Suma Jacob

Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism.

The oxytocin receptor gene (OXTR) has been studied in autism because of the role of oxytocin (OT) in social cognition. Linkage has also been demonstrated to the region of OXTR in a large sample. Two single nucleotide polymorphisms (SNPs) and a haplotype constructed from them in OXTR have been associated with autism in the Chinese Han population. We tested whether these associations replicated in a Caucasian sample with strictly defined autistic disorder. We genotyped the two previously associated SNPs (rs2254298, rs53576) in 57 Caucasian autism trios. Probands met clinical, ADI-R, and ADOS criteria for autistic disorder. Significant association was detected at rs2254298 (p=0.03) but not rs53576. For rs2254298, overtransmission of the G allele to probands with autistic disorder was found which contrasts with the overtransmission of A previously reported in the Chinese Han sample. In both samples, G was more frequent than A. However, in our Caucasian autism trios and the CEU Caucasian HapMap samples the frequency of A was less than that reported in the Chinese Han and Chinese in Bejing HapMap samples. The haplotype test of association did not reveal excess transmission from parents to affected offspring. These findings provide support for association of OXTR with autism in a Caucasian population. Overtransmission of different alleles in different populations may be due to a different pattern of linkage disequilibrium between the marker rs2254298 and an as yet undetermined susceptibility variant in OXTR.

Psychological State and Mood Effects of Steroidal Chemosignals in Women and Men

We tested the hypothesis that isolated steroids, claimed to act like pheromones, affect human psychological state or mood. In the first experiment, we established that two steroids, Delta4, 16-androstadien-3-one and 1,3,5(10)16-estratetraen-3-ol, modulated emotional states within 6 min of exposure. In men and women, neither steroid had specific effects on states of alertness or negative-confused mood. However, both steroids increased positive stimulated mood state in women but decreased it in men. These psychological findings do not parallel the reported sexually specific effects of these two steroids on the surface potential activity of putative vomeronasal epithelium. In a second experiment on women, we replicated that Delta4,16-androstadien-3-one modulated their general mood state, even when women were not aware of its odor and gave identical olfactory descriptions for the steroid and the control carrier solutions. In this within-subjects, repeated-measures experiment, androstadienone prevented the deterioration in general mood which occurred during exposure to the clove oil carrier solution in the laboratory environment. Thus, androstadienone appears to modulate affect, rather than releasing stereotyped behaviors or emotions. It is premature to call these steroids human pheromones. They are nonetheless psychologically potent, mandating future work delineating their function-i.e., whether these steroids are communicative chemosignals, context specific, or related to unconscious associations. In light of these modulatory effects and the complexity of human behavior, the function of chemosignals and pheromonal systems in a variety of species may need to be expanded to include the concept of modulators, as well as the traditional releasers, primers, and signaling compounds.

Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles.

BACKGROUND Oxytocin (OT) is a hormone shown to be involved in social bonding in animal models. Intranasal OT is currently in clinical trials for use in disorders such as autism and schizophrenia. We examined long-term effects of intranasal OT given developmentally in the prairie vole (Microtus ochrogaster), a socially monogamous rodent, often used as an animal model to screen drugs that have therapeutic potential for social disorders. METHODS We treated voles with one of three dosages of intranasal OT, or saline, from day 21 (weaning) through day 42 (sexual maturity). We examined both social behavior immediately following administration, as well as long-term changes in social and anxiety behavior after treatment ceased. Group sizes varied from 8 to 15 voles (n = 89 voles total). RESULTS Treatment with OT resulted in acute increases in social behavior in male voles with familiar partners, as seen in humans. However, long-term developmental treatment with low doses of intranasal OT resulted in a deficit in partner preference behavior (a reduction of contact with a familiar opposite-sex partner, used to index pair-bond formation) by male voles. CONCLUSIONS Long-term developmental treatment with OT may show results different to those predicted by short-term studies, as well as significant sex differences and dosage effects. Further animal study is crucial to determining safe and effective strategies for use of chronic intranasal OT, especially during development.

Context-dependent effects of steroid chemosignals on human physiology and mood.

We examined the physiological and psychological effects of nanomolar amounts of steroids applied directly under the nose (Delta4,16-androstadien-3-one and 1,3,5,(10),16-estratetraen-3-ol). These potential human chemosignals were not consciously discernible in a strong-odor carrier (clove oil and propylene glycol). In a double-blind, within-subject, repeated-measures experiment with 65 subjects, we demonstrated that both steroids produced sustained changes in digit skin temperature and palmar skin conductance (an indicator of sympathetic nervous system tone) while the subjects were completing psychological questionnaires or reading. These effects, however, did not follow the sex-stereotyped pattern predicted by a sex attractant function. Both androstadienone and estratetraenol raised the skin temperature of mens hands and lowered it in women. Likewise, each steroid increased skin conductance, with a significantly greater effect on women than men. Womens responses were observed only in the sessions run by the male tester, an effect that may or may not be solely attributable to tester sex. Mens responses, in contrast, were not affected by this difference in socioexperimental condition. Similarly, women experienced an immediate increase in positive mood only in the presence of the male tester, while mens responses were unaffected by this socioexperimental context. One source of this sex difference may be the fact that the majority of women were in the late follicular phase of their menstrual cycle. Although it is premature to classify these steroids as pheromones, our data suggest that they function as chemosignals that modulate autonomic nervous system tone as well as psychological state.

Women's sexual experience during the menstrual cycle: Identification of the sexual phase by noninvasive measurement of luteinizing hormone

Imprecise measures of ovulation obscure the relationship between womens sexuality and the menstrual cycle, as does studying women with different contraceptive goals in different social contexts. Here we present a novel noninvasive method to precisely pinpoint the preovulatory surge of Luteinizing Hormone (LH), demarcating hormonally distinct cycle phases with greater than 95% reliability. Women were more sexually active on days prior to and including the preovulatory (LH) surge. This pattern was evident only when women initiated sexual activity and not when their partners did, indicating an increase in womens sexual motivation rather than attractiveness. A second study replicated the 6‐day increase in sexual activity beginning 3 days before the LH surge, accompanied by stronger sexual desire and more sexual fantasies. We propose the term “sexual phase” of the cycle, since follicular phase is over inclusive and ovulatory phase is not sufficient. These findings are striking because the women were avoiding pregnancy and were kept blind to the hypotheses, preventing expectation bias. The sexual phase was more robust in women with regular sexual partners, although the increase in sexual desire was just as great in nonpartnered women, who also reported feeling less lonely at this time. We use these results to evaluate potential neuroendocrine mechanisms underlying womens sexual motivation and activity.

Sustained human chemosignal unconsciously alters brain function.

The human chemosignal, Δ4,16-androstadien-3-one modulates psychological state without being consciously discernible as an odor. This study demonstrates that Δ4,16-androstadien-3-one (androstadienone) alters cerebral glucose utilization both in subcortical regions and in areas of the neocortex not exclusively associated with olfaction. These widely distributed changes are consistent with modulation of an integrated neural network for regulation of emotional and attentional states. This is the first study to demonstrate the effects of a sustained chemosignal on brain metabolism and to show that they are similar to those of long acting chemical substances that affect psychological states. Moreover, this provides the first evidence that a human chemosignal has distributed effects on cortical processes and brain metabolism even when it is not detected consciously.

Intranasal oxytocin in the treatment of autism spectrum disorders: A review of literature and early safety and efficacy data in youth

BACKGROUND There is a paucity of treatments targeting core symptom domains in Autism Spectrum Disorder (ASD). Several animal models and research in typically developing volunteers suggests that manipulation of the oxytocin system may have therapeutic potential for the treatment of social deficits. We review the literature for oxytocin and ASD and report on early dosing, safety and efficacy data of multi-dose oxytocin on aspects of social cognition/function, as well as repetitive behaviors and co-occurring anxiety within ASD. METHODS Fifteen children and adolescents with verbal IQs≥70 were diagnosed with ASD using the ADOS and the ADI-R. They participated in a modified maximum tolerated dose study of intranasal oxytocin (Syntocinon). Data were modeled using repeated measures regression analysis controlling for week, dose, age, and sex. RESULTS Among 4 doses tested, the highest dose evaluated, 0.4 IU/kg/dose, was found to be well tolerated. No serious or severe adverse events were reported and adverse events reported/observed were mild to moderate. Over 12 weeks of treatment, several measures of social cognition/function, repetitive behaviors and anxiety showed sensitivity to change with some measures suggesting maintenance of effect 3 months past discontinuation of intranasal oxytocin. CONCLUSIONS This pilot study suggests that daily administration of intranasal oxytocin at 0.4 IU/kg/dose in children and adolescents with ASD is safe and has therapeutic potential. Larger studies are warranted. This article is part of a Special Issue entitled Oxytocin and Social Behav.

Psychological effects of musky compounds: Comparison of androstadienone with androstenol and muscone

Previously, we have shown that delta4,16-androstadien-3-one modulates psychological state, reducing negative mood and increasing positive mood (Jacob and McClintock, 2000; Jacob et al., 2001a). In order to determine whether similar musky compounds also produce these effects, we compared the effects of androstadienone to those of androstenol and muscone, measuring the psychological states of 37 participants. Androstenol and muscone were chosen because they too have a musky odor at high concentrations, while androstenol is a steroid like androstadienone and muscone is not. In a controlled laboratory setting, we conducted a double-blind, within-subject, repeated-measures experiment counterbalanced for order of presentation. Under each participants nose, a nanomolar amount of each compound was presented, masked by clove oil to minimize perceptible olfactory differences. Participants completed a baseline psychological battery and twice again at 25-min intervals after exposure. Androstadienones effects on psychological state were unique in comparison with those of androstenol and with muscone. Exposure through passive inhalation, rather than dermal contact, was sufficient for these effects. Although this is additional evidence that androstadienone may be a pheromone, it is yet to be determined whether humans exude concentrations into the air adequate for social communication or process this chemical information within natural social contexts.

Long-term exposure to intranasal oxytocin in a mouse autism model

Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse’s chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT.

Effects of MDMA and Intranasal Oxytocin on Social and Emotional Processing

MDMA (±3,4-methylenedioxymethamphetamine, ‘ecstasy’) is used recreationally, reportedly because it increases feelings of empathy, sociability, and interpersonal closeness. One line of evidence suggests that MDMA produces these effects by releasing oxytocin, a peptide involved in social bonding. In the current study, we investigated the acute effects of MDMA and oxytocin on social and emotional processing in healthy human volunteers. MDMA users (N=65) participated in a 4-session, within-between-subjects study in which they received oral MDMA (0.75, 1.5 mg/kg), intranasal oxytocin (20 or 40 IU), or placebo under double-blind conditions. The primary outcomes included measures of emotion recognition and sociability (desire to be with others). Cardiovascular and subjective effects were also assessed. As expected, MDMA dose-dependently increased heart rate and blood pressure and feelings of euphoria (eg, ‘High’ and ‘Like Drug’). On measures of social function, MDMA impaired recognition of angry and fearful facial expressions, and the larger dose (1.5 mg/kg) increased desire to be with others, compared with placebo. Oxytocin produced small but significant increases in feelings of sociability and enhanced recognition of sad facial expressions. Additionally, responses to oxytocin were related to responses to MDMA with subjects on two subjective measures of sociability. Thus, MDMA increased euphoria and feelings of sociability, perhaps by reducing sensitivity to subtle signs of negative emotions in others. The present findings provide only limited support for the idea that oxytocin produces the prosocial effects of MDMA.