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Official websites use. Share sensitive information only on official, secure websites. Release of serotonin 5-HT is thought to have an important role in the increase in social behaviors, but the mechanisms underlying these effects are poorly understood. Despite the advantages of nonhuman primate models, no studies have examined the mechanisms of the social effects of MDMA in nonhuman primates. The behavior and vocalizations of four group-housed squirrel monkeys were examined following administration of MDMA, its enantiomers, and methamphetamine. Data were analyzed using linear mixed-effects models. MDMA and its enantiomers increased affiliative social behaviors and vocalizations, whereas methamphetamine had only modest effects on affiliative behaviors. Nonhuman primates show MDMA-specific increases in affiliative social behaviors following MDMA administration, in concordance with human and rodent studies. Understanding the neurochemical mechanisms mediating the prosocial effects of MDMA could help in the development of novel therapeutics with the unique social effects of MDMA but fewer of its limitations. MDMA increases social interaction, self-reported ratings of social feelings, and the number of social words used in humans, as well as increasing adjacent lying a passive social interaction and social conditioned place preference in rodents see Kamilar-Britt and Bedi, The potency for 5-HT release is greater than other psychostimulants Rothman et al , , which is thought to mediate the unique subjective profile of racemic MDMA Liechti et al , a. However, additional mechanisms underlying the prosocial effects of MDMA are not well understood. However, human studies using pindolol, a beta-adrenergic antagonist that also partially blocks 5-HT 1A receptors, found that 5-HT 1A receptors were not necessary for MDMA-induced social feelings or changes in emotional empathy van Wel et al , ; Kuypers et al , Several of the effects of MDMA are 5-HT 2A receptor dependent, including hyperlocomotion Herin et al , , changes in body temperature Herin et al , , and striatal dopamine overflow Schmidt et al , The present study evaluated the social effects of MDMA, its enantiomers, and methamphetamine in squirrel monkeys. Methamphetamine was used to examine the social effects of a similar amphetamine-derivative but with a higher dopamine to 5-HT release profile Rothman et al , Additionally, this study examined the receptor pharmacology underlying MDMA-induced social behaviors. Animal experiments allow for the use of novel, and more selective, antagonists to better understand the pharmacological mechanism of the social effects of MDMA. Further, squirrel monkeys have a pharmacokinetic profile for MDMA similar to humans Mueller et al , , providing considerable translational relevance, given the concern that different pharmacokinetic processing can alter the effects of MDMA Green et al , Despite these advantages, only one study has examined the social effects of MDMA in nonhuman primates Ballesta et al , , and no studies have used nonhuman primates to analyze the mechanisms underlying the social effects of MDMA. Here behavioral and vocal changes were examined following administration of MDMA, its enantiomers, or methamphetamine. Subjects were group housed in a 1. Subjects were fed twice daily monkey chow: Harlan Teklad, Madison, WI; fresh fruits and vegetables , had ad libitum access to water, and received daily enrichment ie, foraging opportunities and different toys that were changed daily. However, the last drug exposure for all animals was at least 2 years before the beginning of this study. For experimental sessions, the home cage was moved to a laboratory room separated from the colony. All subjects were given the same dose of racemic MDMA 0. Doses of drugs were given in a randomized order with at least 2 days in between drug administrations. Pretreatments with M M 0. These doses and time frames were chosen because they have been shown previously to affect behavior, neuroendocrine response, and neurotransmitter release following stimulant administration eg, Fantegrossi et al , Dose and timing were based on previous studies in marmosets Harder and Ridley, and rodents Thompson et al , Saline sterile 0. Experiments were broken into two testing phases, with baselines collected at the beginning of the experiment and before WAY and WAY testing. Dunlop et al , For behavioral outcomes, a reviewer blinded to drug condition watched the video recordings and used a behavioral ethogram to score duration of behaviors J-Watcher v1. A single rater, trained to high inter-rater reliability across multiple training videos, scored all videos being compared statistically. The behavioral ethogram used huddling as the main affiliative behavior squirrel monkeys, unlike other nonhuman primates, do not groom socially; Baldwin and Baldwin, The ethogram also included duration of activity, aggression eg, chasing and head grasping , and residual ie, not performing other scored behaviors Hopf et al , The focal animal scoring technique Altmann, was used to assess duration of behaviors. The order of scoring was randomized across trials but kept consistent across the three blocks within a single hour session. Vocalizations were distinguished based on shape of spectrogram and classified into one of the three categories. Vocalizations categorized as affiliative were chucks, purrs, and pulsed calls. These call types are associated with huddling, soliciting contact from a partner, or providing important information to the troop, respectively Jurgens, ; Smith et al , The other two vocalizations were growls, calls commonly observed in connection with threat displays and aggression, and peeps, observed during exploration and after changes in the environment Winter, ; Jurgens, M was dissolved in sterile saline and 1. Doses were calculated from salt weights. This method reliably controls type I error rates and is more parsimonious than generalized linear mixed-effects models GLMMs that are often applied to non-Gaussian data when testing for significance of regression coefficients Warton et al , GLMM results did not qualitatively differ from the linear model results and are therefore reported in Supplementary Table S1 instead of the main text. As dose—response curves are sometimes non-linear, we also tested for polynomial relationships between drug dosage and behavioral and vocalization responses by re-running each LMM with an orthogonal, second-order polynomial ie, quadratic dosage term as a fixed effect. We tested for improvements in fit over the simpler monomial linear models using chi-squared statistics implemented in lme4. When results of the likelihood-ratio test suggested an improved fit for the polynomial models, we tested for significance of the fixed effects and report regression coefficients and t- statistics from the polynomial models Supplementary Table S1. Model residuals were visually inspected for homoscedasticity, and normality was assessed using the one-sample Komlogorov—Smirnov test to examine deviation of standardized residuals from a theoretical standard normal distribution. Model degrees of freedom df , t- statistics, and p -values for fixed effects in LMMs were obtained by using residual maximum likelihood tests with Satterthwaite approximations of df using the lmerTest package Kuznetsova et al , No aggressive interactions were observed during testing and stereotypies were not quantified, but no adverse effects were seen. MDMA and its enantiomers, but not methamphetamine, increase huddling. Average time in min spent huddling a, c, e, and g and active b, d, f, and h during 1-h observations following drug administration. Collapsed across group of four monkeys. Number of sessions was between 3 and 5 for each dose. Error bars represent SEM for variation between subjects. In contrast, methamphetamine was not associated with increased affiliative vocalizations Figure 2e ; Supplementary Table S1. MDMA and its enantiomers, but not methamphetamine, increase affiliative vocalizations. Average number of affiliative calls emitted during the 1-h session following drug administration a, c, d, and e. Affiliative calls broken into three call types chuck, purr, and pulsed calls b. Error bars represent SEM for variation across sessions. Changes to two other main categories of vocalizations, peeps and growls, were also examined following drug administration. MDMA and its enantiomers decrease peeps and increase growl calls. Average number of peep a, c, e, and g and growl b, d, f, and h calls emitted during the 1-h session following drug administration. To examine the receptor pharmacology underlying the effects of MDMA on nonhuman primate behaviors and vocalizations, we administered 5-HT receptor antagonists or agonists prior to MDMA administration. Average time in min spent huddling a, c, and e and average number of affiliative calls b, d, and f during 1-h observations following drug administration. M M is a selective 5-HT 2A receptor antagonist a and b. Number of sessions was between 2 and 5 for each dose. Error bars represent SEM for variation between subjects huddling or across sessions vocalizations. One animal in the group of four squirrel monkeys initially showed low levels of group huddling following MDMA administration Figure 1b. However, following repeated, acute administration of racemic MDMA and its enantiomers over the course of the study, developed similar levels of huddling as the other three subjects. Future studies could examine the potential long-term social and group effects of MDMA in a more controlled manner. The aim of the present study was to examine the affiliative social effects of MDMA in socially housed squirrel monkeys and to examine the 5-HT receptor pharmacology underlying MDMA-induced social behaviors. MDMA and its enantiomers dose-dependently increased huddling and the number of affiliative vocalizations emitted by group-housed squirrel monkeys. Studies have shown that MDMA increases feelings of sociability in humans and increases social interaction in rodents Kamilar-Britt and Bedi, In concordance with this research, the present experiments found that MDMA significantly increases huddling and affiliative calls in squirrel monkeys. MDMA also increased growl calls, vocalizations usually connected with aggression Jurgens, No aggressive behaviors or other aggressive calls were seen and growl calls, when they occur with chucks, have been seen during huddling Winter, This suggests that growls are not exclusively aggressive and may not be indicating aggression in this context, although further studies are necessary. In contrast with the behavioral changes following MDMA administration, methamphetamine did not significantly increase huddling or affiliative vocalizations. These findings support the unique, robust social effects of MDMA and the use of group-housed squirrel monkeys to further examine those social effects and the underlying mechanisms of MDMA. One limitation of our study was that vocalizations were examined by group, making it impossible to determine if all subjects drove the increase in affiliative vocalizations equally. Future studies could separate calls by subject in order to examine individual differences in MDMA-induced vocalizations. The effects of MDMA in female and juvenile group-housed squirrel monkeys should also be examined to determine whether sex and age have a role in MDMA-induced social behaviors. Interestingly, despite its structural similarity to psychostimulant compounds, MDMA significantly decreased activity in nonhuman primates. This finding supports other studies showing decreased activity levels following MDMA Crean et al , and no stimulant effects on operant behavior Fantegrossi et al , Another interpretation, however, could be that increases in huddling are driven by decreases in locomotion. Previous research supports the conclusion that huddling is independent of locomotor effects following drug administration. Drugs that decrease locomotion do not reliably increase huddling Miczek et al , and the effects of stimulants on locomotion and social behaviors are not mediated by the same mechanisms Miczek and Yoshimura, This is further supported by our findings showing dissociation between the effects of 5-HT receptor ligands on MDMA-induced huddling and locomotion. Additionally, the 5-HT 2A receptor is expressed extensively throughout the amygdala Bombardi and Di Giovanni, and reduces amygdala-dependent reactivity and anxiety-related behaviors Weisstaub et al , ; Fisher et al , Given the model that MDMA produces a valence-specific shift in response to social cues, with an increase in recognition of positive social signals and a decrease in response and recognition of negative ones Kamilar-Britt and Bedi, , the striatal and amygdalar effects of 5-HT 2A receptor activation provide a potential mechanism by which 5-HT 2A receptors could mediate increased sociality following MDMA. One potential caveat with the present study is that MDMA has pronounced effects on body temperature eg, Banks et al , and antagonism of the 5-HT 2A receptor attenuates MDMA-induced changes in body temperature in rodents Herin et al , and humans Liechti et al , b. The temperature of the laboratory near an ambient temperature in which MDMA administration did not change body temperature in nonhuman primates; Banks et al , and correlation between affiliative vocalizations and huddling following MDMA Supplementary Figure S4A suggest the findings are not driven by changes in body temperature. Additionally, methamphetamine stimulates even more pronounced changes in body temperature Crean et al , but did not induce a similar increase in huddling. In rodents, 5-HT 1A receptor stimulation is necessary for MDMA-induced increases in adjacent lying and oxytocin release Thompson et al , and activation of oxytocin neurons Hunt et al , Further, one study showed positive correlation between plasma oxytocin and social ratings in the laboratory Dumont et al , The present study supports evidence in the human literature showing that blocking 5-HT 1A receptors does not change increases in self-reported ratings of sociality or emotional empathy following MDMA van Wel et al , ; Kuypers et al , and null correlations between plasma oxytocin and social feelings eg, Kuypers et al , Administration of an SSRI increases body contact and grooming behaviors in cynomolgous macaques Shively et al , , indicating that 5-HT release alone can increase social contact in nonhuman primates. However, further studies are needed to confirm that 5-HT 1A receptor antagonism is enhancing MDMA-induced huddling by blunting autoreceptor feedback. We propose a model for the unique social effects of MDMA, in which 5-HT release, combined with receptor-selective direct agonist effects, enhances sociality. In this model, 5-HT release alone can enhance some social behaviors as seen with increased body contact following SSRI administration; Shively et al , , but the addition of receptor-selective activation enhances these social effects, leading to the unique and robust social behavior caused by MDMA. This model is supported by the dissociation between huddling and affiliative vocalizations following 5-HT 1A receptor antagonism, with additional 5-HT release increasing huddling but not affecting affiliative vocalizations. The differing magnitude of effects of the MDMA enantiomers also provides support for the above model. An increase in therapeutic alliance from increased sociality and openness following MDMA is thought to have a role in the therapeutic potential of MDMA Mithoefer et al , However, there are still concerns about the potential neurotoxicity and abuse potential that limit its clinical appeal Rietjens et al , Understanding the neuropharmacological mechanisms of the prosocial effects of MDMA could allow for the development of novel therapeutics that specifically target social behavior, while limiting abuse potential, toxicity, and other side effects, which may be especially advantageous in vulnerable clinical populations. The authors declare no conflict of interest. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Find articles by Elizabeth G Pitts. Find articles by Adelaide R Minerva. Find articles by Erika B Chandler. Find articles by Jordan N Kohn. Find articles by Meghan T Logun. Find articles by Agnieszka Sulima. Find articles by Kenner C Rice. Find articles by Leonard L Howell. Open in a new tab. Click here for additional data file. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

Faculty Publications - 2017

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The first evidence of an active transport of serotonin 5-hydroxytryptamine, 5-HT came from pioneer studies in the late s showing an uptake of 5-HT into the blood platelets from rabbit or guinea pig. A few years later, a similar mechanism was observed in the rat brain Schanberg The mechanism of this transport, involving the sodium and potassium ionic gradients, was rapidly elucidated, and the existence of a dedicated transporter protein postulated. Historical Background The first evidence of an active transport of serotonin 5-hydroxytryptamine, 5-HT came from pioneer studies in the late s showing an uptake of 5-HT into the blood platelets from rabbit or guinea pig.

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