases in stereotypical behaviors compared with the mother-reared monkeys. These results demonstrate that the deleterious effects of MS on rhesus monkeys cannot be compensated by a later normal social life, suggesting that the effects of MS are long-lasting and that the maternal-separated rhesus monkeys are a good animal model to study early adversity and to investigate the development of psychiatric disorders induced by exposure to early adversity.     

Pathology of dual Mycobacterium leprae and simian immunodeficiency virus infection in rhesus monkeys

Three rhesus monkeys were experimentally inoculated with sooty-mangabey-derived Mycobacterium leprae and were inadvertently infected with the simian immunodeficiency virus (SIV) as well. They died of an immunodeficiency syndrome, and at autopsy all had lesions caused by M. leprae. One monkey was inoculated twice with M. leprae, initially with an inoculum from a sooty mangabey that was not infected with SIV and, subsequently, with an inoculum from a mangabey that was SIV infected. The monkey did not develop clinical lesions and became strongly lepromin skin test (LST) positive after the first inoculation, but became infected with both agents and LST negative following the second inoculation. These observations suggest that SIV-infected rhesus monkeys have an increased susceptibility to M. leprae infection and, by analogy, imply that HIV-infected human beings may have an increased susceptibility as well.     

Behavioral, adrenal, and sympathetic responses to long-term administration of an oral corticotropin-releasing hormone receptor antagonist in a primate stress paradigm

CRH is a main regulator of the stress response. This neuropeptide and its specific receptors, CRHR-1 and CRHR-2, are disseminated throughout the central nervous system. There is a significant interspecies difference in the distribution of CRHR within the central nervous system. CRH-R1 antagonists may attenuate stress-related behavior in rats without compromising adrenal function, but few studies have addressed the same question in higher mammals. Antalarmin (AA) is a specific CRHR-1 antagonist suitable for oral administration. Social separation is a potent stressor for rhesus monkeys. Therefore, we sought to investigate the hormonal responses to chronic administration of AA using a primate stress model. Eight preadolescent (4-6 kg) male rhesus monkeys received AA (20 mg/kg.d) or placebo (PBO) orally. All animals were on a regular day/light cycle and were fed with standard monkey chow daily. The study (114 d) was comprised of the following consecutive phases: adaptation, baseline, separation (stress), recovery, and cross-over. During social separation, solid panels separated the individuals. Cerebrospinal fluid (CSF) and femoral venous blood samples were obtained once a week on the fourth day of separation under ketamine anesthesia. Serum samples were also obtained 1 and 2 h after separation. CSF samples were assayed for CRH, AA, norepinephrine (NE) and epinephrine (EPI). Plasma was assayed for ACTH, cortisol, NE, and EPI. AA was detected in the plasma of each monkey while they were taking the active drug and in none of the animals on PBO. Among the behaviors assessed, environmental exploration, a behavior inhibited by stress, was increased during AA administration. However, AA at this dose did not affect other anxiety-related behavioral end points, including self-directed behavior, vocalization, or locomotion. We also observed that: 1) ACTH decreased between adaptation and baseline, indicating that the animals had adjusted to the novel environment; 2) ACTH and cortisol increased significantly after social separation, indicating that social separation was an adequate model for acute stress; 3) NE and EPI increased significantly during acute stress in the AA and PBO groups (P < 0.005, NE; P < 0.001, EPI); 4) after chronic stress, by d 4 of separation, ACTH levels were no longer significantly different from baseline, and NE and EPI remained slightly elevated when compared with baseline (P < 0.05, NE; P < 0.01, EPI); and 5) all the animals remained healthy and gained the expected weight during the study. In summary, oral chronic administration of a specific CRH-R1 antagonist to rhesus monkeys does not blunt the sympathoadrenal response to stress while increasing environmental exploration, a behavior that is normally suppressed during stressful events. Taken together, these findings suggest that CRHR-1 antagonists may be a valid treatment for stress-related disorders.     

The effect of caloric restriction on glycation and glycoxidation in skin collagen of nonhuman primates

The accumulation of Maillard reaction products increases with age in long-lived proteins and can be retarded by caloric restriction. Here we determined whether caloric restriction inhibits formation of glycation and glycoxidation products in skin collagen of squirrel and rhesus monkeys between 1990-1997. Restricted monkeys (n = 11, n = 30, respectively) were maintained at 70% of caloric intake of controls (n = 25, n = 32, respectively). Glycation was assessed by furosine and glycoxidation by pentosidine and carboxymethyl-lysine. With age, the rate of furosine formation moderately but nonsignificantly (p >.05) increased in both control monkey groups. It significantly (p =.011) decreased in the caloric-restricted rhesus, but not squirrel monkeys. Caloric restriction did not significantly decrease the pentosidine or carboxymethyl-lysine rates in either species of monkeys. These results suggest that caloric restriction, when maintained long-term in nonhuman primates, tends to decrease glycation, but not glycoxidation.