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Bipolar disorders (BDs) exhibit high heritability and symptoms typically first occur during late adolescence or early adulthood. Affected individuals may experience alternating bouts of mania/hypomania and depression, with euthymic periods of varying lengths interspersed between these extremes of mood. Clinical research studies have consistently demonstrated that BD patients have disturbances in circadian and seasonal rhythms, even when they are free of symptoms. In addition, some BD patients display seasonal patterns in the occurrence of manic/hypomanic and depressive episodes as well as the time of year when symptoms initially occur. Finally, the age of onset of BD symptoms is strongly influenced by the distance one lives from the equator. With few exceptions, animal models useful in the study of BD have not capitalized on these clinical findings regarding seasonal patterns in BD to explore molecular mechanisms associated with the expression of mania- and depression-like behaviors in laboratory animals. In particular, animal models would be especially useful in studying how rates of change in photoperiod that occur during early spring and fall interact with risk genes to increase the occurrence of mania- and depression-like phenotypes, respectively. Another unanswered question relates to the ways in which seasonally relevant changes in photoperiod affect responses to acute and chronic stressors in animal models. Going forward, we suggest ways in which translational research with animal models of BD could be strengthened through carefully controlled manipulations of photoperiod to enhance our understanding of mechanisms underlying seasonal patterns of BD symptoms in humans. In addition, we emphasize the value of incorporating diurnal rodent species as more appropriate animal models to study the effects of seasonal changes in light on symptoms of depression and mania that are characteristic of BD in humans.

Bipolar disorders have an onset in late adolescence or early adulthood and patients may experience alternating episodes of mania and depression, with euthymic periods interspersed between these extremes of mood. Clinical research studies have shown that bipolar disorder patients exhibit disruptions in circadian and seasonal rhythms, even when they are symptom free. In addition, some bipolar patients display pronounced seasonal patterns in occurrence of manic and depressive episodes, time of year for disease onset, and age of onset. Several groups have emphasized the impact of seasonal changes in sunlight intensity on bipolar disorder, especially in locations farther from the equator. In this paper, we examine rate of change of solar insolation during the spring and fall in locations that vary in their distance from the equator and propose that seasonal changes in sunlight intensity may be tracked by the suprachiasmatic nucleus and affect disease onset and progression in seasonally susceptible bipolar patients.

The consensus in the literature is that bipolar disorder is seasonal. We argue that there is finer detail to seasonality and that changes in mood and energy in bipolar disorder are dictated by the rate of change of solar insolation.

A series of forebrain, midbrain, and brainstem nuclei exert stimulatory or inhibitory effects on sympathetic outflow from the intermediolateral cell column in thoracic and lumbar areas of the spinal cord. Some of these brain areas contain cell bodies that serve as command neurons that can simultaneously activate sympathetic outflow to multiple target tissues. CRF-containing cell bodies in the paraventricular nuclei receive multiple direct and indirect inputs from various brain areas that participate in the regulation of the HPA axis. Hormones of the adrenal cortex have been shown to exert damaging structural effects on the structure of neurons in the hippocampus and amygdala. The immune system is stress-responsive, and circulating immune cells and proinflammatory cytokines are able to penetrate the blood-brain barrier during exposure to stressors. Brain microglia appear to serve as neuroimmune sensors of stress. Optogenetic and chemogenetic techniques have been essential tools in probing the functions of stress-responsive brain circuits and their impact on behavior.

Animal models of autism spectrum disorder (ASD) seek to capture three of the cardinal symptoms of the disorder in affected children: deficits in social interactions, deficits in communication, and repetitive behaviors. In addition, males are more likely to develop ASD than females. The complex and variable presentation of ASD appears to involve genetic, environmental, and epigenetic contributions. The inbred BTBR mouse strain has frequently been utilized as an animal model of ASD. Other animal models have included a variety of prenatal insults, including maternal immune activation or administration of drugs that affect the developing fetus. A newer line of investigation has examined contributions of the brain-immune-gut axis in the development of symptoms of ASD in laboratory mice. Finally, the polarity change of GABAergic neurons in the cerebral cortex from excitatory to inhibitory at birth appears to be connected to the surge in oxytocin, and this key developmental process may be disrupted in children with ASD and in animal models of ASD.

Modern conceptions of health and disease can be traced back to early Chinese, Indian, Egyptian, and Greek civilizations. Galen of Pergamon, a Greek physician who practiced medicine for most of his career in Rome, had an enduring impact on the medical sciences for almost 15 centuries with his writings on the balance among the four humors: black bile, yellow bile, blood, and phlegm. At the end of the 19th century, Claude Bernard in Paris wrote about the importance of the constancy of the internal environment. In the early 20th century, Walter Cannon introduced the concept of homeostasis and studied the emergency function of the adrenal medulla. Hans Selye is credited with popularizing the concept of stress, and he introduced the concept of the general adaptation syndrome. More recent additions to the nomenclature on stress include allostasis, or stability through change, and allostatic load, which relates to a failure to adapt to chronic stressors.

Several exciting lines of research have emerged from the study of animal models of mental disorders. This chapter presents seven opportunities for enhancing the diagnosis and treatment of mental disorders. They include improvements to the system for diagnosis of mental disorders, use of induced pluripotent stem cells from patients to generate neuronal cultures for in vitro determination of effective drug therapies for those individuals, use of data-mining techniques for understanding patient variability, a commitment to a greater focus on the prevention of mental disorders, innovative uses of smartphones to track patients and individuals at high risk of developing a mental disorder, and developing next-generation therapies and delivery systems that target a specific area of the brain rather than the entire brain. A common theme in these seven thoughts for the future is a commitment to bringing precision medicine tools to the treatment of patients with mental disorders.

Much of the research relating to animal models of anxiety has been devoted to developing more effective drugs for the treatment of the various anxiety disorders. Using selective breeding of laboratory mice and rats, investigators have developed high-anxiety and low-anxiety lines that have been especially valuable for basic research purposes. Other approaches to enhance the expression of an anxiety-like phenotype have included prenatal or early postnatal exposure to stressors, maternal immune activation, or selecting offspring based upon differences in the maternal behaviors of their mothers. In addition, risk genes for anxiety disorders have been studied in animal models, including genes related to serotonin, neuropeptide Y, neuropeptide S, and corticotropin-releasing factor signaling in the brain. Finally, some infant rhesus monkeys display an anxious temperament and extreme behavioral inhibition when separated from their mothers. This nonhuman primate model affords many opportunities to explore brain mechanisms and interventions that may be effective in preventing the further development of an anxious phenotype as these monkeys mature.

A consistent finding from research on animal models of depression and PTSD is that some animals are highly susceptible to the effects of stressful stimulation, while others show few obvious effects. A relatively new of line of research on resilience has emerged and has directed attention to those animals that are resistant to the effects of chronic or traumatic stressors. By tracking animals that are resistant to the behavioral effects of these stressful paradigms, one can then explore the molecular underpinnings of resilience in the brains of these same animals. Using chronic social defeat stress, some investigators have focused their attention on the ventral tegmental area, nucleus accumbens, and the prefrontal cortex. Other systems that have been studied include signaling molecules of the immune system and communication pathways between the immune system and the brain. A related line of research has addressed the possibility that prior exposure to stressors may inoculate animals to the deleterious effects of later stressor exposure.

Genome-wide association studies (GWAS) have revolutionized the field of psychiatric genetics by examining genetic variation at millions of single-nucleotide polymorphisms (SNPs) in many thousands of individual genome using microarrays. The sample sizes for these studies range from tens of thousands on up. Results to date from GWAS have called into question the validity of current diagnostic categories in psychiatry. For example, there may be some level of genetic risk that is shared across many psychiatric disorders, with the final symptom clusters of a given disorder being shaped by other genetic, epigenetic, and environmental variables. Research findings on three mental disorders are evaluated to make the case that stressful life events play a crucial role in the etiology of mental disorders. The mental disorders discussed include schizophrenia, bipolar disorder, and depression. These findings set the stage for the remainder of the book.

Animal models of bipolar disorder (BD) should capture the switching of mood states from mania to depression and vice versa. Dopamine signaling pathways in brain, including variations in the dopamine transporter protein, have been a focus of many animal models of BD. Another aspect of BD in humans is reflected in circadian and seasonal changes in onset of symptoms. Other animal models of BD include the Myshkin and Madison mouse strains, both of which display mania-like behavior that is reversed by treatment with lithium or valproic acid. Another experimental approach has been to manipulate circadian clock genes and examine effects on dopamine signaling and behavior. Finally, manipulations of risk genes for BD in laboratory mice have advanced our understanding of the molecular mechanisms involved in extreme alterations in mood state.

Developing animal models of schizophrenia is challenging because of the uniquely human nature of some of the classic symptoms of the disorder (e.g., hallucinations, delusions, disordered thought). Several efforts have been guided by the neurodevelopmental hypothesis of schizophrenia and have included exposure of animals to stressful stimulation. Other animal models have involved prenatal exposure to maternal immune activation or drugs that disrupt neuronal development, followed by stress during adolescence or in early adulthood to unmask vulnerabilities. Neonatal hippocampal lesions have been employed in other animal models of schizophrenia. Another profitable approach has been to selectively breed laboratory mice or rats for their susceptibility to dopaminergic drugs. A more recent approach has been to develop laboratory mice with targeted alterations in risk genes for schizophrenia that were previously identified in clinical studies. In many cases, the effects of these risk genes are unmasked by exposure of animals to stressful stimulation during specific stages of postnatal development.

For more than 50 years, there has been an interest in the nongenetic transmission of information from parents to their offspring, especially as it relates to the impact of maternal behavior on the development of offspring. One such mechanism to explain this mode of inheritance is through epigenetic alterations in DNA or histone proteins, but without changes in the sequence of DNA base pairs. Another mechanism that alters extranuclear gene expression involves synthesis of non-coding miRNAs. Paternal influences on fetal development may be mediated by signaling molecules contained within microvesicles in semen. Other experiments have focused on the placenta as a partial barrier to elevations in adrenal steroids and other stress-sensitive molecules in blood. These mechanisms also explain in part how experiences of mothers and fathers prior to mating can be conveyed to their offspring and even succeeding generations.

Two especially valuable animal models of post-traumatic stress disorder (PTSD) have been developed, including brief exposure of laboratory rats to a predator (a cat) or its odor, and the single prolonged stress paradigm. In each of these models, laboratory animals are evaluated for behavioral changes several days to several weeks following the stressful experience and are compared to unstressed controls. In both of these models, stressed animals display behavioral changes consistent with a PTSD-like phenotype. Using these models, investigators have explored central and peripheral neural and endocrine changes associated with the onset of PTSD-like symptoms and approaches to prevent or block the effects of the traumatic stressor on behavioral changes. Two particularly effective treatments that have been described include administration of a protein synthesis inhibitor and intra-nasal administration of neuropeptide Y. Animal models also provide an opportunity to study transgenerational transmission of PTSD risk.

Three interacting peripheral stress effector systems are activated during exposure of humans and other animals to acute as well as chronic stressors. They include the sympathetic-adrenal medullary (SAM) system, the hypothalamic-pituitary-adrenocortical (HPA) axis, and the innate immune system. The SAM system includes the release of norepinephrine from sympathetic nerve terminals and epinephrine from the adrenal medulla. Plasma levels of norepinephrine and epinephrine have been utilized as an index of SAM activity under basal conditions and following exposure to stress. The HPA axis involves release of corticotropin-releasing factor from neurons in the paraventricular nucleus of the hypothalamus, which stimulates adrenocorticotrophic hormone (ACTH) release from the anterior pituitary, followed by cortisol or corticosterone release from the adrenal cortex. The HPA axis is regulated in part by a system of negative feedback loops. The chemical messengers of the innate immune system include proinflammatory (IL-1β‎, IL-6, and TNF-α‎) and anti-inflammatory cytokines (IL-4 and IL-10).

Stress has now been recognized as an important factor in the development or recurrence of various mental disorders, from major depressive disorder to bipolar disorder to anxiety disorders. Stressful stimuli appear to exert their effects by acting upon individuals with susceptible genotypes. Over the past 50 years, animal models have been developed to study these dynamic interactions between stressful stimuli and genetically susceptible individuals during prenatal and postnatal development and into adulthood. This book begins with a discussion of the history of psychiatric diagnosis and the recent goal of moving toward precision psychiatry, followed by a review of clinical research on connections between stressful stimuli and the development of psychiatric disorders. Chapters are also included on neuroendocrine, immune, and brain systems involved in responses to stress. Additional chapters focus on the development of animal models in psychiatry and the susceptibility of the developing organism to stressful stimuli. Subsequent chapters are devoted to animal models of specific stress-sensitive psychiatric disorders, including schizophrenia, autism spectrum disorders, bipolar disorder, anxiety disorders, depression, and post-traumatic stress disorder. These chapters also focus on the identification of promising molecular targets for development of new drug therapies; a chapter examines animal models of resilience to stress-induced behavioral alterations as a newer approach to understand why some animals (e.g., inbred mice) are susceptible to stress and others are resilient, even if they are essentially genetically identical. The final chapter discusses how these basic laboratory animal models are providing promising leads for future breakthroughs in the diagnosis, treatment, and prevention of mental disorders.

Current systems for diagnosis of mental disorders have their roots in 19th-century German psychiatry. DSM-5 and ICD-11 are categorical systems (well versus ill), while other systems take a dimensional approach. Dimensional approaches include the Research Domain Criteria (RDoC) development by the National Institute of Mental Health and the Hierarchical Taxonomy of Psychopathology (HiTOP). Currents efforts are focused on the identification of valid biomarkers for specific mental disorders and the development of precision medicine approaches in psychiatric practice. Associated with the incorporation of principles of precision medicine in psychiatry will be decision-support tools at the point of care that consider a patient’s genotype in decisions relating to optimal choices of a given treatment regimen. These challenges are especially critical to address given the significant contribution of mental disorders to the global burden of disease.

Darwin made a compelling case that studies of animals could provide insights into the behavior of humans. Early studies by Pavlov and Harlow paved the way for further developments of animal models of psychiatric disorders. Seligman and Maier’s learned helplessness model continues to be employed in laboratory studies of stress and depression. It has become clear that no single animal model can possibly reproduce all of the critical facets of a mental disorder in humans. However, animal models do provide an essential element in attempts to understand the mechanisms that underlie mental disorders and to reveal molecular targets for the development of new drug therapies. Concerns have been raised about the reproducibility of laboratory experiments with inbred strains of laboratory mice and rats. Any animal model should be evaluated based upon a battery of behavioral tests and the parameters of stressful stimulation employed in experiments should be chosen with care.

Major depressive disorder is a significant contributor to the global burden of disease, and it appears to be a mental disorder that is strongly dependent upon exposure to stressful stimuli. A major concern related to the development of animal models of depression is to capture those variables that explain the much higher incidence of depression in human females compared to males. Several genetically selected animal models have been studied, including the Flinders sensitive strain and the WKY strain. In addition, a strain of rats has been selected that is highly susceptible to the development of learned helplessness. Two especially valuable animal models of depression involve exposure of inbred mice to chronic social defeat stress (CSDS) or to chronic unpredictable mild stress. Results from these animal models point to disruptions in dopamine circuits in the brain as critical for the expression of depressive symptoms.

This chapter on animal models of depression includes a summary of additional approaches to modeling a depression-like phenotype in animals. Several risk genes have been evaluated, including genes involved in dopamine, serotonin, and corticotropin-releasing factor signaling. Using a two-hit model, some investigators have examined the effects of early life stress combined with stress in adulthood to unmask the risk for a depression-like phenotype. Female mice were more sensitive than male mice to a sub-chronic paradigm of chronic variable stress and displayed depression-like behavioral changes. A naturally occurring depression-like phenotype has also been documented in captive social groups of cynomolgous monkeys. Three additional approaches to study mechanisms involved in the onset of depression have included stress and neurogenesis, stress and epigenetic alterations in gene transcription, and stress and immune signaling through proinflammatory cytokines. Taken together, these experiments have identified multiple potential targets for future drug development.

On a standard interpretation, Hume argued that reason is not practical, because its operations are limited to “demonstration” and “probability.” But recent critics claim that by limiting reason’s o...

Bipolar disorders (BDs) exhibit high heritability and symptoms typically first occur during late adolescence or early adulthood. Affected individuals may experience alternating bouts of mania/hypomania and depression, with euthymic periods of varying lengths interspersed between these extremes of mood. Clinical research studies have consistently demonstrated that BD patients have disturbances in circadian and seasonal rhythms, even when they are free of symptoms. In addition, some BD patients display seasonal patterns in the occurrence of manic/hypomanic and depressive episodes as well as the time of year when symptoms initially occur. Finally, the age of onset of BD symptoms is strongly influenced by the distance one lives from the equator. With few exceptions, animal models useful in the study of BD have not capitalized on these clinical findings regarding seasonal patterns in BD to explore molecular mechanisms associated with the expression of mania- and depression-like behaviors in laboratory animals. In particular, animal models would be especially useful in studying how rates of change in photoperiod that occur during early spring and fall interact with risk genes to increase the occurrence of mania- and depression-like phenotypes, respectively. Another unanswered question relates to the ways in which seasonally relevant changes in photoperiod affect responses to acute and chronic stressors in animal models. Going forward, we suggest ways in which translational research with animal models of BD could be strengthened through carefully controlled manipulations of photoperiod to enhance our understanding of mechanisms underlying seasonal patterns of BD symptoms in humans. In addition, we emphasize the value of incorporating diurnal rodent species as more appropriate animal models to study the effects of seasonal changes in light on symptoms of depression and mania that are characteristic of BD in humans.

Major advances in behavioral neuroscience have been facilitated by the development of consistent and highly reproducible experimental paradigms that have been widely adopted. In contrast, many different experimental approaches have been employed to expose laboratory mice and rats to acute versus chronic intermittent stress. An argument is advanced in this review that more consistent approaches to the design of chronic intermittent stress experiments would provide greater reproducibility of results across laboratories and greater reliability relating to various neural, endocrine, immune, genetic, and behavioral adaptations. As an example, the H-H* experimental design incorporates control, homotypic (H), and heterotypic (H*) groups and allows for comparisons across groups, where each animal is exposed to the same stressor, but that stressor has vastly different biological and behavioral effects depending upon each animal's prior stress history. Implementation of the H-H* experimental paradigm makes possible a delineation of transcriptional changes and neural, endocrine, and immune pathways that are activated in precisely defined stressor contexts.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states.

The categorical imperative can be construed as a universalization test for moral permissibility. False negatives of the categorical imperative would be maxims failing this test, despite the permissibility of their actions; maxims like: ‘I’ll withdraw all my savings on April 15th’. Examples of purported false negatives familiar from the literature can be grouped into three general categories, and dispatched by applying category-specific methods for proper formulation of their maxims, or for proper testing. Methods for reformulating failing maxims, such as the addition of appropriate conditional clauses, do not generate false-positive counterexamples in other instances.

In this review, nonassociative learning is advanced as an organizing principle to draw together findings from both sympathetic-adrenal medullary and hypothalamic–pituitary–adrenocortical (HPA) axis responses to chronic intermittent exposure to a variety of stressors. Studies of habituation, facilitation and sensitization of stress effector systems are reviewed and linked to an animal’s prior experience with a given stressor, the intensity of the stressor and the appraisal by the animal of its ability to mobilize physiological systems to adapt to the stressor. Brain pathways that regulate physiological and behavioral responses to stress are discussed, especially in light of their regulation of nonassociative processes in chronic intermittent stress. These findings may have special relevance to various psychiatric diseases, including depression and post-traumatic stress disorder (PTSD).

Certains ont critique la derivation de la formule de la loi universelle de Kant parce que la logique en serait lacunaire. Je prends la defense de la derivation, en mettant d'abord l'accent sur un principe teleologique auquel Kant fait allusion dans son argument et, ensuite, en clarifiant ce que celui-ci entend par la «conformite a la loi universelle» des actions. Kant maintenait que les actions etaient conformes a une loi universelle seulement lorsque leurs maximes appartiennent a un systeme unifie de principes. Une analogie avec la conformite a la loi universelle des objets dans la nature aide a montrer pourquoi Kant avait raison de deriver la formule de la loi universelle des premisses de son argument.

In Religion within the Boundaries of Mere Reason Kant wrote that ‘freedom of the power of choice has the characteristic, entirely peculiar to it, that it cannot be determined to action through any incentive except insofar as the human being has incorporated it into his maxim.’ This is an obscure statement, in both meaning and provenance. Yet almost all recent interpreters of Kant's practical philosophy find it crucial for understanding his theories of freedom and motivation, since it seems to indicate what we are required to do in order to act by our own free choice. Here I refer to Kant's statement expressing the requirement that incentives be incorporated into maxims as his ‘incorporation requirement.’ How that requirement is best understood will be the leading question in what follows: a question I shall answer by showing why the incorporation requirement, and Kant's theories of freedom and motivation, should be understood differently from the way they are now usually understood.

The general adaptation syndrome (GAS) was first proposed by Hans Selye in his classic 1936 letter to the editor of Nature. The GAS consisted of three phases: (i) the alarm phase, (ii) the phase of adaptation, and (iii) the phase of exhaustion. Selye held that the stress syndrome was always a nonspecific response of the body to any demand and included a triad of responses: enlargement of the adrenal cortex, decrease in size of the thymus and lymphatic tissue, and ulceration of the stomach and duodenum. Selye also promoted the concept of diseases of adaptation that were connected to stressful stimulation. Much of Selye’s work has been discounted as knowledge of neural and endocrine systems expanded and new analytical techniques were introduced. In particular, the doctrine of nonspecificity has been rejected and replaced with the indication that a given stressor stimulates a unique neuroendocrine signature in test subjects. In addition, many studies have demonstrated that prior stress history affects future stress responses across several neural and endocrine systems. Stress remains a key component of the etiology of many diseases and that is an enduring part of Selye’s legacy.

The fight-or-flight response was a concept developed by Walter B. Cannon in the course of his studies on the secretion of epinephrine from the adrenal medulla of laboratory animals. This concept was an outgrowth of his studies of homeostatic mechanisms, particularly as they related to the sympathetic-adrenal medulla system. Cannon’s research on homeostasis and the fight-or-flight response led him to delve into mechanisms of “voodoo death” and to propose a new theory of emotions, known as the Cannon-Bard theory. Cannon thought that the sympathetic nervous system and the adrenal medulla operated as a functional unit, with epinephrine as the chemical messenger. He did not understand that the postganglionic sympathetic nerves utilized norepinephrine as a chemical transmitter. Cannon’s research legacy is a rich one and his work is still cited frequently by contemporary researchers in the field of stress.

The American Psychologist is the official journal of the American Psychological Association. As such, it is a valued outlet for articles dealing with reviews of current topics in psychology, policy issues, and critiques of current research. S. O. Lilienfeld submitted a manuscript to the journal that was accepted by the ad hoc action editor; however, the action editor's decision was later overruled by the editor, and additional changes to the manuscript were requested. Because of this editorial decision, a controversy arose that played out on various Internet discussion groups. The author presents his perspective as the editor in this controversy. Points of emphasis include the need to protect the integrity and the confidentiality of the peer review process for scientific journals.

Purpose: Hyperactive voiding and elevated smooth muscle NGF output are traits of the spontaneously hypertensive rat (SHR). Elevated target-derived NGF is associated with hypertension and hyperactive voiding in SHRs. In the present study, we tested for possible genetic links between hypertension, hyperactive voiding and augmented bladder smooth muscle cell (BSMC) NGF secretion.Materials and Methods: We crossed SHRs with WKYs to produce a gene segregating F2 population. We measured F2 mean arterial blood pressure (BP) and six-hour voiding frequency. BSMCs were cultured from ‘Low BP F2s’ (95 +/− 2) and ‘High BP F2’ (141 +/− 3 mm. Hg) and conditioned medium tested for NGF with a two-site ELISA. The NGF regulators isoproterenol, platelet-derived growth factor (PDGF) and phorbol-12-myristate-13-acetate were tested in F2 BSMC cultures.Results: A positive correlation (r = 0.75) between blood pressure and voiding frequency existed in this F2 population. As BP rose voiding frequency increased and volume per...

Administration of d-glucose enhances learning and memory in several tasks and also attenuates memory impairments and other behavioral effects of several drugs, including morphine. The present experiment compared the effects of peripherally administered d-glucose with those of l-glucose, a stereoisomer of d-glucose that is not metabolized and does not readily cross the blood-brain barrier. Like d-glucose, though at somewhat different doses, peripherally administered l-glucose attenuated morphine-induced deficits in spontaneous alternation performance in rats and mice and attenuated morphine-induced hyperactivity in mice. l-Glucose did not raise circulating levels of plasma d-glucose, suggesting that the effects of l-glucose are not secondary to increased availability of d-glucose. Using direct injections of d- and l-glucose and morphine into the medial septum of rats, the findings indicate that d-glucose but not l-glucose attenuated morphine-induced deficits in spontaneous alternation performance; indeed, intraseptal injections of l-glucose alone impaired spontaneous alternation performance. These findings suggest that peripheral l-glucose antagonizes morphine-induced behavioral effects by a peripheral signaling mechanism, one distinct from the mechanisms that mediate at least some of the effects of d-glucose on brain function.

Elevated bladder smooth muscle cell (BSMC) nerve growth factor (NGF) secretion and related neuroplasticity are associated with hyperactive voiding in spontaneously hypertensive rats (SHRs: hypertensive, behaviorally hyperactive), compared with control Wistar-Kyotos (WKYs). We used two inbred strains (WKHT: hypertensive; WKHA: hyperactive) to further investigate this phenomenon. WKHA BSMCs secreted higher basal levels of NGF than WKHT BSMCs. Antagonists did inhibit NGF output in WKHA but not WKHT cultures. Thus augmented basal secretion of NGF cosegregates with a hyperactive phenotype, whereas a lack of regulatory inhibition of NGF output cosegregates with a hypertensive phenotype. Bladder norepinephrine content paralleled NGF content, with WKHTs > SHRs > WKHAs > WKYs, providing evidence that a lack of inhibition is the greatest contributor to elevated bladder NGF and noradrenergic innervation. Protein kinase C (PKC) agonists affected NGF production differentially depending on strain, suggesting that altered PKC signaling may contribute to strain differences in NGF secretion. Finally, 6-h voiding frequency differed between the strains, with SHRs > WKHTs = WKHAs > WKYs. Thus aspects of both the hypertensive and hyperactive phenotypes may be associated with elevated SHR bladder NGF and hyperactive voiding.

A comparison was made of the dynamics of sympathoadrenal activity in 11 age-matched male and female rats, under basal conditions and after exposure to footshock. Rats were prepared with indwelling catheters in the tail artery 24 h before the experiment. Measurements were made of plasma corticosterone (COR), norepinephrine (NE), epinephrine (EPI), dihydroxyphenylalanine (DOPA), dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC) under resting conditions, after transfer to the shock box (novelty) and at various times after footshock. Under basal conditions, males have significantly higher blood pressure and plasma DHPG/NE ratios but lower plasma levels of COR, NE and DOPAC than females. Three min after exposure to the shock chamber (novelty stress) there were significant increases in COR, EPI, NE and DHPG in both sexes, while DOPA increased only in females and DOPAC remained unchanged in both sexes. Footshock produced a further increase in EPI, NE and DOPAC within 2 min, which lasted about 15 min. There were significant sex differences in the extent and duration of the response of COR, EPI and DHPG. The data show that the female sympathoadrenal system is more reactive than that of the male to the stresses of a novel environment and footshock. The smaller DHPG/NE ratios in females at rest and after stress suggest that neuronal uptake of NE is lower in females than in males. The finding that stress produces larger increments of plasma DOPA and DOPAC in female rats indicates that tyrosine hydroxylase in the sympathetic nerve terminals and adrenal medulla may also be higher than in males.

Elevated nerve growth factor secreted by bladder smooth muscle may be associated with noradrenergic hyperinnervation of the bladder and hyperactive voiding in spontaneously hypertensive rats (SHR) and rats with bladder outlet obstruction. The present study was undertaken to determine if changes occur in efferent and afferent pathways supplying the SHR bladder similar to those in rats with bladder outlet obstruction. Fluoro-Gold (FG) retrograde tracing studies were conducted to examine the postganglionic efferent limb (major pelvic ganglion; MPG) and sensory afferent limb (L1, L2, L6, and S1 dorsal root ganglion; DRG) of the micturition reflex pathway of the SHR and Wistar-Kyoto (WKY) normotensive rat. A significant increase in cross sectional area profiles for labeled neurons in the MPG was observed in SHRs (830.5 +/- 9.0 microns2) as compared to WKYs (736.3 +/- 16.6 microns2). Neuronal cell areas in L2 (1,010.9 +/- 18.6 microns2) and S1 (1,024.6 +/- 28.3 microns2) of SHRs were significantly larger than those of WKYs (L2, 865.3 +/- 12.6 microns2, S1, 778.3 +/- 11.2 microns2). There was an increase in number of labeled cells in L6 within SHRs over WKYs. These results provide evidence that both efferent and afferent changes in neuronal innervation of the bladder occur in SHRs. The SHR strain may represent a genetic model to study changes in micturition reflex pathways that result from alterations in neuronal morphology such as those that occur with urethral outlet obstruction.

Young adult (3-month-old) and aged (24-month-old) Fischer-344 male rats received i.v. infusions of 3H-labeled norepinephrine (NE) and epinephrine (EPI) to examine the effects of aging on the neuronal uptake of NE and sympathoadrenal release of NE and EPI. Spillovers of NE and EPI into plasma and their clearance from the circulation were estimated from plasma concentrations of endogenous and 3H-labeled NE and EPI. The efficiency of neuronal uptake was assessed from changes in plasma clearance of NE and concentrations of its intraneuronal metabolite, dihydroxyphenylglycol (DHPG), during immobilization stress or neuronal uptake blockade with desipramine. Stress-induced increases in plasma NE and higher plasma NE concentrations in aged compared to young adult rats were due to both decreases in NE clearance and increases in NE spillover. EPI spillover and clearance were reduced in aged compared to young adult rats, so that plasma EPI levels did not differ between groups. Young adult and aged rats had similar desipramine-induced decreases in NE clearance, whereas desipramine-sensitive decreases and stress-induced increases in plasma DHPG were larger in aged rats. This indicates that neuronal uptake is intact and that increased NE spillover at rest and during stress in aged rats reflects increased NE release from sympathetic nerves. The results show that aging is associated with divergent decreases in EPI release from the adrenal medulla and increases in NE release from sympathetic nerves. Increased plasma concentrations of NE in aged compared to young adult rats also result from decreased circulatory clearance of NE, but this does not reflect any age-related impairment of NE reuptake.

Abstract To examine the contribution of the sympathetic nervous system to the development of hypertension, we injected spontaneously hypertensive rat (SHR) pups and normotensive Wistar-Kyoto rat (WKY) pups twice daily with saline (1.0 mL/kg SC) or terazosin (0.5 mg/kg SC), an α 1 -adrenoceptor antagonist, from postnatal day 1 through 21. We determined the effectiveness and duration of action of this terazosin dose in pilot studies with adult SHR and WKY. Body weights of WKY pups were greater than body weights of SHR pups from postnatal day 1 through 21. In addition, body weights of terazosin-treated pups of both strains were comparable to body weights of saline-injected littermate controls. Indirectly measured systolic pressures of terazosin-treated SHR were reduced significantly at 60 and 90 days of age but not at 30 days of age compared with saline-injected littermate controls. Terazosin did not affect systolic pressures of WKY, measured at 30, 60, and 90 days of age. At 100 days of age, in chronically catheterized rats, mean arterial pressures of terazosin-treated SHR were reduced significantly compared with those of saline-injected littermate controls. In contrast, terazosin did not affect mean arterial pressures of WKY at 100 days of age. Finally, preweanling treatment with terazosin did not alter patterns of open field behavior of adult SHR or WKY. SHR were significantly more active and reared more frequently compared with WKY. These findings indicate that the time between birth and weaning at 21 days of age is critical for the full expression of the hypertensive phenotype in SHR. Chronic blockade of α 1 -adrenoceptors during the preweanling period in SHR may reduce vascular hypertrophy, leading to long-term reductions in arterial pressure.

To examine the effects of the preweanling maternal environment on the development of adult blood pressure, individual spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive pups were reciprocally cross-fostered between mothers of the same or opposite strain. With this design, each SHR and WKY foster mother reared 7 of her own pups and 1 SHR or WKY foster pup. All litters were weaned at 21 days of age and body weights were obtained. At 110 days of age, SHR and WKY males were weighed and surgically prepared with chronic tail artery catheters. One day later, basal measures of mean arterial pressure (MAP, mmHg) and heart rate (HR, beats per min) were obtained while animals were resting and undisturbed in their home cages. Our findings indicate that adult SHRs reared by WKY foster dams displayed significant reductions in MAP compared to SHRs that were reared by their natural mothers or by SHR foster mothers. In contrast, MAPs of WKYs did not differ across rearing conditions. Weanling body weights of cross-fostered SHRs were significantly greater than control-reared SHRs while weanling body weights of cross-fostered WKYs were significantly lower than control-reared WKYs. However, by 110 days of age, there were no treatment-related effects on body weights of males of either strain. These findings underscore the importance of genotype × maternal environment interactions during the preweanling period for the development of cardiovascular phenotype in SHRs.

OBJECTIVE Research on the relationship between physiological responses to stressful stimulation and the onset of psychosomatic illnesses has been an area of intense interest for many years. Studies using animal models have contributed significantly to this field of inquiry by taking several complementary approaches. METHOD Three specific research strategies taken in our laboratory will be highlighted here. Each involves studies in conscious, freely behaving animals. RESULTS Genetically selected animals have been exposed to acute stressors to unmask neuroendocrine and autonomic abnormalities related to disease susceptibility. In addition, studies of aged animals suggest that exaggerated physiological responses to acute stress may underlie some age-related pathologies. Finally, a series of studies has revealed that exposure of laboratory animals to stressful stimulation may exert long-lasting influences on the ways in which these subjects respond in the future to the same or novel stressors. CONCLUSIONS These findings illustrate how studies with laboratory animals have the potential for refining the questions that are posed in research with clinical populations and for providing insight into the underlying physiological mechanisms of individual variability in disease susceptibility and the development of appropriate therapeutic interventions.

Young adult (3 months) and aged (22 months) Fischer 344 male rats were prepared with chronic tail artery catheters. Two days after surgery, rats were transferred to a test chamber and exposed to a single footshock (0, 0.25, 0.50, or 1.0 mA for 1 s). Blood samples were obtained from each rat under basal conditions and at timed intervals after exposure to footshock. Basal plasma levels of norepinephrine (NE) and epinephrine (EPI) were similar for 3- and 22-month-old rats. In contrast, plasma glucose (GLU) levels were significantly lower in aged rats compared to young adults. Increments in plasma levels of EPI were greater in aged rats compared to young adult controls following transfer of rats to the test chamber. In addition, aged rats had potentiated plasma EPI responses to footshock. Finally, aged rats had greater plasma levels of both catecholamines up to 5 min after a single training footshock compared to young adult controls. However, the increased responsiveness of EPI in aged rats was not accompanied by proportionate increases in plasma GLU levels, i.e., the EPI-GLU relationship was uncoupled in aged rats. These findings point to dramatic differences between young adult and aged rats in their plasma EPI responses to inhibitory avoidance training. Age-related increases in EPI secreted from the adrenal medulla, together with decreased blood GLU responses, may contribute in part to age-related deficits in memory modulatory processes.

L'A. retrouve le sens aristotelicien d'«excellence» pour le terme de vertu en se demandant si, comme l'affirme Slote, il existe des vertus immorales. A travers l'exemple de Gauguin qui a «failli a ses devoirs familiaux» pour partir vivre sa passion, l'A. met en relief l'importance du concept d'admiration pour une vertu et ses rapports avec la morale

Plasma levels of norepinephrine and epinephrine provide an accurate assessment of the functional state of the sympathetic-adrenal medullary system. In laboratory rats, plasma levels of both catecholamines increase monotonically with increases in stressor intensity. In addition, plasma catecholamine responses are reduced in animals exposed repeatedly to the same stressor (habituation). In contrast, plasma catecholamine responses increase significantly when animals are exposed repeatedly to an intense stressor (sensitization). Finally, plasma catecholamine responses are increased markedly when previously stressed animals are exposed to a novel stressor (dishabituation). Nonassociative processes appear to underlie the adaptive responses of the sympathetic-adrenal medullary system in animals exposed to chronic intermittent stress.

Sur la conception kantienne du sentiment de respect a l'egard de la loi morale et le role necessaire du sentiment moral dans sa motivation.