Oxytocin,testosterone, and human social cognition

I describe an integrative social‐evolutionary model for the adaptive significance of the human oxytocinergic system. The model is based on a role for this hormone in the generation and maintenance of social familiarity and affiliation across five homologous, functionally similar, and sequentially co‐opted contexts: mothers with offspring, female and male mates, kin groups, individuals with reciprocity partners, and individuals within cooperating and competing social groups defined by culture. In each situation, oxytocin motivates, mediates and rewards the cognitive and behavioural processes that underlie the formation and dynamics of a more or less stable social group, and promotes a relationship between two or more individuals. Such relationships may be positive (eliciting neurological reward, reducing anxiety and thus indicating fitness‐enhancing effects), or negative (increasing anxiety and distress, and thus motivating attempts to alleviate a problematic, fitness‐reducing social situation). I also present evidence that testosterone exhibits opposite effects from oxytocin on diverse aspects of cognition and behaviour, most generally by favouring self‐oriented, asocial and antisocial behaviours. I apply this model for effects of oxytocin and testosterone to understanding human psychological disorders centrally involving social behaviour. Reduced oxytocin and higher testosterone levels have been associated with under‐developed social cognition, especially in autism. By contrast, some combination of oxytocin increased above normal levels, and lower testosterone, has been reported in a notable number of studies of schizophrenia, bipolar disorder and depression, and, in some cases, higher oxytocin involves maladaptively ‘hyper‐developed’ social cognition in these conditions. This pattern of findings suggests that human social cognition and behaviour are structured, in part, by joint and opposing effects of oxytocin and testosterone, and that extremes of such joint effects partially mediate risks and phenotypes of autism and psychotic‐affective conditions. These considerations have direct implications for the development of therapies for alleviating disorders of social cognition, and for understanding how such disorders are associated with the evolution of human cognitive‐affective architecture.     

Autistic-Like Traits in Adult Patients with Mood Disorders and Schizophrenia

Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipolar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of evaluating autistic-like traits/symptoms underlying adult-onset psychiatric disorders for the best-suited treatment. Further studies with a prospective design and larger samples are needed.     

Broadening the diagnosis of bipolar disorder: benefits vs. risks

There is considerable debate over whether bipolar and related disorders that share common signs and symptoms, but are currently defined as distinct clinical entities in DSM-IV and ICD-10, may be better characterized as falling within a more broadly defined "bipolar spectrum". With a spectrum view in mind, the possibility of broadening the diagnosis of bipolar disorder has been proposed. This paper discusses some of the rationale for an expanded diagnostic scheme from both clinical and research perspectives in light of potential drawbacks. The ultimate goal of broadening the diagnosis of bipolar disorder is to help identify a common etiopathogenesis for these conditions to better guide treatment. To help achieve this goal, bipolar researchers have increasingly expanded their patient populations to identify objective biological or endophenotypic markers that transcend phenomenological observation. Although this approach has and will likely continue to produce beneficial results, the upcoming DSM-IV and ICD-10 revisions will place increasing scrutiny on psychiatry's diagnostic classification systems and pressure to re-evaluate our conceptions of bipolar disorder. However, until research findings can provide consistent and converging evidence as to the validity of a broader diagnostic conception, clinical expansion to a dimensional bipolar spectrum should be considered with caution.     

Mathematical limits of multilocus models: the genetic transmission of bipolar disorder.

We describe a simple, graphical method for determining plausible modes of inheritance for complex traits and apply this to bipolar disorder. The constraints that allele frequencies and penetrances lie in the interval 0-1 impose limits on recurrence risks, KR, in relatives of an affected proband for a given population prevalence, KP. We have investigated these limits for KR in three classes of relatives (MZ co-twin, sibling, and parent/offspring) for the general single-locus model and for two types of multilocus models: heterogeneity and multiplicative. In our models we have assumed Hardy-Weinberg equilibrium, an all-or-none trait, absence of nongenetic resemblance between relatives, and negligible mutation at the disease loci. Although the true values of KP and the KR''s are only approximately known, observed population and family data for bipolar disorder are inconsistent with a single-locus model or with any heterogeneity model. In contrast, multiplicative models involving three or more loci are consistent with observed data and, thus, represent plausible models for the inheritance of bipolar disorders. Studies to determine the genetic basis of most bipolar disorder should use methods capable of detecting interacting oligogenes.     

Prolonged Subcutaneous Administration of Oxytocin Accelerates Angiotensin II-Induced Hypertension and Renal Damage in Male Rats

Oxytocin and its receptor are synthesised in the heart and blood vessels but effects of chronic activation of this peripheral oxytocinergic system on cardiovascular function are not known. In acute studies, systemic administration of low dose oxytocin exerted a protective, preconditioning effect in experimental models of myocardial ischemia and infarction. In this study, we investigated the effects of chronic administration of low dose oxytocin following angiotensin II-induced hypertension, cardiac hypertrophy and renal damage. Angiotensin II (40 μg/Kg/h) only, oxytocin only (20 or 100 ng/Kg/h), or angiotensin II combined with oxytocin (20 or 100 ng/Kg/h) were infused subcutaneously in adult male Sprague-Dawley rats for 28 days. At day 7, oxytocin or angiotensin-II only did not change hemodynamic parameters, but animals that received a combination of oxytocin and angiotensin-II had significantly elevated systolic, diastolic and mean arterial pressure compared to controls (P < 0.01). Hemodynamic changes were accompanied by significant left ventricular cardiac hypertrophy and renal damage at day 28 in animals treated with angiotensin II (P < 0.05) or both oxytocin and angiotensin II, compared to controls (P < 0.01). Prolonged oxytocin administration did not affect plasma concentrations of renin and atrial natriuretic peptide, but was associated with the activation of calcium-dependent protein phosphatase calcineurin, a canonical signalling mechanism in pressure overload-induced cardiovascular disease. These data demonstrate that oxytocin accelerated angiotensin-II induced hypertension and end-organ renal damage, suggesting caution should be exercised in the chronic use of oxytocin in individuals with hypertension.     

Aripiprazole in the maintenance treatment of bipolar disorder: a critical review of the evidence and its dissemination into the scientific literature

Background

Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature.

Methods and Findings

We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations.

Conclusions

A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial''s interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature. Please see later in the article for the Editors'' Summary     

Brain oxytocin inhibits the (re)activity of the hypothalamo-pituitary-adrenal axis in male rats: involvement of hypothalamic and limbic brain regions

In response to various stressors, oxytocin is released not only into blood, but also within hypothalamic and extrahypothalamic limbic brain regions. Here, we describe the involvement of intracerebrally released oxytocin in the regulation of the activity of the hypothalamo-pituitary-adrenal (HPA) axis by infusion of the oxytocin receptor antagonist (des Gly-NH(2) d(CH(2))(5) [Tyr(Me)(2), Thr(4)] OVT; pH 7.4; Dr. M. Manning, Toledo, OH, USA) either into the lateral cerebral ventricle (icv[0.75 microg/5 microl,]) or via retrodialysis (10 microg/ml, 3.3 microl/min, 15 min) into the hypothalamic paraventricular nuclei (PVN), the medio-lateral septum or the amygdala. Male Wistar rats fitted with a chronic jugular vein catheter and an icv guide cannula or a microdialysis probe targeting the respective brain region 4 days prior to the experiment were blood sampled under basal as well as stressful conditions. Rats were exposed to the elevated platform (emotional stressor) and/or to forced swimming (combined physical and emotional stressor). Blockade of the receptor-mediated action of endogenous oxytocin within the PVN resulted in an enhanced basal secretion of ACTH whereas, in response to forced swimming, ACTH secretion was rather reduced, indicating a tonic inhibitory effect of OXT on basal HPA axis activity, but a potentiating action under conditions of stress. Within the medio-lateral septum, antagonist treatment did not alter basal ACTH secretion, but significantly disinhibited ACTH secretion in response to the elevated platform, but not to forced swimming. Within the amygdala, no significant effects either on basal or stress-induced HPA axis activity could be found. The results indicate a differential involvement of brain oxytocin in the regulation of the HPA axis activity which depends both on the site of intracerebral oxytocin release and the stressor the animals are exposed to.     

Topography of oxytocinergic estradiol target neurons in the mouse hypothalamus

Combined (3H) estradiol autoradiography and oxytocin immunocytochemistry were used in order to study co-localization of cytoplasmic oxytocin immunoreactivity and nuclear uptake of (3H) estradiol in the forebrain of adult ovariectomized mice. Labelling with (3H) estradiol was found in subpopulations of neurons that constitute between 10 to 40% of the oxytocinergic cells in the paraventricular nucleus, the supraoptic nucleus and the intersupraoptico-paraventricular islands. Oxytocinergic neurons in the septohypothalamic nucleus, the anterior commissural nucleus, the periventricular nucleus and the zona incerta only occasionally showed nuclear uptake of (3H) estradiol. The results indicate that oxytocinergic cell groups within the classical magnocellular nuclei have much higher numbers of estrogen receptors than the so called accessory oxytocin neurons. Oxytocinergic neuronal systems seem to constitute functionally heterogenous populations of cells, differently influenced by estradiol.     

Hypothalamo-neurohypophysial system in hagfish: localization of neurophysin-, arg-vasopressin- and oxytocin-like immunoreactivity

Serial paraffin sections of hagfish brain (Eptatretus burgeri) were immunocytochemically examined for porcine neurophysin (NEU), arg-vasopressin (AVP) and oxytocin (OT). A big number of NEU-immunoreactive nerve cells were visible in the frontal part of the ventromedial hypothalamus in close vicinity of the third ventricle. These cells were bipolar in most cases and sometimes additionally stained for AVP but not for OT. NEU-reactive neurons extended axons to the median eminence and the posterior lobe of the pituitary which also contained AVP or OT-like immunoreactivity. Immunostaining outside the hypothalamus could not be observed. It is likely that there exists a mammalian-like oxytocinergic and a vasopressinergic hypothalamo-neurohypophysial system in hagfish, despite the large differences in levels of organization.     

A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder

Background

Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders.

Methods

Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium.

Results

The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope.

Conclusions

Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders.     

Antisense oligodeoxynucleotide effects on the hypothalamic-neurohypophysial system and the hypothalamic-pituitary-adrenal axis

The possibility of sequence-dependent, transient, and local inhibition of neuropeptide or neuropeptide receptor expression within the brain makes antisense targeting an attractive approach for those interested in the involvement of brain neuropeptide systems in behavioral and neuroendocrine regulation. Here, I describe our attempts to manipulate the synthetic activity of peptidergic systems of the hypothalamic-neurohypophysial system, i.e. , oxytocin and vasopressin, and the hypothalamic-pituitary-adrenal (HPA) axis by antisense oligodeoxynucleotides. Detailed experimental protocols including different approaches for intracerebral antisense application in anesthetized or conscious rats are provided. As a consequence of local oxytocin or vasopressin antisense treatment within the hypothalamic supraoptic nucleus, various aspects of the neuronal activity are already altered after a few hours. Thus, we monitored electrophysiological parameters of oxytocinergic and vasopressinergic neurons, stimulus-induced expression of the Fos protein in oxytocin neurons, and stimulated release of oxytocin or vasopressin into blood as well as within the hypothalamus by dendrites and cell bodies as measured by simultaneous microdialysis in blood and brain, shortly after a single acute antisense infusion. We also employed chronic antisense infusion via osmotic minipumps or by repeated local infusion into the targeted brain region; for example, septal vasopressin receptor downregulation impairs the ability of male rats to discriminate between juvenile rats. Further, reduction of the amount of available CRH, vasopressin, and oxytocin within the hypothalamic paraventricular nuclei alters the neuroendocrine stress response of the HPA axis.     

The satiety signal oleoylethanolamide stimulates oxytocin neurosecretion from rat hypothalamic neurons

The anandamide monounsaturated analogue oleoylethanolamide (OEA) acts as satiety signal released from enterocytes upon the ingestion of dietary fats to prolong the interval to the next meal. This effect, which requires intact vagal fibers and intestinal PPAR-alpha receptors, is coupled to the increase of c-fos and oxytocin mRNA expression in neurons of the paraventricular nucleus (PVN) and is prevented by the intracerebroventricular administration of a selective oxytocin antagonist, thus suggesting a necessary role of oxytocinergic neurotransmission in the pro-satiety effect of OEA. By brain microdialysis and immunohistochemistry, in this study we demonstrate that OEA treatment can stimulate oxytocin neurosecretion from the PVN and enhance oxytocin expression at both axonal and somatodendritic levels of hypothalamic neurons. Such effects, which are maximum 2 h after OEA administration, support the hypothesis that the satiety-inducing action of OEA is mediated by the activation of oxytocin hypothalamic neurons.     

Coexistence of intestinal trefoil factor (hITF) and oxytocin in magnocellular neurons in the human hypothalamus.

Human intestinal trefoil factor hITF, a polypeptide of the P-domain family, was found to occur in hypothalamic neurons. With combined immunofluorescence and immunoperoxidase technique we investigated the coexistence of hITF with the neurohypophysial peptide oxytocin and the associated neurophysin I in sections of the human hypothalamus. In the supraoptic nucleus, 39.2% of magnocellular oxytocinergic perikarya show hITF immunoreactivity. A similar distribution was observed in perivascular hypothalamic oxytocinergic neurons, whereas in the paraventricular nucleus, 99% of the oxytocinergic neurons show hITF coexpression. In the periventricular nucleus (PEV), single, scattered neurons with both immunoreactivities occur. Our findings indicate that hITF and oxytocin are coexpressed in a portion of the magnocellular neurons in the human hypothalamus, and that hITF is among the neurohypophysial peptides.     

Development of oxytocin- and vasopressin-network in the supraoptic and paraventricular nuclei of fetal sheep

The hypothalamic supraoptic and paraventricular nuclei consist of oxytocin and arginine vasopressin synthesizing neurons that send projections to the neurohypophysis. A growing body of evidence in adult animals and young animals at near term confirmed the structure and function in the vasopressinergic and oxytocinergic network. However, whether those distinctive neural networks are formed before near term is largely unknown. This study determined the special patterns in location and distribution of oxytocin- and vasopressin-neurons in the paraventricular and supraoptic nuclei from preterm to term in the ovine fetuses. The results showed that oxytocin- and vasopressin-neurons were present in both nuclei at the three gestational time periods (preterm, near term, and term). In the paraventricular nuclei, vasopressin-cells concentrated mainly in the core of the middle magnocellular paraventricular nuclei, and oxytocin-cells were scattered surrounding the core. In the supraoptic nuclei, vasopressin-cells mostly located in the ventral part, and oxytocin-cells in the dorsal part. The data demonstrated that the special distributed patterns of vasopressin- and oxytocin-neuron network have formed in those two nuclei at least from preterm. Intracerebroventricular injection of angiotensin II significantly increased fetal plasma oxytocin and vasopressin levels at preterm, which was associated with an increase of oxytocin- and vasopressin-neuron activity marked with c-fos expression. The data provided new evidence for the structural and functional development of the oxytocin- and vasopressin-network before birth.     

The contribution of oxytocin and vasopressin to mammalian social behavior: potential role in autism spectrum disorder

Oxytocin (OT) and arginine-vasopressin (AVP) are 2 peptides that are produced in the brain and released via the pituitary gland to the peripheral blood, where they have diverse physiological functions. In the last 2 decades it has become clear that these peptides also play a central role in the modulation of mammalian social behavior by their actions within the brain. Several lines of evidence suggest their involvement in autism spectrum disorder (ASD), which is known to be associated with impaired social cognition and behavior. Recent clinical trials using OT administration to autistic patients have reported promising results. Here, we aim to describe the main data that suggest a connection between these peptides and ASD. Following a short illustration of several major topics in ASD biology we will (a) briefly describe the oxytocinergic and vasopressinergic systems in the brain, (b) discuss a few compelling cases manifesting the involvement of OT and AVP in mammalian social behavior, (c) describe data supporting the role of these peptides in human social cognition and behavior, and (d) discuss the possibility of the involvement of OT and AVP in ASD etiology, as well as the prospect of using these peptides as a treatment for ASD patients.     

Xylazine activates oxytocinergic but not vasopressinergic hypothalamic neurons under normal and hyperosmotic conditions in rats

Role of central alpha2-adrenoceptors in the regulation of hypothalamic magnocellular cells was studied under hyperosmotic challenge elicited by hypertonic saline (HS). Rats pretreated with receptor agonist, xylazine (XYL), were injected intraperitoneally with different (low: 0.375, moderate: 0.75, high: 1.5 M) HS 30 min later. The activity of the paraventricular (PVN) and supraoptic (SON) vasopressin and oxytocin perikarya was established by Fos-dual-immunohistochemistry 60 min after HS administration. Results showed that 1/XYL is a potent stimulus for oxytocin but not vasopressin magnocellular cells under basal and weak hyperosmotic conditions 2/highHS completely overlaps the effect of XYL. In addition, XYL partially suppressed Fos expression in the parvocellular PVN cells activated by highHS. The data suggest that alpha2-adrenoceptors may play an important role in the regulation of oxytocinergic PVN and SON neurons under basal and weak hyperosmotic conditions and that alpha2-adrenoceptors may also participate in the control of PVN parvocellular cells under intense osmotic challenge.     

Oxytocinergic activity is linked to lower blood pressure and vascular resistance during stress in postmenopausal women on estrogen replacement

Estrogen administration results in increased release of the oxytocin (OT) prohormone reflected by increases in oxytocin intermediate peptide (OT Int) in both animal models and humans, and sequential treatment of ovariectomized rats with estrogen/progesterone then progesterone withdrawal leads to increased hypothalamic OT mRNA. Blood pressure (BP) reductions have been related to increased exogenous and endogenous OT in rats and to higher endogenous OT activity in premenopausal women, but not previously in postmenopausal women. Thus, we used plasma obtained at rest and during a speech stressor from 54 postmenopausal women who participated in a 6-month randomized trial of oral conjugated estrogens vs. placebo to examine effects of estrogen replacement therapy (ERT) on plasma OT and OT Int levels and their relationships to changes in BP during the trial. ERT alone and with progesterone (but not placebo) led to significant increases in plasma levels of OT Int, but no change in plasma OT levels. Women showing greater increases in OT Int during treatment showed greater decreases in BP and total vascular resistance during a series of behavioral stressors compared to women with moderate or no increases in OT Int, even after controlling for effects related to treatment condition or to changes in plasma estradiol. The findings suggest that enhanced oxytocinergic activity may contribute to BP decreases associated with ERT in more responsive postmenopausal women.     

Distribution of F-actin in the compound eye of the blowfly,Calliphora erythrocephala (Diptera,Insecta)

Summary Sexual stimulation of males has been reported to affect hypothalamic oxytocinergic systems. In the present study we used radioimmunoassays of micro-dissected forebrain regions and immunocytochemical analysis of Vibratome sections to study the oxytocin systems of naive males, males killed after one mating, and males mated daily with different receptive females for 3 weeks. In males that had mated once, less oxytocin-immunoreactive neurons were observed in the paraventricular (PVN), supraoptic (SON) and periventricular (NPE) nuclei than in naive males. However, after repeated matings, the number of immunoreactive neurons and their staining intensity was increased in these regions. Furthermore, additional oxytocinergic neurons could be found in the lateral subcommissural nucleus, the zona incerta and the ansa lenticularis of repeatedly mated males. Oxytocin-immunoreactive neurons were only occasionally seen in these areas in unmated males or in animals that had been killed after initial mating. Radio-immunoassays of microdissected PVN, SON, NPE and the lateral hypothalamus confirmed the reduction in oxytocin-immunoreactive levels after a first mating by a male and the increase after repeated matings. It is likely that oxytocin secretion into peripheral and portal circulation is stimulated by the endocrine conditions associated with initial mating. These immediate effects may be followed by the activation of synthesis in oxytocin neurons in several sites of the basal forebrain.     

Modulation of phosphoinositide-protein kinase C signal transduction by omega-3 fatty acids: implications for the pathophysiology and treatment of recurrent neuropsychiatric illness

The phosphoinositide (PI)-protein kinase C (PKC) signal transduction pathway is initiated by pre- and postsynaptic Galphaq-coupled receptors, and regulates several clinically relevant neurochemical events, including neurotransmitter release efficacy, monoamine receptor function and trafficking, monoamine transporter function and trafficking, axonal myelination, and gene expression. Mounting evidence for PI-PKC signaling hyperactivity in the peripheral (platelets) and central (premortem and postmortem brain) tissues of patients with schizophrenia, bipolar disorder, and major depressive disorder, coupled with evidence that PI-PKC signal transduction is down-regulated in rat brain following chronic, but not acute, treatment with antipsychotic, mood-stabilizer, and antidepressant medications, suggest that PI-PKC hyperactivity is central to an underlying pathophysiology. Evidence that membrane omega-3 fatty acids act as endogenous antagonists of the PI-PKC signal transduction pathway, coupled with evidence that omega-3 fatty acid deficiency is observed in peripheral and central tissues of patients with schizophrenia, bipolar disorder, and major depressive disorder, support the hypothesis that omega-3 fatty acid deficiency may contribute to elevated PI-PKC activity in these illnesses. The data reviewed in this paper outline a potential molecular mechanism by which omega-3 fatty acids could contribute to the pathophysiology and treatment of recurrent neuropsychiatric illness.     

Effects of central oxytocin receptor blockade on water and saline intake,mean arterial pressure,and c-Fos expression in rats

Central injection of ANG II has been proposed to have dual effects on salt appetite including a direct stimulatory effect and an indirect inhibitory effect through an activation of central oxytocinergic neurons. The inhibition was demonstrated by pretreating rats with central ornithine vasotocin (OVT; oxytocin antagonist) 30 min before a central ANG II injection. The OVT pretreatment produced a large increase in ANG II-induced saline intake. The present paper reports a failure to replicate that influential experiment. However, we also report for the first time that OVT by itself: 1) provokes drinking of both water and saline solution with a latency almost as short as that produced by ANG II; 2) produces a mild pressor response; and 3) increases c-Fos expression in the organum vasculosum laminae terminalis (OVLT) and the median preoptic nucleus (MnPO). Oxytocin activity may provide an inhibitory control of drinking responses as has been suggested, but the inhibition is tonic and includes both water and saline drinking. Inhibition of this tonic activity may stimulate drinking by increasing neural activity in the OVLT and MnPO.