Innovative solutions to novel drug development in mental health.

There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.

Facilitation of affiliation and pair-bond formation by vasopressin receptor gene transfer into the ventral forebrain of a monogamous vole.

Behaviors associated with monogamy, including pair-bond formation, are facilitated by the neuropeptide vasopressin and are prevented by a vasopressin receptor [V1a receptor (V1aR)] antagonist in the male prairie vole. The neuroanatomical distribution of V1aR dramatically differs between monogamous and nonmonogamous species. V1aR binding is denser in the ventral pallidal region of several unrelated monogamous species compared with nonmonogamous species. Because the ventral pallidum is involved in reinforcement and addiction, we hypothesize that V1aR activation in this region promotes pair-bond formation via a mechanism similar to conditioning. Using an adeno-associated viral vector to deliver the V1aR gene, we increased the density of V1aR binding in the ventral pallial region of male prairie voles. These males exhibited increased levels of both anxiety and affiliative behavior compared with control males. In addition, males overexpressing the V1aR in the ventral pallidal region, but not control males, formed strong partner preferences after an overnight cohabitation, without mating, with a female. These data demonstrate a role for ventral pallidal V1aR in affiliation and social attachment and provide a potential molecular mechanism for species differences in social organization.

Increased affiliative response to vasopressin in mice expressing the V1a receptor from a monogamous vole.

Arginine vasopressin influences male reproductive and social behaviours in several vertebrate taxa through its actions at the V1a receptor in the brain. The neuroanatomical distribution of vasopressin V1a receptors varies greatly between species with different forms of social organization. Here we show that centrally administered arginine vasopressin increases affiliative behaviour in the highly social, monogamous prairie vole, but not in the relatively asocial, promiscuous montane vole. Molecular analyses indicate that gene duplication and/or changes in promoter structure of the prairie vole receptor gene may contribute to the species differences in vasopressin-receptor expression. We further show that mice that are transgenic for the prairie vole receptor gene have a neuroanatomical pattern of receptor binding that is similar to that of the prairie vole, and exhibit increased affiliative behaviour after injection with arginine vasopressin. These data indicate that the pattern of V1a-receptor gene expression in the brain may be functionally associated with species-typical social behaviours in male vertebrates.

Gene targeting approaches to neuroendocrinology: oxytocin, maternal behavior, and affiliation.

Transgenic technology affords exciting new opportunities in the field of behavioral neuroendocrinology. We have extended our research into the behavioral function of oxytocin in maternal and social behavior using two transgenic approaches: (i) targeted deletion of the oxytocin gene in mice and (ii) augmented oxytocin receptor expression in the brain. Mice genetically deficient in oxytocin can mate, give birth, and display normal maternal behavior; however, milk ejection and certain aspects of social behavior are affected. Comparative studies of oxytocin receptors have led to the observation that species differences in social organization are associated with differences in receptor distribution. Specifically, monogamous prairie voles and nonmonogamous, asocial montane voles exhibit different patterns of OT receptor expression in the brain. Transgenic mice have been created with a reporter gene driven by the prairie vole oxytocin receptor gene promoter. Analysis of the expression pattern suggests that it should be possible to manipulate receptor expression in the vole brain in order to examine the effects of receptor distribution on behavior.

Immunoreactivity of central vasopressin and oxytocin pathways in microtine rodents: a quantitative comparative study.

The genus Microtus includes several closely related species of voles with diverse patterns of social organization. Comparative studies of these species have previously tested hypotheses related to the evolution of monogamy and affiliation. In earlier studies, monogamous voles have been reported to differ from closely related nonmonogamous voles in the neural distribution of oxytocin and vasopressin receptors. These receptors have also been implicated in the behavioral differences relevant to monogamy, as oxytocin and vasopressin influence pair-bond formation in the monogamous species. In the current study, two monogamous and two nonmonogamous vole species were compared for the distribution of oxytocin and vasopressin immunoreactivity. Contrary to our predictions, gender dimorphisms in vasopressin immunoreactivity were as evident in the monogamous as in the nonmonogamous species. Also, species differences in oxytocin and vasopressin staining were subtle relative to the profound species differences previously reported for receptor binding. These results are consistent with the hypothesis that neuroendocrine systems may evolve by changes in receptor distribution rather than by restructuring the presynaptic pathway.

Patterns of brain vasopressin receptor distribution associated with social organization in microtine rodents.

Central vasopressin pathways have been implicated in the mediation of paternal behavior, selective aggression, and affiliation in monogamous prairie voles. Here we demonstrate markedly different patterns of brain vasopressin receptor binding in the monogamous prairie vole and the congeneric nonmonogamous (promiscuous) montane vole. Vasopressin binding was assessed with both 3H-vasopressin and 125I-sarc-AVP using receptor autoradiography. The specificity of binding was consistent with a V1a receptor, the saturation kinetics were similar in the two species, and neither species showed evidence of sexual dimorphisms. In the prairie vole, highest specific binding was observed in the accessory olfactory bulb, diagonal band, laterodorsal thalamus, and superior colliculus. In the montane vole, specific binding was observed in the accessory olfactory bulb and superior colliculus as well, but in several other regions with high levels of binding in the prairie vole, binding was low or undetectable in the montane vole. In this nonmonogamous species, specific binding was high in lateral septum. Functional studies demonstrated the induction of phosphoinositol by AVP in the septum of the montane vole but not in the prairie vole. The pattern of 125I-sarc-AVP binding to lateral septum may reflect the social organization of these two species, as similar differences in AVP receptor distribution in the lateral septum were also observed in two related species, pine voles and meadow voles, which are monogamous and nonmonogamous, respectively. These results, along with earlier studies of AVP's effects on pair bonding, suggest the importance of this neuropeptide for the mediation of behaviors related to social organization.

A role for central vasopressin in pair bonding in monogamous prairie voles.

Monogamous social organization is characterized by selective affiliation with a partner, high levels of paternal behaviour and, in many species, intense aggression towards strangers for defence of territory, nest and mate. Although much has been written about the evolutionary causes of monogamy, little is known about the proximate mechanisms for pair bonding in monogamous mammals. The prairie vole, Microtus ochrogaster, is a monogamous, biparental rodent which exhibits long-term pair bonds characterized by selective affiliation (partner preference) and aggression. Here we describe the rapid development of both selective aggression and partner preferences following mating in the male of this species. We hypothesized that either arginine-vasopressin (AVP) or oxytocin (OT), two nine-amino-acid neuropeptides with diverse forebrain projections, could mediate the development of selective aggression and affiliation. This hypothesis was based on the following observations: (1) monogamous and polygamous voles differ specifically in the distribution of forebrain AVP and OT receptors; (2) AVP innervation in the prairie vole brain is sexually dimorphic and important for paternal behaviour; (3) central AVP pathways have been previously implicated in territorial displays and social memory; and (4) central OT pathways have been previously implicated in affiliative behaviours. We now demonstrate that central AVP is both necessary and sufficient for selective aggression and partner preference formation, two critical features of pair bonding in the monogamous prairie vole.

Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles.

The neuropeptide oxytocin has been implicated in the mediation of several forms of affiliative behavior including parental care, grooming, and sex behavior. Here we demonstrate that species from the genus Microtus (voles) selected for differences in social affiliation show contrasting patterns of oxytocin receptor expression in brain. By in vitro receptor autoradiography with an iodinated oxytocin analogue, specific binding to brain oxytocin receptors was observed in both the monogamous prairie vole (Microtus ochrogaster) and the polygamous montane vole (Microtus montanus). In the prairie vole, oxytocin receptor density was highest in the prelimbic cortex, bed nucleus of the stria terminalis, nucleus accumbens, midline nuclei of the thalamus, and the lateral aspects of the amygdala. These brain areas showed little binding in the montane vole, in which oxytocin receptors were localized to the lateral septum, ventromedial nucleus of the hypothalamus, and cortical nucleus of the amygdala. Similar differences in brain oxytocin receptor distribution were observed in two additional species, the monogamous pine vole (Microtus pinetorum) and the polygamous meadow vole (Microtus pennsylvanicus). Receptor distributions for two other neurotransmitter systems implicated in the mediation of social behavior, benzodiazepines, and mu opioids did not show comparable species differences. Furthermore, in the montane vole, which shows little affiliative behavior except during the postpartum period, brain oxytocin receptor distribution changed within 24 hr of parturition, concurrent with the onset of maternal behavior. We suggest that variable expression of the oxytocin receptor in brain may be an important mechanism in evolution of species-typical differences in social bonding and affiliative behavior.

Oxytocin--a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies.

Oxytocin (OT) is a nine amino acid peptide synthesized in hypothalamic cells which project either to the neurohypophysis or to sites within the central nervous system. Although neurohypophyseal OT release has long been associated with uterine contraction and milk ejection, the function of intracerebral OT remains unclear. On the basis of behavioral, cellular, and comparative studies, this review suggests that brain OT influences the formation of social bonds. The first part of this review examines evidence linking central OT to several forms of affiliation. Central administration of OT induces maternal and reproductive behaviors in rats primed with gonadal steroids. OT antagonists and hypothalamic lesions block the initiation of maternal and reproductive behaviors but have no effects on these behaviors once established. Our new studies in rat pups demonstrate that central OT selectively decreases the separation response, an effect which mimics social contact. These studies of parental, reproductive, and attachment behaviors suggest that exogenous OT has "prosocial" effects and that endogenous OT may be essential for initiating social interaction. In a second series of experiments, we investigated the cellular mechanisms for OT's effects on social behavior by means of autoradiographic receptor binding. In the rat forebrain, OT receptors are expressed in several limbic regions believed to be involved in the integration of sensory processing. The regulation of these receptors is surprisingly resistant to either ablation of OT cells or repeated central administration of OT. However, receptors in two regions, the bed nucleus of the stria terminalis (BNST) and the ventromedial nucleus of the hypothalamus (VMN), appear selectively induced by exogenous or endogenous increases in gonadal steroids. At parturition, binding to OT receptors increases 84% in the BNST, and at estrus, binding increases 35% in the VMN. These results demonstrate that physiologic changes in gonadal steroids can alter receptor expression in anatomically discrete target fields and thereby direct responsiveness to endogenous neuropeptide release. A model for OT's effects on social behavior is proposed, which relies on the heterologous regulation of the brain OT receptor. A third series of experiments tested the hypothesis that brain OT influences affiliation by comparing prairie and montane voles, two closely related species with dichotomous systems of social organization. Although no differences appear in the presynaptic expression of the neuropeptide, OT receptors are distributed in complementary patterns in the two species. In the highly affiliative prairie vole, receptors are most evident in the BNST and one of its primary afferents, the lateral amygdala, highlighting a circuit previously implicated in maternal behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

Social status in pairs of male squirrel monkeys determines the behavioral response to central oxytocin administration.

Oxytocin, when administered centrally, has been associated with the modulation of various social initiatives including maternal and sexual behaviors. The nature of these effects depends on gonadal hormone status. In the present experiments, we investigated the effects of centrally administered oxytocin on the behavior of pair-housed male squirrel monkeys during interactions with a familiar female monkey. Pairs of male squirrel monkeys established reliable and persistent dominance relationships with dominant males showing increased sexual and aggressive behavior as well as higher plasma concentrations of testosterone. Oxytocin (0.1, 1.0 micrograms) increased the sexual and aggressive behavior of dominant monkeys without affecting these measures in the subordinate monkeys. In contrast to these effects in the dominant monkeys, oxytocin increased associative and marking behaviors only in subordinate monkeys. Central administration of the oxytocin receptor antagonis d(CH2)5 [Tyr(Me)2, Thr4,Tyr-NH2(9)] OVT (OTA; 0.05 microgram) had no intrinsic effect on behavior but blocked the effects of exogenous oxytocin. To investigate further the specificity of oxytocin's effects on social behavior, we administered the structurally related peptide arginine vasopressin under identical conditions. Vasopressin (0.5, 5.0 micrograms) decreased social behaviors and increased motor activity in both dominant and subordinate monkeys. Previous studies in rodents have demonstrated that oxytocin receptors are induced by gonadal steroids in a regionally specific fashion. The status-related behavioral effects of oxytocin in the squirrel monkey may reflect differences in brain oxytocin receptor density associated with the higher concentrations of testosterone in the dominant animal. Alternatively, the status-related effects may depend on the conditioned behavioral differences associated with social organization.