AN INTEGRATIVE MODEL OF PERSONALITY DISORDER: PART 3: MECHANISM-BASED APPROACH TO THE PHARMACOTHERAPY OF PERSONALITY DISORDER: AN EMERGING CONCEPT

Temperament traits of Novelty Seeking, Harm Avoidance, Reward Dependence, and Persistence, are well defined in terms of their neural circuitry, neurochemical modulators, and patterns of associative learning. When heritably excessive, each of these traits may become a mechanistically fundamental biogenetic trait vulnerability for personality disorder. The other main risk factor for personality disorder is environmental, notably abuse, neglect, and psychological trauma. The emerging concept of mechanism-based pharmacotherapy aims to activate the brain’s homeostasis as the only available delivery system to re-calibrate complex neurophysiological participants in each of the temperament traits. In a positive feedback, a homeostasis-driven improvement of excessive temperament is expected to facilitate maturation of neocortical networks of cognition, most reliably in expert psychotherapy (Part I of this paper) and, ultimately, thereby improve top-down cortical control of subcortical affect reactivity. As an emerging concept informed by neuroscience and clinical research, mechanism based pharmacotherapy has the potential to be superior to traditional symptom-based treatments. Such mechanism-based approach illustrates what the pharmacological treatment of Research Domain Criteria (RDoC) might look like

Oxytocin signaling as a target to block social defeat-induced increases in drug abuse reward

There is huge scientific interest in the neuropeptide oxytocin (OXT) due to its putative capacity to modulate a wide spectrum of physiological and cognitive processes including motivation, learning, emotion, and the stress response. The present review seeks to increase the understanding of the role of OXT in an individual’s vulnerability or resilience with regard to developing a substance use disorder. It places specific attention on the role of social stress as a risk factor of addiction, and explores the hypothesis that OXT constitutes a homeostatic response to stress that buffers against its negative impact. For this purpose, the review summarizes preclinical and clinical literature regarding the effects of OXT in different stages of the addiction cycle. The current literature affirms that a well-functioning oxytocinergic system has protective effects such as the modulation of the initial response to drugs of abuse, the attenuation of the development of dependence, the blunting of drug reinstatement and a general anti-stress effect. However, this system is dysregulated if there is continuous drug use or chronic exposure to stress. In this context, OXT is emerging as a promising pharmacotherapy to restore its natural beneficial effects in the organism and to help rebalance the functions of the addicted brain

Regulation of social behaviour via oxytocin receptor signaling in the caudodorsal lateral septum in Long-Evans male and female rats

The oxytocin receptor (OTR), a class A G-protein coupled receptor, is highly expressed in the lateral septum (LS), a brain region that regulates social behaviors in rodents. This thesis investigates whether OTRs within the LS modulate social approach-avoidance behavior, acquisition of long-term social recognition memory, and anxiety-like behavior in adult male and female rats. In the first experiment, L-368, 899, a selective OTR antagonist, was infused locally into the caudodorsal lateral septum (LSc.d), resulting in the attenuation of social approach, enhancement of social vigilance, and reduction in social novelty preference in male and female rats, with no effect on locomotion. In the second experiment, carbetocin, a biased OTR/Gq agonist, was locally delivered into the LSc.d, leading to reduced social approach and social novelty preference (a measure of social memory), with no effect on social vigilance or locomotion. Intriguingly, carbetocin increased latency to consumption of a highly palatable food only in male rats in the novelty-induced hypophagia test, indicating the sex-specific anxiogenic effects of the OTR/Gq signaling pathway in the region. In the third experiment, a selective full agonist of the OTR, (Thr4,Gly7)-Oxytocin, was infused into the LSc.d of male rats, resulting in a slight, but non-significant increase in social approach. Unlike the antagonist and the biased agonist, (Thr4,Gly7)-Oxytocin-treated rats showed social novelty preference 24 h after familiarization. Moreover, (Thr4,Gly7)-Oxytocin decreased latency to consumption of a highly palatable food compared to vehicle-treated rats, suggesting anxiolytic effects of the OTR full agonism. In conclusion, the findings suggest that OTR signaling in the LSc.d regulates social approach-avoidance, acquisition of social recognition memory and anxiety-like behavior depending on the activation of a specific upstream signaling arm of the receptor. I demonstrated that the OTR/Gq signaling pathway within the LSc.d promotes social avoidance in both sexes and triggers anxiogenic effects only in males, contrasting with the effects induced by the full agonism of the receptor

Anatomy and Physiology of the Nucleus Paragigantocellularis: Neural Regulation of Genital Reflexes in Male and Female Rats

The supraspinal control of descending inhibition of genital reflexes (such as ejaculation) is poorly understood but is important in our global comprehension of how neural signals are integrated to produce sexual behavior, and in our understanding of sexual dysfunction. Sexual dysfunctions, such as premature ejaculation/delayed ejaculation in men, and involuntary vaginal spasms, dyspareunia, and anorgasmia in women, are common. An underlying dysregulation of genital reflexes may produce these dysfunctions, especially in those individuals being treated for depression and anxiety with serotonergic drugs. The nucleus paragigantocellularis (nPGi) of the rat medulla has been described as a descending inhibitory system for genital reflexes in rats, and a homologue is known in humans. Through retrograde tracing of nPGi afferents with the tracer Fluorogold in rats, we found that a number of brain regions implicated in sexual behavior, such as the medial preoptic area, paraventricular nucleus of the hypothalamus, and periaqueductal gray (PAG) provide sexually dimorphic projections to the nPGi, and that many of these regions contain receptors for gonadal steroids and are active during sexual behavior. We also found that excitotoxic lesions of the nPGi with N-methyl-D-aspartate facilitate male sexual behavior by reducing the number of intromissions required for ejaculation, and decreasing ejaculation latency. In females, such lesions attenuated sexual behavior by reducing the amount of time the female spent mating and reducing the reinforcement value of vaginocervical stimulation. Lastly, we found that by removing the source of serotonin to the nPGi (from the ventrolateral PAG) with the serotonergic neurotoxin 5,7-DHT in male rats, we were able to mimic the effects of nPGi lesions and facilitated male sexual behavior indicating that serotonin neurotransmission at the level of the nPGi is critical for genital reflex control. Taken together our results indicate that the nPGi is an important site of integration of internal signals for the regulation of sexual behavior that is sexually dimorphic and under serotonergic control. Our understanding of normal and dysfunction genital reflex control, and possible treatment options in people, is complemented by these results

Does activation of oxytocinergic reward circuits postpone the decline of the aging brain?

Oxytocin supports reproduction by promoting sexual- and nursing behavior. Moreover, it stimulates reproductive organs by different avenues. Oxytocin is released to the blood from terminals of oxytocinergic neurons which project from the hypothalamus to the pituitary gland. Concomitantly, the dendrites of these neurons discharge oxytocin into neighboring areas of the hypothalamus. At this location it affects other neuroendocrine systems by autocrine and paracrine mechanisms. Moreover, sensory processing, affective functions, and reward circuits are influenced by oxytocinergic neurons that reach different sites in the brain. In addition to its facilitating impact on various aspects of reproduction, oxytocin is revealed to possess significant anti-inflammatory, restoring, and tranquilizing properties. This has been demonstrated both in many in-vivo and in-vitro studies. The oxytocin system may therefore have the capacity to alleviate detrimental physiological- and mental stress reactions. Thus, high levels of endogenous oxytocin may counteract inadequate inflammation and malfunctioning of neurons and supportive cells in the brain. A persistent low-grade inflammation increasing with age—referred to as inflammaging—may lead to a cognitive decline but may also predispose to neurodegenerative diseases such as Alzheimer’s and Parkinson. Interestingly, animal studies indicate that age-related destructive processes in the body can be postponed by techniques that preserve immune- and stem cell functions in the hypothalamus. It is argued in this article that sexual activity—by its stimulating impact on the oxytocinergic activity in many regions of the brain—has the capacity to delay the onset of age-related cerebral decay. This may also postpone frailty and age-associated diseases in the body. Finally, oxytocin possesses neuroplastic properties that may be applied to expand sexual reward. The release of oxytocin may therefore be further potentiated by learning processes that involves oxytocin itself. It may therefore be profitable to raise the consciousness about the potential health benefits of sexual activity particularly among the seniors

Dissecting social decision-making: A spotlight on oxytocinergic transmission

Social decision-making requires the ability to balance both the interests of the self and the interests of others to survive in social environments. Empathy is essential to the regulation of this type of interaction, and it often sustains relevant prosocial behaviors such as altruism and helping behavior. In the last decade, our capacity to assess affective and empathy-like behaviors in rodents has expanded our understanding of the neurobiological substrates that underly social decision-making processes such as prosocial behaviors. Within this context, oxytocinergic transmission is profoundly implicated in modulating some of the major components of social decision-making. Thus, this review will present evidence of the association between oxytocin and empathy-like and prosocial behaviors in nonhuman animals. Then, we will dissect the involvement of oxytocinergic transmission-across different brain regions and pathways-in some of the key elements of social decision-making such as emotional discrimination, social recognition, emotional contagion, social dominance, and social memory. Evidence of the modulatory role of oxytocin on social decision-making has raised considerable interest in its clinical relevance, therefore we will also discuss the controversial findings on intranasal oxytocin administration

Exploring sex differences in the response to tickling in juvenile Wistar rats

Positive welfare is considered not simply the absence of suffering, but also the presence of positive experiences. ‘Tickling’ induces positive affective states in laboratory rats as evidenced by the production of 50 kHz ultrasonic vocalisations (USVs). Few studies have investigated the effect of tickling on females, and whether there is a sex difference in response to tickling and the involvement of the neuroendocrine system. Here I investigated whether there are sex differences in behavioural responses to tickling in juvenile Wistar rats due to sex-specific neural regulation of positive affective states. I tested the following hypotheses that: (i) specific elements of the behavioural response to tickling (including USVs) differ between sexes; (ii) 50 kHz USV subtypes are produced in a temporally specific manner during tickling, and they may be paired with different behaviours observed during tickling; (iii) the behavioural response to tickling is regulated by brain regions and neural circuits that are associated with social play in rats, and this is sex specific; (iv) oxytocin and vasopressin neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) are involved in the behavioural response to tickling in a sex specific manner; and (v) 50 kHz USV production in response to tickling is related to measures of motivation for the reward of tickling, and this is greater in females. In experiment 1, rats were tickled or had no hand contact during two minutes of testing per day for 10 days. Play-related behaviours (hand approaches and solitary play) and 50 kHz USVs were quantified. Female rats made more 50 kHz USVs after 10, but not five, days of tickling. Tickled rats made more trill 50 kHz USVs, regardless of sex, while female rats emitted more flat 50 kHz USVs than males after 10 days of testing. Both treatment and sex affected flat 50 kHz USVs, with females producing more flat 50 kHz USVs and regardless of sex, tickled rats producing more trill 50 kHz USVs than controls. Females paired more flat 50 kHz USVs with scampering and approaches, while tickled rats of both sexes paired more trills with those behaviours. Tickled rats elicited more solitary play scampering than control rats, and this was greatest in females. Tickling did not increase hand approaches, and control females approached the hand more than tickled rats. Double-labelled immunohistochemistry was used to quantify c-fos expression (a neuronal activity marker) in oxytocinergic and vasopressinergic neurons that are known to be involved in social behaviours (e.g. social conspecific play) and reward pathways. Tickling did not increase Fos immunoreactivity in the social behaviour, reward or mid- or hind-brain brain regions. Control rats had more correlated Fos immunoreactivity between regions of the social behaviour network and reward pathway. In the PVN, tickled rats, regardless of sex, had lower numbers of Fos positive parvocellular, but not magnocellular, oxytocin and vasopressin neurons. There was no effect of tickling on Fos immunoreactivity in oxytocin and vasopressin SON neurons. In experiment 2, rats were tickled or had no hand contact during two minutes of testing per day for five days, followed by testing in a modified runway test for two days to measure motivation for tickling, and a modified preference test to measure preference for the hand over a novel object. Tickling did not affect the time taken to traverse the runway, but tickled rats made more total and trill 50 kHz USVs while traversing the runway. Tickling did not change preference for a novel object or the hand, but control rats made more visits to the novel object. In summary, there are sex differences in the behavioural response to tickling, but this appears to be dependent on the number of days of tickling and specific to individuals. Tickling did not increase neuronal activity in key regions associated with social behaviours and reward and this may be a consequence of individual responses to tickling. Alternatively, tickling, while rewarding, was not perceived as a social stimulus. This is an important consideration for future tickling studies as tickling should not necessarily be construed as mimicking rat social conspecific play and responses to tickling by both sexes should be considered

A comprehensive assay of social motivation reveals sex-specific roles of autism-associated genes and oxytocin

Social motivation is critical to the development of typical social functioning. Social motivation, specifically one or more of its components (e.g., social reward seeking or social orienting), could be relevant for understanding phenotypes related to autism. We developed a social operant conditioning task to quantify effort to access a social partner and concurrent social orienting in mice. We established that mice will work for access to a social partner, identified sex differences, and observed high test-retest reliability. We then benchmarked the method with two test-case manipulations

Rescue of oxytocin response and social behaviour in a mouse model of autism

A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases1,2,3. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin4,5,6, which regulate aspects of social behaviour in mammals7. However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3-knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor Nlgn3, regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions