Interactions In Rhesus Monkeys Research Articles

Rejecting Behaviour and Separation Initiatives as Aspects of the Mother-infant Independence Dynamics in Rhesus Monkeys

This paper suggests that attachment, rejecting behaviour and independence initiatives among rhesus monkeys (Macaca mulatta) constitute the most critical elements of mother-infant interactions. Results of previous studies of different family groups indicate that both the mothers' rejecting behaviour and the infants' independence initiatives (or social activities) are not homogeneus but instead differ from each other, depending on subjects' individual differences and on the diverse relationships and experiences among members of the family groups. These findings underline the relevance of a methodology that takes into account individual, dyadic and social variables among subjects. This complex of variables represents a potentially useful methodology for studies on the attachment-independence process in mother-infant interactions in rhesus monkeys and in many other species of monkeys.

Neonatal amygdala lesions alter mother-infant interactions in rhesus monkeys living in a species-typical social environment.

The current study examined the effects of neonatal amygdala lesions on mother-infant interactions in rhesus monkeys reared in large species-typical social groups. Focal observations of mother-infant interactions were collected in their social group for the first 12 months postpartum on infants that had received amygdala lesions (Neo-A) at 24-25 days of age and control infants. Early amygdala lesions resulted in subtle behavioral alterations. Neo-A females exhibited earlier emergence of independence from the mother than did control females, spending more time away from their mother, whereas Neo-A males did not. Also, a set of behaviors, including coo vocalizations, time in contact, and time away from the mother, accurately discriminated Neo-A females from control females, but not Neo-A and control males. Data suggest that neonatal amygdalectomy either reduced fear, therefore increasing exploration in females, or reduced the positive reward value of maternal contact. Unlike females, neonatal amygdala lesions had little measurable effects on male mother-infant interactions. The source of this sex difference is unknown.

Anti-human VWF monoclonal antibody SZ-123 prevents arterial thrombus formation by inhibiting VWF–collagen and VWF–platelet interactions in Rhesus monkeys

The interactions between collagen, von Willebrand factor (VWF), and glycoprotein Ib (GPIb) are crucial for hemostasis and thrombosis. This axis represents a promising target for the development of new antithrombotic agents. In this study, we investigate the in vivo antithrombotic efficacy of an anti-VWF monoclonal antibody SZ-123 and its potential underlying mechanisms. Cyclic flow reductions (CFRs), an indicator of arterial thrombosis, were measured in the femoral artery of anesthetized Rhesus monkeys before and after intravenous administration of SZ-123. Ex vivo VWF binding to collagen, platelet agglutination, platelet count, and template bleeding time were used as measurements of antithrombotic activity. In addition, plasma VWF and SZ-123 levels, and VWF occupancy were measured by ELISA. Administration of 0.1, 0.3, and 0.6mg/kg SZ-123 resulted in 45.3%, 78.2%, and 100% reductions in CFRs, respectively. When 0.3 and 0.6mg/kg SZ-123 were administered, 100% of VWF was occupied by the antibody. Moreover, 100% ex vivo inhibition of VWF–collagen binding and 60–95% inhibition of platelet agglutination were observed from 15min to 1h. None of the doses resulted in significant prolongation of bleeding time. In vitro experiments revealed that SZ-123 not only blocks the collagen–VWF A3 interaction but also indirectly inhibits VWF A1 binding to GPIbα induced by ristocetin. Thus, we demonstrate that SZ-123 prevents in vivo arterial thrombus formation under high shear conditions by inhibiting VWF A3–collagen and VWF A1–platelet interactions and does not significantly prolong bleeding time.

Anti-Human VWF Monoclonal Antibody SZ-123 Prevents Arterial Thrombus Formation by Inhibiting VWF–collagen and VWF-Platelet Interactions in Rhesus Monkeys

Abstract 5194 Objective:To investigate the in vivo antithrombotic efficacy of an anti-VWF monoclonal antibody SZ-123, and its potential underlying mechanism. Methods and Results:Cyclic flow reductions (CFRs) were measured in the femoral artery of monkeys before and after intravenous administration of SZ-123. Ex vivo VWF binding to collagen, platelet aggregation, platelet count and template bleeding time were performed as measurements of antithrombotic activity. In addition, plasma VWF, SZ-123 levels, and VWF occupancy were measured by ELISA. Administration of 0. 1, 0. 3, and 0. 6 mg/kg SZ-123 resulted in 45. 3%, 78. 2%, and 100% reduction in CFRs, respectively. When 0. 3 and 0. 6 mg/kg SZ-123 were administrated, 100% of VWF was occupied by the antibody. Moreover, 100% ex vivo inhibition of VWF-collagen binding and 60–95% inhibition of platelet aggregation were observed from 15 min to 1h. None of the doses resulted in significant prolongation of bleeding time. In vitro experiment also revealed that SZ-123 not only blocks collagen-VWF A3 interaction but also inhibits indirectly VWF A1 binding to GPIba induced by ristocetin. Conclusions:SZ-123 prevents in vivo arterial thrombus formation under high shear conditions by inhibiting VWF A3–collagen and VWF A1-platelet interactions and does not prolong bleeding time. Disclosures:No relevant conflicts of interest to declare.

Risk, resilience, and gene x environment interactions in rhesus monkeys

Risk, resilience, and gene x environment interactions in rhesus monkeys

Role of delta opioid efficacy as a determinant of mu/delta opioid interactions in rhesus monkeys

Delta opioid agonists can selectively enhance the antinociceptive effects of mu opioid agonists without enhancing some other, potentially undesirable mu agonist effects. However, the degree of delta receptor efficacy required to produce this profile of interactions is unknown. To address this issue, the present study examined interactions produced by the mu agonist fentanyl and the intermediate-efficacy delta opioid MSF61 in rhesus monkeys. For comparison, interactions were also examined between fentanyl and the relatively high-efficacy delta agonist SNC243A and the delta antagonist naltrindole, which has negligible efficacy at delta receptors. Two different behavioral procedures were used: (a) a warm-water tail-withdrawal assay of thermal nociception, and (b) an assay of schedule-controlled responding for food reinforcement. Drug interactions within each procedure were evaluated using dose-addition analysis to compare experimental results with expected additivity. Drug interactions across procedures were evaluated using dose–ratio analysis to assess relative potencies to produce antinociception vs. response-rate suppression. As expected, dose-addition analysis found that fentanyl/SNC243A interactions were superadditive in the assay of antinociception but additive in the assay of schedule-controlled responding. Conversely, fentanyl/MSF61 interactions were generally additive in both procedures, and fentanyl/naltrindole interactions were additive or subadditive in both procedures. Dose–ratio analysis found that fentanyl alone produced antinociception and rate suppression with similar potencies. Some fentanyl/SNC243A mixtures produced antinociception with up to 4-fold greater potency than rate-suppression. However, fentanyl/MSF61 and fentanyl/naltrindole mixtures produced antinociception with lower potency than rate suppression. These results suggest that relatively high delta receptor efficacy is required for mu/delta antinociceptive synergy.

Role of delta receptor efficacy as a determinant of delta/mu opioid interactions in rhesus monkeys

Delta opioid agonists have been reported to selectively enhance the antinociceptive effects of mu opioid agonists without enhancing other, potentially untoward mu agonist effects such as sedation, respiratory depression or abuse potential. The purpose of the present study was to examine the role of delta receptor efficacy as a determinant of delta/mu interactions in rhesus monkeys in two different behavioral procedures: (a) an assay of schedule‐controlled responding maintained by food reinforcement, and (b) an assay of thermal nociception. The effects of the selective mu agonist fentanyl were examined in combination with the high‐efficacy delta agonist SNC243A, the intermediate‐efficacy agonist MSF61, or the delta antagonist naltrindole. Fentanyl was tested in combination with three different proportions of each delta opioid. Fentanyl/SNC243A interactions were superadditive in the assay of antinociception and additve in the assay of schedule‐controlled responding. Fentanyl/MSF61 interactions were additive in both procedures, and fentanyl/naltrindole interactions were additive or subadditive in both procedures. These results suggest that high efficacy at delta receptors is required for synergistic delta/mu interactions in assays of antinociception in rhesus monkeys. Supported by R01 DA11460 from NIDA/NIH.

Mu/kappa opioid interactions in rhesus monkeys: Implications for analgesia and abuse liability.

Micro opioid receptor agonists are clinically valuable as analgesics; however, their use is limited by high abuse liability. Kappa opioid agonists also produce antinociception, but they do not produce micro agonist-like abuse-related effects, suggesting that they may enhance the antinociceptive effects and/or attenuate the abuse-related effects of micro agonists. To evaluate this hypothesis, the present study examined interactions between the micro agonist fentanyl and the kappa agonist U69,593 in three behavioral assays in rhesus monkeys. In an assay of schedule-controlled responding, monkeys responded under a fixed-ratio 30 (FR 30) schedule of food presentation. Fentanyl and U69,593 each produced rate-decreasing effects when administered alone, and mixtures of 0.22:1, 0.65:1, and 1.96:1 U69,593/fentanyl usually produced subadditive effects. In an assay of thermal nociception, tail withdrawal latencies were measured from water heated to 50 degrees C. Fentanyl and U69,593 each produced dose-dependent antinociception, and effects were additive for all mixtures. In an assay of drug self-administration, rhesus monkeys responded for intravenous drug injection, and both dose and FR values were manipulated. Fentanyl maintained self-administration, whereas U69,593 did not. Addition of U69,593 to fentanyl produced a proportion-dependent decrease in rates of fentanyl self-administration. Moreover, addition of U69,593 increased the sensitivity of fentanyl self-administration to increases in the FR value. Taken together, these results suggest that simultaneous activation of mu and kappa receptors, either with a mixture of selective drugs or with a single drug that targets both receptors, may reduce abuse liability without reducing analgesic effects relative to selective micro agonists administered alone.

Risk, Resilience, and Gene × Environment Interactions in Rhesus Monkeys

Recent research with both humans and rhesus monkeys has provided compelling evidence of gene-environment (GxE) interactions throughout development. For example, a specific polymorphism ("short" allele) in the promoter region of the serotonin transporter (5-HTT) gene is associated with deficits in neurobehavioral functioning during infancy and in poor control of aggression and low serotonin metabolism throughout juvenile and adolescent development in monkeys who were reared with peers but not in monkeys who were reared with their mothers and peers during infancy. In contrast, monkeys possessing the "long" allele of the 5-HTT gene exhibit normal neurobehavioral functioning, control of aggression, and serotonin metabolism regardless of their early social rearing history. One interpretation of these GxE interaction data is that the "long" 5-HTT allele somehow confers resiliency to adverse early attachment relationships on those individuals who carry it ("good genes"). An alternative interpretation of the same data is that secure attachment relationships somehow confer resiliency to individuals who carry alleles that may otherwise increase their risk for adverse developmental outcomes ("maternal buffering"). These two interpretations are not mutually exclusive, but the difference in their respective implications for developing prevention and even intervention strategies is considerable. Moreover, the allelic variation seen in certain genes in rhesus monkeys and humans but apparently not in other primate species may actually contribute to their remarkable adaptability and resilience at the species level.

Opioid interactions in rhesus monkeys: effects of delta + mu and delta + kappa agonists on schedule-controlled responding and thermal nociception.

Agonists at delta, mu, and kappa opioid receptors produce interacting effects in rodents and nonhuman primates. To further evaluate the determinants of these interactions, this study examined the effects of mixtures of delta + mu and delta + kappa agonists in rhesus monkeys (n = 4-5) using two behavioral procedures, an assay of schedule-controlled responding for food reinforcement and an assay of thermal nociception. Results were analyzed using dose-addition analysis. In the assay of schedule-controlled responding, the delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide (SNC80); the mu agonists methadone, fentanyl, morphine, and nalbuphine; and the kappa agonists (5alpha,7alpha,8beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide (U69,593) and bremazocine all dose dependently decreased rates of food-maintained responding when administered alone. Fixed ratio mixtures of SNC80 + mu agonists produced additive or subadditive effects, whereas SNC80 + kappa agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas mu and kappa agonists produced dose-dependent antinociception. SNC80 + mu agonist mixtures produced superadditive effects manifested as leftward shifts in mu agonist dose-effect curves. This synergism was antagonized by the delta-selective antagonist naltrindole, suggesting that SNC80-induced enhancement of mu agonist antinociception was delta receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective kappa agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective kappa agonist bremazocine. These results suggest that delta agonists may selectively enhance the antinociceptive effects of mu agonists in rhesus monkeys. These results also confirm that opioid agonist interactions may depend on the receptor selectivity and relative doses of the agonists and on the experimental endpoint.

The effects of bilateral lesions of the amygdala on dyadic social interactions in rhesus monkeys (Macaca mulatta).

The role of the amygdala in dyadic social interactions of adult rhesus monkeys (Macaca mulatta) was assessed after bilateral ibotenic acid lesions. Social, nonsocial, and spatial behaviors of amygdalectomized and control monkeys were assessed in 3 dyadic experiments: constrained, unconstrained, and round robin. Lesions produced extensive bilateral damage to the amygdala. Across all experiments, the amygdalectomized monkeys demonstrated increased social affiliation, decreased anxiety, and increased confidence compared with control monkeys, particularly during early encounters. Normal subjects also demonstrated increased social affiliation toward the amygdalectomized subjects. These results indicate that amygdala lesions in adult monkeys lead to a decrease in the species-normal reluctance to immediately engage a novel conspecific in social behavior. The altered behavior of the amygdalectomized monkeys may have induced the increased social interactions from their normal companions. This is contrary to the idea that amygdalectomy produces a decrease in social interaction and increased aggression from conspecifics.

The effects of bilateral lesions of the amygdala on dyadic social interactions in rhesus monkeys (Macaca mulatta).

The effects of bilateral lesions of the amygdala on dyadic social interactions in rhesus monkeys (Macaca mulatta).

Effects of Mu Opioid Agonists Alone and in Combination with Cocaine and D-Amphetamine in Rhesus Monkeys Trained to Discriminate Cocaine

Psychomotor stimulants and mu opioid agonists are often used together by polydrug abusers, and it has been suggested that this form of polydrug abuse may result from the ability of stimulants and mu agonists to enhance each other’s abuse-related effects. To investigate this possibility, the present study examined stimulant-opioid interactions in rhesus monkeys trained to discriminate cocaine. Specifically, the effects of the mu opioid agonists heroin, alfentanil, fentanyl, and morphine administered alone or in combination with cocaine or d-amphetamine were examined in five monkeys trained to discriminate 0.4 mg/kg cocaine (IM) from saline in a two-lever, food-reinforced drug discrimination procedure. When administered alone, the rapid onset mu agonists heroin (0.032–0.32 mg/kg) and alfentanil (0.01–0.1 mg/kg) substituted completely for cocaine in three of five monkeys but produced primarily saline-appropriate responding in the other two monkeys. The slower onset mu agonists fentanyl (0.0056–0.056 mg/kg) and morphine (0.56–10 mg/kg) substituted for cocaine in only one of five monkeys. When administered as pretreatments to cocaine, morphine and fentanyl increased levels of cocaine-appropriate responding produced by low doses of cocaine in some monkeys. Morphine pretreatment also increased levels of cocaine-appropriate responding produced by low doses of amphetamine in some monkeys. However, in other monkeys, morphine and fentanyl pretreatment did not alter the discriminative stimulus effects of cocaine or amphetamine. These results indicate that there are substantial individual difference in the effects of mu agonists in cocaine-discriminating rhesus monkeys. In some monkeys, mu agonists mimic or enhance the discriminative stimulus of cocaine, whereas in other monkeys, mu agonists neither mimic nor enhance the effects of stimulants.

Mother-Infant Interaction in Rhesus Monkeys Treated Chronically with Delta-9-Tetrahydrocannabinol

Mother-Infant Interaction in Rhesus Monkeys Treated Chronically with Delta-9-Tetrahydrocannabinol

Mother-Infant Interaction in Rhesus Monkeys Treated Chronically with Delta-9-Tetrahydrocannabinol

Behavior was studied in 15 rhesus monkeys mother-infant pairs, 5 of whom were exposed to delta-9-tetrahydrocannabinol continuously throughout gestation and the nursing period via drug treatment of mother (2.4 mg/kg/day). The drug-exposed mother-infant pairs were similar to nontreated controls in the amount and types displayed at 10 and 90 days of age, and adequate maternal care was demonstrated by all mothers. Drug-exposed pairs, however, showed no increase in interaction patterns that signal the onset of mother-infant independence at about 3 months of age. This finding suggests that mother-infant attachment may be a behavioral system that is particularly sensitive to modification by perinatal exposure to psychoactive drugs.

Quantitative analysis of small group interaction in rhesus monkeys

AbstractThe effect of role relations on social interaction in small groups of rhesus monkeys was examined quantitatively, through use of an interval scale of social behavior. Concurrent pair interactions were tabulated for all possible combinations in 24 triad groups: Six groups containing three males; six groups containing three females; six groups of one male, two females; and six groups of two males and one female. A specific behavior which involves participation of all three animals at once, the incitement interaction, was found to quantitatively alter each monkey's reaction to other social behaviors displayed at the same time. The interaction demonstrates the monkeys' attention to and manipulation of role relations. In all triad types one could quantitatively document the fact that the most subordinate monkey established a role with the most dominant monkey which allowed it some freedom to behave less submissively when interacting with the middle ranking monkey. This general phenomenon in role relations may contribute to group cohesiveness.

Reduction of sexual interaction in rhesus monkeys by a vaginal action of progesterone.

PROGESTERONE acting in the female seems to reduce sexual interaction in several primate species. It has been reported that sexual activity declines during the luteal phase of the menstrual cycle (when circulating progesterone levels are maximal), in monkeys1–3, lowland gorillas4 and humans5, and that administering progesterone to ovariectomised, oestrogen-treated rhesus monkeys has a similar effect6. A major unresolved question is how progesterone causes these changes in behaviour. One possibility is that progesterone acts on the female's central nervous system, causing her to accept or solicit fewer male mounts. Another is that progesterone somehow alters the vagina thereby changing non-behavioural cues (such as a smell7 or tactile qualities) which contribute to her sexual attractiveness. Here we present evidence favouring the second mechanism, since the reduction in sexual interaction caused by systemic administration of a physiological dose of progesterone to female monkeys could be reproduced by instilling very small amounts of this hormone directly into the vagina.

The effect of a manipulatory incentive on social interactions of rhesus monkeys

Experimental tests of social dominance in pairs of rhesus monkeys have almost invariably used competitive food-getting situations to determine dominance status . Although a few of these studies (Hamilton, 1960 ; Miller & Murphy, 1956) have reported incidences of friendly behaviour (e.g . grooming and huddling) during dominance testing, it is not clear whether such interactions occur during presentations of the food incentive or only between presentations . Presumably, as soon as one of the animals consumes the incentive the competitive situation is terminated-allowing for only a brief competitive interaction . If, however, a situation was designed in which the element of competition was persistent, it would then be possible to study and directly compare continuous competitive social interactions with interactions during non-competitive conditions . It has been shown that manipulatory objects are effective incentives for rhesus monkeys (Harlow, Harlow & Meyer, 1950) and it seems reasonable that such objects could serve as incentives in competitive test situations . The purpose of the present study was to determine whether a manipulatory object would have any effect on the social interactions of young rhesus monkeys. More specifically, a piece of rope was introduced into the home cage of a pair of rhesus monkeys to determine whether there was any change in the form and frequency of social responses from that of the normal social activity shown by the pairs. The length of the rope was varied to determine the effect of this variable on competitive interaction .

Social Interactions of Rhesus Monkeys: I. Food-Getting Dominance as a Dependent Variable

(1956). Social Interactions of Rhesus Monkeys: I. Food-Getting Dominance as a Dependent Variable. The Journal of Social Psychology: Vol. 44, No. 2, pp. 249-255.

Social interactions of Rhesus monkeys. II. Effects of social interaction on the learning of discrimination tasks.

Social interactions of Rhesus monkeys. II. Effects of social interaction on the learning of discrimination tasks.