Showing papers in "Dialogues in Clinical Neuroscience in 2002"

The biology of fear- and anxiety-related behaviors

Abstract: Anxiety is a psychological, physiological, and behavioral state induced in animals and humans by a threat to well-being or survival, either actual or potential. It is characterized by increased arousal, expectancy, autonomic and neuroendocrine activation, and specific behavior patterns. The function of these changes is to facilitate coping with an adverse or unexpected situation. Pathological anxiety interferes with the ability to cope successfully with life challenges. Vulnerability to psychopathology appears to be a consequence of predisposing factors (or traits), which result from numerous gene-environment interactions during development (particularly during the perinatal period) and experience (life events), in this review, the biology of fear and anxiety will be examined from systemic (brain-behavior relationships, neuronal circuitry, and functional neuroanatomy) and cellular/molecular (neurotransmitters, hormones, and other biochemical factors) points of view, with particular reference to animal models. These models have been instrumental in establishing the biological correlates of fear and anxiety, although the recent development of noninvasive investigation methods in humans, such as the various neuroimaging techniques, certainly opens new avenues of research in this field. Our current knowledge of the biological bases of fear and anxiety is already impressive, and further progress toward models or theories integrating contributions from the medical, biological, and psychological sciences can be expected.

Pathophysiology of depression and mechanisms of treatment.

Abstract: Major depression is a serious disorder of enormous sociological and clinical relevance. The discovery of antidepressant drugs in the 1950s led to the first biochemical hypothesis of depression, which suggested that an impairment in central monoaminergic function was the major lesion underlying the disorder. Basic research in all fields of neuroscience (including genetics) and the discovery of new antidepressant drugs have revolutionized our understanding of the mechanisms underlying depression and drug action. There is no doubt that the monoaminergic system is one of the cornerstones of these mechanisms, but multiple interactions with other brain systems and the regulation of central nervous system function must also be taken into account In spite of all the progress achieved so far, we must be aware that many open questions remain to be resolved in the future.

On the role of corticotropin-releasing hormone receptors in anxiety and depression.

Abstract: On the basis of extensive basic and clinical studies, corticotropin-releasing hormone (CRH) and its related family members are considered to play a pivotal role in stress-related disorders, such as anxiety and depression. CRH is regarded as the principal mediator in the brain of the stress response, as it mediates neuroendocrine, autonomic, and behavioral responses to stressful challenges. Recently, this neuropeptide family has expanded due to the discovery of two new members, urocortin II (also termed stresscopin-related peptide) and urocortin III (also termed stresscopin), which are selective agonists for the CRH receptor type 2. They show a discrete neuroanatomical localization and are involved in stress-coping responses, such as anxiolysis. Here, on the basis of recent developments, we suggest that CRH, the urocortins, and their receptors form a complex system in the brain, which is recruited during both the acute and the recovery phases of the stress response.

Gender differences in aging: cognition, emotions, and neuroimaging studies.

Abstract: Gender and aging moderate brain-behavior relationships. Advances in neuroscience enable integration of neurobehavioral, neuroanatomic, and neurophysiology measures. Here we present neurobehavioral studies thai examine cognitive and emotion processing in healthy men and women and highlight the effects of sex differences and aqinq. Neuroanatomic studies with maqnetic resonance imaging (MRI) indicate that the progressive decrease in brain volume affects froniotemporal brain regions in men more than in Vi/omen, Functional imaging methods suggest sex differences in rate of blood flow, pattern of glucose metabolism, and receptor activity. The role of ovarian hormones is important in elucidating the observed relationships. A life span perspective on gender differences through the integration of available methodologies will advance understanding healthy people and the effects of brain disorders.

Placebo response in depression.

Abstract: With its naturally fluctuating course, depression is a highly placebo-responsive condition: mean placebo response rates in antidepressant clinical trials are 30% to 40%. We review the history and terminology of placebo and the proposed mechanisms underlying the placebo response, including the physician-patient relationship and biological, sociocultural, and treatment situation factors. We identify the predictors and patterns of placebo response in depressed patients, both within and outside of the clinical trial context, and differentiate between true drug response and placebo pattern response. We discuss the strategies now being advanced to minimize the placebo response given the increased placebo drift reported in recent trials, and the ethical guidelines governing placebo administration. Potential areas for future research include the identification of biological markers of placebo response, such as functional neuroimaging and quantitative electroencephalography, the development and testing of more sophisticated, alternative research designs, and the design of valid biological tools to assess antidepressant efficacy.

Psychopharmacology of anxiety disorders

Abstract: Exposure of the general population to a 1:4 lifetime risk of disabling anxiety has inspired generations of fundamental and clinical psychopharmacologists, from the era of the earliest benzodiazepines (BZ) to that of the selective serotonin reuptake inhibitors (SSRIs) and related compounds, eg, the serotonin and norepinephrine reuptake inhibitors (SNRIs). This comprehensive practical review summarizes current therapeutic research across the spectrum of individual disorders: generalized anxiety disorder (GAD), panic disorder (PD) and agoraphobia (social anxiety disorder), compulsive disorder (OCD), phobic disorder (including social phobia), and posttraumatic stress disorder (PTSD). Specific diagnosis is a precondition to successful therapy: despite substantial overlap, each disorder responds preferentially to specific pharmacotherapy. Comorbidity with depression is common; hence the success of the SSRIs, which were originally designed to treat depression. Assessment (multidomain measures versus individual end points) remains problematic, as-frequently-do efficacy and tolerability The ideal anxiolytic remains the Holy Grail of worldwide psychopharmacologic research.

Opposite effects of stressful experience on memory formation in males versus females

Abstract: It has become increasingly clear that males and females differ even more dramatically than we previously thought. Not only do they exhibit differing responses to stress and environmental experience, but they can also respond in opposite directions. In rats, it has been shown that exposure to an acute stressful event can enhance subsequent learning in males while dramatically impairing learning in females. These opposite effects of stress on memory formation are accompanied by similarly opposite effects on neuroanatomical measures, such as dendritic spines in the hippocampal formation. Moreover, these opposite effects of stress are mediated by different hormonal systems between the sexes. These unique responses to stressful experience in male versus female rats may be used to model sex differences in mental illness, such as those that exist for depression and posttraumatic stress disorder.

Simulating the anhedonia symptom of depression in animals.

Abstract: One of the two core symptoms of depression is anhedonia, the loss of interest or pleasure in daily activities. Stressful life events are recognized as predisposing factors in the etiology of depression. Rats subjected to a chronic, mild, unpredictable stress regimen exhibit behavioral deficits consistent with a loss of responsiveness to reward, such as decreased sucrose consumption, decreased ability to associate rewards with a distinctive environment, and decreased sensitivity to rewarding electrical brain stimulation. Normal behavior is restored by chronic treatment with antidepressants or electroshocks. Chronically stressed animals also exhibit sleep abnormalities resembling those observed in depressed patients and recognized as biological markers of depression. Thus, stress-induced anhedonia in rats represents an original animal model of some aspects of human depression offering convergent elements of biological, symptomatological, etiological, and therapeutic validity. This simulation of depression may prove useful for better understanding of the pathophysiological mechanisms involved in depressive disorders.

Estrogen and neuroprotection: from clinical observations to molecular mechanisms.

Abstract: We now appreciate that estrogen is a pleiotropic gonadal steroid that exerts profound effects on the plasticity and cell survival of the adult brain. Over the past century, the life span of women has increased, but the age of the menopause remains constant. This means that women may now live over one third of their lives in a hypoestrogenic, postmenopausal state. The impact of prolonged hypoestrogenicity on the brain is now a critical health concern as we realize that these women may suffer an increased risk of cognitive dysfunction and neurodegeneration due to a variety of diseases. Accumulating evidence from both clinical and basic science studies indicates that estrogen exerts critical protective actions against neurodegenerative conditions such as Alzheimer's disease and stroke. Here, we review the discoveries that comprise our current understanding of estrogen action against neurodegeneration. These findings carry far-reaching possibilities for improving the quality of life in our aging population.

Gonadal steroids, brain, and behavior: role of context.

Abstract: The nature and extent of the impact of gender and reproductive function on mood has been the subject of speculation and controversy for centuries. Over the past 50 years, however, it has become increasingly clear that not only is the brain a major target of reproductive steroid hormones, but additionally, the steroid hormones, as neuroregulators, create a context thai influences a broad range of brain activities; ie, neural actions and resultant behaviors are markedly different in the presence and absence of gonadal steroids. In turn, the actions of gonadal steroids are themselves context-dependent. Thus, even where it can be demonstrated thai gonadal steroids trigger mood disorders, the triggers are normal levels of gonadal steroids (to be contrasted with the mood disturbances accompanying endocrinopathies), and the mood disorders appear only in a subset of susceptible individuals. The context specificity and differential susceptibility to affective dysregulation seen in women with reproductive endocrine-related mood disorders are undoubtedly important underlying characteristics of a wide range of psychiatric disorders in which the triggers have not yet been identified. Consequently, reproductive endocrine-related mood disorders offer unparalleled promise for the identification of those contextual variables that permit biological stimuli to differentially translate into depression in individuals at risk.

Anatomic magnetic resonance imaging studies of attention-deficit/hyperactivity disorder.

Abstract: Neuroimaging techniques are increasingly being applied to the study of attention-deficit/hyperactivity disorder (ADHD). This review focuses on magnetic resonance imaging studies of the brain anatomy of ADHD. Such studies were first conducted over a decade ago, and most focus on frontal-striatal regions and tend to find smaller volumes in ADHD children than in controls. Recently published analyses with the largest sample so far of patients and controls found that ADHD is associated with a statistically significant 3% to 4% global reduction in brain volume in both boys and girls, with abnormally small caudate nuclei only being found in younger patients. After adjusting for global brain differences, only cerebellar hemispheric volumes remained significantly smaller in ADHD, and these differences continued throughout childhood and adolescence. Pathophysiological models of ADHD need take into account cerebellar dysfunction, as well as prefrontal-striatal dysregulation.

Treatment of depression associated with the menstrual cycle: premenstrual dysphoria, postpartum depression, and the perimenopause.

Abstract: Several forms of depression are unique to women because of their apparent association with changes in gonadal hormones, which in turn modulate neuroregulatory systems associated with mood and behavior. This review examines the evaluation and treatment of depression that occurs premenstrually, postpartum, or in the perimenopause on the basis of current literature. The serotonergic antidepressants consistently show efficacy for severe premenstrual syndromes (PMSs) and premenstrual dysphoric disorder (PMDD), and are the first-line treatment for these disorders. The use of antidepressants for postpartum depression is compromised by concerns for effects in the infants of breast-feeding mothers, but increasing evidence suggests the relative safety of the antidepressant medications, and the risk calculation should be made on an individual basis. Estradiol may be effective for postpartum depression and for moderate-to-severe major depression in the perimenopause. In spite of its frequent use, progesterone is not effective for the mood and behavioral symptoms of PMS/PMDD, postpartum depression, or perimenopausal depressive symptoms.

Interaction between the serotonergic system and HPA and HPT axes in patients with major depression: implications for pathogenesis of suicidal behavior.

Abstract: Disturbances in the serotonin (5-hydroxytryptamine, 5-HT) system constitute the neurobiological abnormality most consistently associated with suicide. This abnormality could be a marker of vulnerability predisposing individuals to auto-aggressive and impulsive behavior. However, other abnormalities, such as hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, have also been described in suicide victims. While inhibitory effects of adrenocorticosteroids on 5-HT(1A) receptor function have been shown in animals, HPA axis hyperactivity does not seem to be responsible for the reduced 5-HT activity found in depressed patients with a history of suicidal behavior. On the other hand, hypothalamic-pituitarythyroid (HPT) axis dysfunction, frequently observed in depression, may represent a compensatory response to reduced central 5-HT neurotransmission. Moreover, in depressed patients with a history of suicidal behavior, the absence of a functional link between HPT and dopamine activity at the hypothalamic level may be implicated in the pathophysiology of suicidal behavior. Future research is needed to determine why compensatory mechanisms are not efficient in patients with suicidal behavior.

Childhood predictors of states of anxiety

Abstract: Development of the characteristics of social phobia often requires a diathesis in the form of a temperamental bias. A behavioral profile marked by vigorous motor activity and crying to unfamiliar stimuli at 4 months of age - called high reactivity- is characteristic of about 20% of healthy, Caucasian infants. This pattern predicts shy behavior in preschool children and symptoms of social anxiety at age 7, and, at age 11, a subdued personality and biological features that are consonant with a hypothesis of amygdalar excitability. The biological variables that best characterize the children who had been high-reactive infants are right-hemisphere activity in the electroencephalogram (EEC), a larger evoked potential from the inferior colliculus, higher sympathetic tone in the cardiovascular system, and larger event-related potentials to discrepant stimuli. About a quarter of 11-year-olds who had been high reactives displayed behavioral and biological characteristics that are in theoretical accord with the hypothesis of amygdalar excitability, while only 1 of 20 displayed a profile characterized by features in opposition to their temperament. The evidence points to a modest temperamental contribution to the development of symptoms currently regarded as diagnostic of social phobia.

Nonpharmacological treatments for anxiety disorders

Abstract: An evidence-based review of nonpharmacological treatments for anxiety disorders is presented. The vast majority of the controlled research is devoted to cognitive behavior therapy (CBT) and shows its efficiency and effectiveness in all the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) anxiety disorders in meta-analyses. Relaxation, psychoanalytic therapies, Rogerian nondirective therapy, hypnotherapy and supportive therapy were examined in a few controlled studies, which preclude any definite conclusion about their effectiveness in specific phobias, agoraphobia, panic disorder, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD), CBT was clearly better than psychoanalytic therapy in generalized anxiety disorder (GAD) and performance anxiety Psychological debriefing for PTSD appeared detrimental to the patients in one high-quality meta-analysis. Uncontrolled studies of psychosurgery techniques for intractable OCD demonstrated a limited success and detrimental side effects. The same was true for sympathectomy in ereutophobia. Transcranial neurostimulation for OCD is under preliminary study. The theoretical and practical problems of CBT dissemination are discussed.

The role of substance P in depression: therapeutic implications.

Abstract: Substance P (for “powder”), identified as a gut tachykinin in 1931 and involved in the control of multiple other autonomic functions, notably pain transmission, is the focus of intense fundamental and clinical psychiatric research as a central neurotransmitter, neuromodulator, and immunomodulator, along with sister neurokinins A and B (NKA and NKB), discovered in 1984. Substance P is widely distributed throughout the central nervous system, where if is often colocalized with serotonin, norepinephrine, and dopamine. Many neurokinin (NK) receptor antagonists and agonists have been synthesized and some clinically tested. A double-blind study of MK869, a selective NK1 receptor antagonist that blocks the action of substance P, showed significant activity versus placebo and fewer sexual side effects than paroxetine in outpatients with major depression and moderate anxiety. Substance P, which is degraded by the angiotensin-converting enzyme (ACE), may mediate modulation of therapeutic outcome in affective disorders by functional polymorphism within the ACE gene: the D allele is associated with higher ACE levels and increased neuropeptide degradation, with the result that patients with major depression who carry the D allele have lower depression scores and shorter hospitalization. ACE polymorphism genotypinq might thus identify those patients with major depression likely to benefit from NK1 receptor antagonist therapy.

Pathophysiological aspects of diversity in neuronal inhibition: a new benzodiazepine pharmacology.

Abstract: Inhibitory interneurons in the brain provide the balance to excitatory signaling. On the basis of brain imaging and human genetics, a deficit in GABAergic inhibition (GABA, γ-aminobuiyric acid) has been identified as contributing to the pathophysiology of anxiety disorders, epilepsy, and schizophrenia. Therapeutically, GABA(A) receptors play a major role as targets for benzodiazepine drugs. The therapeutic relevance of the multitude of structurally diverse GABA(A) receptor subtypes has only recently been identified. α(1)-GABA(A) receptors were found to mediate sedation, anterograde amnesia, and part of the seizure protection of these drugs, whereas α(2)-GABA(A) receptors, but not α(3)-GABA(A) receptors, mediate anxiolysis. Rational drug targeting to specific receptor subtypes has now become possible. Only restricted neuronal networks will be modulated by the upcoming subtype-selective drugs. For instance, anxiolytics devoid of drowsiness and sedation promise more sophisticated interventions in anxiety disorders. A new pharmacology of the benzodiazepine site is on the horizon.

Historical aspects of anxiety.

Abstract: “Anxiety” is a key term for behavioral, psychoanalytic, neuroendocrine, and psychopharmacological observations and theories. Commenting on its historical aspects is difficult, since history is properly a study of primary data. Unfortunately, much clinical anecdote does not correspond to factual records of a long time ago. Even reports of objective studies may suffer from allegiance effects. This essay therefore primarily reflects the personal impact of others' work against the background of my experiences, clinical and scientific. These lead me to question the assumption that “anxiety”, as it exists in syndromal disturbances, is simply the quantitative extreme of the normal “anxiety” that occurs during the anticipation of danger. An alternative view that emphasizes dysfunctions of distinct evolved adaptive alarm systems is presented.

Reproductive hormonal treatments for mood disorders in women

Abstract: There has been a century-long view in medicine that reproductive function in both men and women is intimately involved with mood regulation. The 19th century witnessed a proliferation of medical reports documenting beneficial effects on mood and behavior after medical or surgical manipulations of women's reproductive function. More recently, the results of several studies suggest that gonadal steroids do regulate mood in some women. Thus, there is considerable interest in the potential role of reproductive therapies in the management of depressive illness, including both classical and reproductive endocrine-related mood disorders. Future studies need to determine the predictors of response to hormonal therapies compared with traditional antidepressant agents, and to characterize the long-term safety and benefits of these therapies.

The clinical pharmacology of depressive states

Abstract: Antidepressants have good efficacy in the treatment of mood disorders, with effect sizes that have consistently been found to be greater than those of placebo The more recent antidepressants do not have better efficacy than the compounds discovered 40 to 50 years ago, but they do have a more favorable configuration of side effects, leading to fewer dropouts This favorable situation has made it possible to prescribe the newer antidepressants in less severe depression and in several anxiety disorders, with considerable benefit to patients During the last decades, research into the pathophysiology of mood and anxiety disorders has provided much information on the brain circuitry, neurohormones, and neurotransmitters involved in these disorders In parallel, biological and behavioral work on antidepressants, using animal models and new biochemical techniques, has led to a broader understanding of the mode of action of these drugs Despite this impressive list of discoveries, much research remains to be done on the clinical, psychological, neuropsychological, physiological, and neurochemical aspects, before we can obtain a coherent description of the pathophysiological mechanisms of depression and its treatment This will lead to a better ability to predict the quality of drug response and, therefore, to the individualization of treatment

Sleep-wake mechanisms and drug discovery: sleep EEG as a tool for the development of CNS-acting drugs.

Abstract: Sleep laboratory investigations constitute a unique noninvasive tool to analyze brain functioning, Polysomnographic recordings, even in the very early phase of development in humans, are mandatory in a developmental plan of a new sleep-acting compound. Sleep is also an interesting tool for the development of other drugs acting on the central nervous system (CNS), Indeed, changes in sleep electroencephalographic (EEG) characteristics are a very sensitive indication of the objective central effects of psychoactive drugs, and these changes are specific to the way the drug acts on the brain neurotransmitter systems. Moreover, new compounds can be compared with reference drugs in terms of the sleep EEG profile they induce. For instance, cognitive enhancers involving cholinergic mechanism have been consistently demonstrated to increase rapid eye movement (REM) sleep pressure, and studying drug-induced slow wave sleep (SWS) alteration is a particularly useful tool for the development of CNS compounds acting at the 5-HT(2A/C) receptor, such as most atypical antipsychotics and some antidepressant drugs. The sleep EEG profile of antidepressants, and particularly their effects on REM sleep, are specific to their ability to enhance noradrenergic or serotonergic transmission, it is suggested that the effects of noradrenergic versus serotonergic reuptake inhibition could be disentangled using specific monoamine depletion tests and by studying drug effects on sleep microsiructure.

Studies in schizophrenia: pathophysiology and treatment.

Abstract: Studies on the pathophysiology of schizophrenia have implicated the limbic cortex, using postmortem, structural, and functional data, especially in the hippocampus (HC) and the anterior cingulate cortex (ACC). We have made contributions to the literature consistent with this idea: first, we describe a positive significant correlation between psychotic symptoms in schizophrenia and neuronal activity in the ACC and HC, suggesting the involvement of limbic cortex in the mediation of symptoms in schizophrenia. Second, in the ACC and the anterior HC (but not in the posterior HC), regional cerebral blood flow (rCBF) is abnormal (ie, reduced in the ACC and elevated in the HC) in schizophrenia. Third, the relationship of rCBF to task difficulty in the ACC is altered in schizophrenia, suggesting a failure of participation of the ACC in effortful tasks. Lastly, connectivity between the ACC and HC during the performance of an auditory discrimination task is also lacking, suggesting that cognitive performance in schizophrenia lacks a functional limbic contribution. On the basis of these changes, we studied the effects of antipsychotic drugs in these abnormal areas in persons with schizophrenia. Both first- and second-generation antipsychotics produce functional alterations in these limbic cortical areas, in the direction of normals, putatively acting through the brain's own cortical-subcortical circuits.

Enhancing synaptic plasticity and cellular resilience to develop novel, improved treatments for mood disorders.

Abstract: There is mounting evidence that recurrent mood disorders - once considered “good prognosis diseases”- are, in fact, often very severe and life-threatening illnesses. Furthermore, although mood disorders have traditionally been conceptualized as neurochemical disorders, there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes ofglia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggest that mood disorders are associated with impairments of synaptic plasticity and cellular resilience. In this context, it is noteworthy that there is increasing preclinical evidence that antidepressants regulate the function of the glutamatergic system. Moreover, although clearly preliminary, the available clinical data suggest that attenuation of N-methyl-D-aspartate (NMDA) function has antidepressant effects. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressant agents. Antidepressants and mood stabilizers indirectly regulate a number of factors involved in cell survival pathways, including cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), the antiapoptotic protein bcl-2, and mitogen-activated protein (MAP) kinases, and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects. There is much promise for the future development of treatments that more directly target molecules in critical CNS signaling pathways regulating synaptic plasticity and cellular resilience. These will represent improved long-term treatments for mood disorders.

Are there anxious genes

Abstract: Anxiety comprises many clinical descriptions and phenotypes. A genetic predisposition to anxiety is undoubted; however, the nature and extent of that contribution is still unclear. Methods for the genetic analysis of such complex disorders is briefly reviewed, followed by a discussion of the comorbidity of anxiety with other psychiatric disorders and their possible common genetic etiology. Extensive genetic studies of the serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT) gene have revealed how variation in gene expression can be correlated with anxiety phenotypes. Complete genome-wide linkage scans for panic disorder (PD) susceptibility genes have suggested a locus on chromosome arm 7p, and association studies have highlighted many candidate genes. A highly significant association between phobias, panic disorder, and a duplication at chromosomal region 15q24-26 is one of the most exciting findings to date. Emerging molecular genetic technologies and the use of increasingly sophisticated animal models of anxiety provide great promise for the future of the field.

Japanese pharmaceutical and regulatory environment

Abstract: Drastic regulatory changes in Japan since 1997 have had a considerable impact on the way new medicines are developed. The regulatory authority itself has been transformed. Clinical trials are now performed according to international guidelines. Clinical data generated in one area are acceptable in the rest of the world in some cases through a bridging process that is viewed as only temporary. The future of drug development lies in multinational clinical trials and simultaneous submission to the major regulatory authorities.

Neonatal disconnection of the rat hippocampus: a neurodevelopmental model of schizophrenia.

Abstract: In the context of our current knowledge about schizophrenia, heuristic models of psychiatric disorders may be used to test the plausibility of theories developed on the basis of new emerging biological findings, explore mechanisms of schizophrenia-like phenomena, and develop potential new treatments. In a series of studies, we have shown that neonatal excitotoxic lesions of the rat ventral hippocampus (VH) may serve as a heuristic model. The model appears to mimic a spectrum of neurobiological and behavioral features of schizophrenia, including functional pathology in presumably critical brain regions interconnected with the hippocampal formation and targeted by antipsychotic drugs (the striatum/nucleus accumbens and the prefrontal cortex), and leads in adolescence or early adulthood to the emergence of abnormalities in a number of dopamine-related behaviors. Moreover, our data show that even transient inactivation of the VH during a critical period of development, which produces subtle, if any, anatomical changes in the hippocampus, may be sufficient to disrupt normal maturation of the prefrontal cortex (and perhaps, other interconnected latematuring regions) and trigger behavioral changes similar to those observed in animals with the permanent excitotoxic lesion. These results represent a potential new model of aspects of schizophrenia without a gross anatomical lesion.

Research on serotonin and suicidal behavior: neuroendocrine and molecular approaches.

Abstract: We carried out two studies to test the hypothesis that altered central serotonergic function, as assessed by lower prolactin (PRL) response to fenfluramine (D-FEN), is more closely associated with suicidal behavior than a particular psychiatric diagnosis. A D-FEN test was performed in 85 major depressed inpatients, 33 schizophrenic inpatients, and 18 healthy controls. We showed that PRL response to D-FEN is a marker of suicidality, regardless of psychiatric disorder. We then examined the association en the serotonin (5-hydroxytryptamine) receptor 5-HT(2A) gene polymorphism (T102C) and suicide in a sample of Brazilian psychiatric inpatients (95 with schizophrenia, 78 with major depression) and 52 healthy controls. No differences were found in genotypic frequencies across patients and controls. Overall, no differences were found between patients with (n=66) and without (n=107) a history of suicide attempt. We also compared patients with a history of severe suicide attempts (lethality>3; n=32) and patients without such a history (n=107), but they did not exhibit different genotypic frequencies either. These results show thai the 5-HT(2A) gene polymorphism (T102C) may not be involved in the genetic susceptibility to suicidal behavior.

Transcranial magnetic stimulation: a new tool in the fight against depression.

Abstract: Since its introduction to the clinical realm in 1985, transcranial magnetic stimulation (TMS) has rapidly developed into a tool for exploring central nervous system function in both health and disease. The antidepressant effects of TMS were initially observed in 1993. Since then, a solid body of evidence has accumulated suggesting antidepressant effects for both slow TMS (sTMS) and repetitive TMS (rTMS). This review is divided into four parts. First, it addresses the basic concepts governing TMS, and then, second, it discusses the technical parameters involved in administering TMS. Knowledge of these parameters is necessary for understanding how TMS is administered, and how manipulation of the technique impacts on the results obtained. Third, we review the most relevant studies on the antidepressant effects of sTMS and rTMS published to date. Finally, we discuss cortical excitability and how the understanding of this basic neurophysiological function of cortical neurons can be used for monitoring the effects of TMS. In our discussion, we conclude that the time has arrived for TMS to be offered to depressed patients as a treatment.

Neurogenetics of emotional reactivity to stress in animals.

Abstract: There is much evidence for the involvement of central monoaminergic systems, the key targets of stress, in the regulation of mood. Animal and human findings indicate that genetics play a role in the etiology of mood disorders, and so we selected divergent inbred rat strains according to their anxiety-related behaviors on exposure to novel environments. We compared these strains for psychoneuroendocrine response to stressors and/or antidepressants. Molecular genetic studies were also performed to localize the genomic regions associated with these strain-dependent anxiety profiles. We then examined human results indicating that allelic variations in the serotonin transporter (5-HTT) may play a role in the etiology of neuroticism and depression. Thus, we compared inbred rat strains for the 5-HTT, with regard to central and peripheral (platelet) protein expression and function, and the consequences of local application of a selective serotonin reuptake inhibitor (SSRI) on extracellular serotonin (5-HT) levels. Our results indicate that spontaneously hypertensive rats and Lewis rats (LEW) selectively diverge in terms of anxiety-related behaviors and that this divergence is located on chromosome 4. The use of social defeat in LEW and the analysis of its psychoneuroendocrine consequences strongly suggest that such a paradigm, which is sensitive to repeated SSRI treatment, models posttraumatic stress disorder. The Wistar-Kyoto rat may be an adequate model to study the consequences of a genetically driven hypersensitivity to stress and noradrenergic antidepressants. Our most recent findings show that the Fischer 344 and LEW strains differ in protein expression and function of hippocampal and platelet 5-HTT; the divergence in protein expression is not due to allelic variations in the gene-coding sequences and leads to marked differences in extracellular 5-HT levels under basal conditions or SSRI. These examples illustrate how the use of inbred rat strains may complement our knowledge on the genetics of behavior, in the same way as the use of transgenic mice.

Objective markers of drug effects on brain function from recordings of scalp potential in healthy volunteers.

Abstract: In order to stress the importance of P300 responses in drug development, we describe the spatiotemporal characteristics of this objective, evoked event-related potential. These brain activations reflect mnemonic function, in which limbic structures play a role. It is demonstrated that a pharmacological challenge concerning, for example, the cholinergic system in young healthy volunteers induces modifications in P300 reminiscent of the aging brain. We use this type of observation to build a model in which it can be verified whether the deterioration can be counteracted by treatment with “cognition-enhancing” drugs. If we accept the extrapolation of the pharmacological effects to symptomatology, scalp potential analysis offers an appropriate tool for the study of drug interactions in early proof-of-concept models.