Effects of arginine vasopressin on human anxiety and associations with sex, dose, and V1a-receptor genotype.

RATIONALE: Arginine vasopressin (AVP) has dose- and sex-specific effects on social behavior, and variation in social responses is related to variation in the V1a receptor gene in animals. Whether such complexity also characterizes AVP effects on anxiety in humans, or whether V1a genotype is related to anxiety and/or AVP's ability to affect it, remains to be determined. OBJECTIVE: To test if AVP has dose-dependent effects on anxiety in men and/or women and if a particular allele within the RS3 promoter region of the V1a receptor gene is associated with anxiety and/or AVP effects on anxiety. METHOD: Men and women self-administered 20 IU or 40 IU intranasal arginine vasopressin (AVP) and placebo in a double-blind, within-subjects design, and State (SA) and Trait (TA) anxiety were measured 60 min later. PCR was used to identify allelic variation within the RS3 region of the V1a receptor gene. RESULTS: AVP decreased SA in men across both doses, whereas only the lower dose had the same effect, across sexes, in individuals who carry at least one copy of a previously identified "risk" allele in the RS3 promoter of the V1a receptor gene. Additionally, after placebo, women who carried a copy of the allele displayed lower TA than women who did not, and AVP acutely increased TA scores in those women. CONCLUSIONS: Exogenous AVP has modest sex- and dose-dependent effects on anxiety/affect in humans. Further, allelic variation in the V1a promoter appears associated with responsiveness to AVP's effects and, at least in women, to stable levels of anxiety/affect.

Acute effects of sex steroids on visual processing in male goldfish.

Elevations of sex steroids induced by social cues can rapidly modulate social behavior, but we know little about where they act within the nervous system to produce such effects. In male goldfish, testosterone (T) rapidly increases approach responses to the visual cues of females through its conversion to estradiol. Because aromatase is expressed in the retina, we tested if T can acutely influence retina responses to visual stimuli, and investigated the receptor mechanisms that may mediate such effects. Specifically, we measured FOS protein immunoreactivity to determine if T affects cellular responses to visual stimuli that include females, and used electrophysiology to investigate whether T can generally affect light sensitivity. We found that T acutely increased FOS responses to the simultaneous onset of light and the presence of female visual stimuli, both of which would normally be associated with early morning spawning, and increased electrophysiological responses to low intensity light pulses. Both effects were blocked by an estrogen receptor beta (ERß) antagonist, indicating that T is likely being converted to estradiol (E2) and acting through an ERß mediated mechanism to acutely modulate visual processing. Changes in sensory processing could subsequently influence approach behavior to increase reproductive success in competitive mating environments.

Pheromones enhance somatosensory processing in newt brains through a vasotocin-dependent mechanism.

We tested whether the sex pheromones that stimulate courtship clasping in male roughskin newts do so, at least in part, by amplifying the somatosensory signals that directly trigger the motor pattern associated with clasping and, if so, whether that amplification is dependent on endogenous vasotocin (VT). Female olfactory stimuli increased the number of action potentials recorded in the medulla of males in response to tactile stimulation of the cloaca, which triggers the clasp motor reflex, as well as to tactile stimulation of the snout and hindlimb. That enhancement was blocked by exposing the medulla to a V1a receptor antagonist before pheromone exposure. However, the antagonist did not affect medullary responses to tactile stimuli in the absence of pheromone exposure, suggesting that pheromones amplify somatosensory signals by inducing endogenous VT release. The ability of VT to couple sensory systems together in response to social stimulation could allow this peptide to induce variable behavioural outcomes, depending on the immediate context of the social interaction and thus on the nature of the associated stimuli that are amplified. If widespread in vertebrates, this mechanism could account for some of the behavioural variability associated with this and related peptides both within and across species.

A primitive social circuit: vasotocin-substance P interactions modulate social behavior through a peripheral feedback mechanism in goldfish.

At its core, the polyvagal theory proposes that peptides affect simple social behaviors through influences on hindbrain autonomic processes. To test this mechanism, we compared the effects of fore- and hindbrain infusions of vasotocin (VT) on social approach behavior in goldfish. VT infusions into the 4th ventricle, which ink infusions verified did not move rostrally to the forebrain, inhibited social approach at a lower dose than did infusions into the 3rd ventricle, which did diffuse to the hindbrain. Thus, VT actions in the hindbrain appear to modulate this simple social behavior. We then identified a population of substance P (SP)-immunoreactive cells in the hindbrain that are encapsulated by putative VT terminals, and determined that those cells project to the periphery. Injecting SP peripherally, as with infusing VT centrally, inhibited social approach, and peripheral injections of an SP antagonist, but not central infusions, abolished the behavioral effects of central VT infusions. We therefore propose that VT inhibits social approach by activating SP cells in the hindbrain, which then induce changes in body state that feed back to the brain. Central VT infusions did not inhibit feeding, suggesting that this VT mechanism selectively affects appetitive social responses. Because VT projections to the hindbrain are highly conserved in vertebrates, influences on peripheral feedback processes like the one we have described in goldfish may reflect how VT affected simple social behaviors in ancestral vertebrates and thus preadapted members of this peptide family to play increasingly complex roles in social and emotional regulation in modern animals.

Sex-specific influences of vasopressin on human social communication.

Arginine vasopressin (AVP) and related peptides affect social behaviors in numerous species, but AVP influences on human social functions have not yet been established. Here, we describe how intranasal AVP administration differentially affects social communication in men and women, and we propose a mechanism through which it may exert those influences. In men, AVP stimulates agonistic facial motor patterns in response to the faces of unfamiliar men and decreases perceptions of the friendliness of those faces. In contrast, in women, AVP stimulates affiliative facial motor patterns in response to the faces of unfamiliar women and increases perceptions of the friendliness of those faces. AVP also affected autonomic responsiveness to threatening faces and increased anxiety, which may underlie both communication patterns by promoting different social strategies in stressful contexts in men and women.

Visual sex discrimination in goldfish: seasonal, sexual, and androgenic influences.

The olfactory signals used by goldfish for sexual and aggressive communication have been studied extensively, but little work has addressed the role of other sensory modalities in social communication in this species. We therefore investigated the role that visual stimuli play in sex discrimination and the ability of androgens, which masculinize courtship behavior, to affect behavioral responses toward female visual stimuli. We found that males selectively orient toward female visual stimuli during the breeding season but not outside it, whereas prostaglandin F2-alpha (PGF2alpha)-injected females do not differentially approach male and female visual stimuli, even during the breeding season. Implanting adult females with testosterone (T) and 11-ketotestosterone (KT), however, induced orientation responses toward female visual stimuli similar to those observed in males. These results indicate that visual sexual stimuli are likely important for reproductive signaling in goldfish, potentially helping males identify ovulating females from a distance in a shoal of fish, and that androgens can influence mechanisms associated with orientation responses toward such stimuli.

The effects of sex steroids and vasotocin on behavioral responses to visual and olfactory sexual stimuli in ovariectomized female roughskin newts.

Previous studies have found that vasotocin (AVT) administration to male roughskin newts (Taricha granulosa) enhances courtship clasping as well as appetitive responses to specific sexual stimuli and that treating female newts with androgens plus AVT induces the expression of male-typical courtship clasping (the selective clasping of females). However, the unique and/or interactive effects of sex steroids and AVT on appetitive responses to specific sexual stimuli have not yet been determined. To first identify male-typical, sexually dimorphic appetitive responses to female sexual stimuli, we tested intact newts during the breeding season and found that males, but not females, are attracted to female visual and pheromonal sexual stimuli. We then used ovariectomized (ovx) females implanted with empty silastic capsules (Blk) or with capsules containing testosterone (T), dihydrotestosterone (DHT), or estradiol (E2) and then injected with either saline or AVT to determine the effects of steroids and AVT, alone or in combination with each other, on male-typical behavioral responses to those stimuli. E2 treatment depressed responses toward female visual stimuli independently of AVT. On the other hand, only T-implanted, AVT-injected females displayed male-typical behavioral responses toward female olfactory stimuli, preferring to spend more time in proximity to female-scented than unscented newt models and selectively clasping the female-scented models. Together, these results support the conclusion that sex steroids and AVT influence behavioral responses to sexual stimuli via sensory-specific mechanisms. Furthermore, they suggest that T and AVT interact within the brain to influence sensorimotor processing in the pathways that integrate olfactory sexual stimuli into male-typical courtship behaviors.

Vasotocin stimulates appetitive responses to the visual and pheromonal stimuli used by male roughskin newts during courtship.

It is now well established that vasotocin (AVT) and its mammalian homologue vasopressin influence various social behaviors in vertebrates, but less is known about the mechanisms through which these peptides modulate behavior. In male roughskin newts, Taricha granulosa, AVT stimulates a courtship behavior, amplectic clasping. Three general explanations for how AVT affects male courtship behavior have been considered: by enhancing a central state of sexual motivation, by affecting sensorimotor integration mechanisms in individual sensory modalities, or by influencing a nonspecific state of attention, arousal, or anxiety. AVT administration enhanced appetitive responses to visual and olfactory sexual stimuli, as would be expected if AVT affects a state of sexual motivation that affects behavioral responses to sexual stimuli regardless of the sensory modality in which they are processed. However, AVT selectively enhanced responses to female olfactory stimuli (sex pheromones), but similarly enhanced responses to female and food-related visual stimuli (worms), thus questioning the utility of such a motivational mechanism, as responses to female stimuli were not selectively enhanced in all sensory modalities. We therefore propose that exogenous AVT independently influences olfactory processes associated with orientation/attraction toward a female sex pheromone and visual processes associated with orientation/attraction toward a visual feature common to females and worms. In further experiments AVT administration failed to stimulate feeding behavior but did decrease locomotor activity. Thus, AVT does not stimulate courtship behavior in this species by enhancing the animals' general state of attention or by decreasing general anxiety, as responses to nonsexual, attractive stimuli were not uniformly enhanced, nor by stimulating general arousal, as activity levels did not increase. Rather, the data support the conclusion that AVT affects courtship by influencing specific sensorimotor processes associated with behavioral responses to individual releasing stimuli, which suggests a mechanistic framework for understanding socially motivated behavior is this species.

Role of the archistriatal nucleus taeniae in the sexual behavior of male Japanese quail (Coturnix japonica): a comparison of function with the medial nucleus of the amygdala in mammals.

Nucleus taeniae (Tn) is a prominent cell group within the medial archistriatum of birds. Based upon similarities in sex-steroid binding sites, this nucleus has been hypothesized to be homologous to the medial nucleus of the amygdala (Me) in mammals, which is known to modulate the expression of sexual behavior in rodents. We therefore tested whether or not Tn likewise plays a role in the expression of sexual behavior in male Japanese quail. We found that bilateral damage to Tn produced deficits in several components of male responses toward female stimuli that were indicative of decreased sexual arousal, including goal-oriented responses, vocalizations associated with courtship, and motor reflexes that precede copulation. Our results suggest that Tn influences a wide range of behavioral functions in response to sexual stimuli, and they indicate a function for this nucleus similar to that subserved by the Me in mammals. These results strengthen the argument that these sex-steroid accumulating cell groups are homologous and suggest a conservation of function for them despite the vastly divergent evolutionary histories separating birds and mammals.

Photoperiod affects the morphology of a sexually dimorphic nucleus within the preoptic area of male Japanese quail.

Changes in the gross and cellular morphology of the nucleus preopticus medianus (POMn) were measured in response to changes in photoperiod in adult male Japanese quail (Coturnix japonica). POMn volume and the soma size of a dorsolateral population of neurons within POMn decreased when birds were moved from long day housing conditions (16L,8D) to short day housing conditions (8L,16D), and then increased again when birds were moved back to long day conditions, presumably as a function of the changes in circulating testosterone that accompanied changing daylengths. Male Japanese quail exhibit sexual behavior only when housed under long day housing conditions that approximate the photoperiod of the spring/summer breeding season, and do not exhibit sexual behavior when housed under short day conditions characteristic of fall/winter. Because POMn is known to be critically involved in the expression of male copulatory behavior, these morphological changes in the adult brain likely represent key functional events associated with the seasonal regulation of sexual behavior in male Japanese quail.

Ontogeny of a sexually dimorphic nucleus in the preoptic area of the Japanese quail (Coturnix japonica).

The nucleus preopticus medianus (POMn) is a sexually dimorphic nucleus in Japanese quail (Coturnix japonica) that is critically involved in the hormonal activation of male copulatory behavior. The larger volume apparent in males appears to depend upon circulating testosterone [Brain Res., 416 (1987) 59-68; J. Comp. Neurol., 303 (1991) 443-456]. The present study determined when during normal development this nucleus becomes dimorphic. POMn and a control nucleus, the nucleus commissurae pallii (nCPa), were traced from Nissl-stained coronal sections (40 microns) from animals sacrificed at 2, 3, 4, 5, 6 or 7 weeks of age. Areas were measured and used to calculate volume. POMn volumes were not significantly different in males and females through 5 weeks of age. The dimorphism in POMn volume then became apparent at 6 weeks of age as a function of an increase in male POMn volume between 5 and 6 weeks of age. No significant differences were apparent at any developmental age in nCPa volume. The appearance of a sexual dimorphism in POMn volume is coincident with the pubertal surge in testosterone that occurs between 5 and 6 weeks of age [Horm. Behav., 11 (1978) 175-182], and is also coincident with behavioral sexual maturity.

Limb salvage and selectivity.

In a group of properly prepared poor risk patients with advanced atherosclerosis of both the aortoiliac and femoropopliteal segments, a combined procedure, extra-anatomic bypass with an extended profundoplasty, was used for successful salvage of their ischemic--mean calf pressure=27 millimeters of mercury--limbs. Prediction of success versus failure could be determined on neither clinical nor angiographic-anatomic grounds but was possible using two simple measurements: a large aortoiliac differential pressure--deltaP--between inflow pressure obtained from a standard arm cuff and outflow pressure measured directly from the femoral artery, 89.3 millimeters of mercury versus 33.2 millimeters of mercury, p less than 0.001, and a potentially adequate outflow bed as determined by the percentage drop in outflow [(deltaPo/Po) per cent] upon papaverine injection, 36.3 versus 11.3 per cent, p less than 0.001. These values became an important part of the selection scheme developed in the approach to 24 ischemic limbs.