Showing papers in "Progress in Neuro-psychopharmacology & Biological Psychiatry in 2005"

Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis.

Abstract: Limbic dysfunction and hypothalamo-pituitary-adrenocortical (HPA) axis dysregulation are key features of affective disorders. The following review summarizes our current understanding of the relationship between limbic structures and control of ACTH and glucocorticoid release, focusing on the hippocampus, medial prefrontal cortex and amygdala. In general, the hippocampus and anterior cingulate/prelimbic cortex inhibit stress-induced HPA activation, whereas the amygdala and perhaps the infralimbic cortex may enhance glucocorticoid secretion. Several characteristics of limbic–HPA interaction are notable: first, in all cases, the role of given limbic structures is both region- and stimulus-specific. Second, limbic sites have minimal direct projections to HPA effector neurons of the paraventricular nucleus (PVN); hippocampal, cortical and amygdalar efferents apparently relay with neurons in the bed nucleus of the stria terminalis, hypothalamus and brainstem to access corticotropin releasing hormone neurons. Third, hippocampal, cortical and amygdalar projection pathways show extensive overlap in regions such as the bed nucleus of the stria terminalis, hypothalamus and perhaps brainstem, implying that limbic information may be integrated at subcortical relay sites prior to accessing the PVN. Fourth, these limbic sites also show divergent projections, with the various structures having distinct subcortical targets. Finally, all regions express both glucocorticoid and mineralocorticoid receptors, allowing for glucocorticoid modulation of limbic signaling patterns. Overall, the influence of the limbic system on the HPA axis is likely the end result of the overall patterning of responses to given stimuli and glucocorticoids, with the magnitude of the secretory response determined with respect to the relative contributions of the various structures.

Cytokines and major depression.

Abstract: In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.

Role of brain norepinephrine in the behavioral response to stress

Abstract: The brain noradrenergic system is activated by acute stress. The post-synaptic effects of norepinephrine (NE), exerted at a cellular or neural circuit level, have been described as modulatory in nature, as NE facilitates responses evoked in target cells by both excitatory and inhibitory afferent input. Over the past few years, we have undertaken a series of studies to understand how these cellular modulatory effects of NE, elicited by acute stress, might translate into modulation of the behavioral-affective components of the whole-animal response to stress. Using microdialysis, we have demonstrated that acute immobilization stress activates NE release in a number of stress-related limbic forebrain target regions, such as the central and medial amygdala, lateral bed nucleus of the stria terminalis, medial prefrontal cortex, and lateral septum. Using microinjections of adrenergic antagonist drugs directly into these regions, we have shown that this stress-induced release of NE facilitates a number of anxiety-like behavioral responses that are mediated in these regions, including stress-induced reduction of open-arm exploration on the elevated plus-maze, stress-induced reduction of social interaction behavior, and activation of defensive burying behavior by contact with an electrified probe. Dysregulation of the brain noradrenergic system may be a factor in determining vulnerability to stress-related pathology, or in the interaction of genetic vulnerability and environmental sensitization. Compared to outbred Sprague-Dawley rats, we have shown that the modulatory effect of NE is deficient in Wistar-Kyoto rats, which also exhibit attenuated behavioral reactivity to acute stress, as well as increased vulnerability to stress-induced gastric ulcers and exaggerated activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. Further, repeated exposure to mild intermittent cold stress resulted in a much greater sensitization of both the brain noradrenergic system and the HPA axis in Wistar-Kyoto rats compared to Sprague-Dawley rats. The recruitment of a robust noradrenergic facilitatory influence following repeated cold exposure in this previously deficient strain resulted in an aberrant HPA response, which may be illustrative of the kinds of neurobiological changes that may contribute to the development of stress-related neuropsychiatric disorders such as depression, post-traumatic stress disorder, or other anxiety disorders in predisposed or susceptible individuals. On the other side of the same issue, regulatory alterations in noradrenergic neurotransmission, or in the stress-modulatory functions of NE, may be important in the behavioral effects of chronic antidepressant drug treatment. We present recent preliminary results addressing the effects of chronic treatment with the selective NE reuptake inhibitor, desipramine, on acute behavioral reactivity to stress. A better understanding of the role of NE in adaptive responses to acute stress, the pathological consequences of prolonged, repeated or severe stress, and the mechanisms of action of drugs used to treat stress-related diseases, may contribute to the future development of more effective strategies for the treatment or even prevention of such disorders.

The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study.

Abstract: Recent studies suggested a role of brain-derived neurotrophic factor (BDNF) in depression. While BDNF levels are lower in depressed patients, antidepressant treatment increases serum BDNF levels of depressed patients. Our study aims to test the effect of chronic venlafaxine treatment on serum BDNF levels in patients with a major depressive disorder. Ten patients diagnosed as major depressive disorder according to DSM-IV are included in the study. Two of the patients had their first episode and were drug-naive, the other eight patients were drug-free for at least 4 weeks. The severity of depression was assessed with Hamilton Depression Rating Scale (HDRS). The control group consisted of ten age- and sex-matched subjects without any psychiatric disorder. Blood samples were collected at the baseline and after 12 weeks of antidepressant treatment (during remission). At the baseline the mean serum BDNF level was 17.9+/-9.1 ng/ml and the mean HDRS score was 23.2+/-4.6. Serum BDNF levels of the study group were significantly lower than in the control group (31.6+/-8.6 ng/ml). At the end of the study, the mean serum BDNF level was 34.6+/-7.1 ng/ml whereas the mean HDRS score was 8.2+/-3.9. From the baseline to the remission after 12 weeks of treatment, the increase in serum BDNF level and the decrease in HDRS score were statistically significant, respectively. When we compared the serum BDNF level of depressed patients at remission to that of the controls, there was no statistically significant difference. This study shows that venlafaxine treatment of depression improves serum BDNF level which may be considered as a nonspecific peripheral marker of depression.

Homocysteine and folate metabolism in depression.

Abstract: Homocysteine is a sensitive marker of folate and vitamin B12 deficiency. Numerous studies have confirmed the association between folate deficiency and depression. It is not completely understood whether homocysteine is solely a marker for folate deficiency or if it may play a more direct role in the expression of mood disorders. This review describes the biochemical, neurochemical and clinical correlations of folate deficiency and hyperhomocysteinemia in relation to depression.

The combined dexamethasone/CRH test as a potential surrogate marker in depression

Abstract: There is compelling evidence that impaired corticosteroid receptor function is the key mechanism in the pathogenesis of depression resulting in a dysfunctional stress hormone regulation, which can be most sensitively detected with the combined dexamethasone (dex)/corticotropin releasing hormone (CRH) test. Treatment with different kinds of antidepressants is associated with a reduction of the hormonal responses to the combined dex/CRH test suggesting normalization of impaired corticosteroid receptor signaling as the final common pathway of these drugs. Consequently, the combined dex/CRH test is suggested as a screening tool to decide whether new compounds designed as antidepressants provide sufficient efficacy to normalize corticoid receptor signaling in depressed patients. We summarize own data and findings from the literature suggesting that (1) the neuroendocrine response to the combined dex/CRH test is elevated during a major depressive episode, but (2) tends to normalize after successful treatment. (3) Favorable response to antidepressant treatment can be predicted by determining the dex suppresser status on admission. For optimal prediction of non-response to antidepressant treatment, however, the results of a second dex/CRH test are necessary. These findings, together with the fact that impaired corticosteroid receptor signaling is considered as key mechanism of the pathogenesis in depression, support the suitability of the combined dex/CHR test as a surrogate marker for treatment response in depression. In conclusion, the combined dex/CRH test is a promising candidate to serve as a screening tool for the antidepressive effects of new compounds in clinical drug trials. Furthermore, the test appears to be capable of predicting the individual likelihood to respond to a current antidepressant treatment. If a drug treatment fails to normalize the outcome of the combined dex/CRH test, a change of the treatment strategy is recommended. Further systematic research is required and already ongoing to confirm the suitability of the combined dex/CRH test as a surrogate marker in depression.

Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients.

Abstract: Several lines of evidence suggest that D-serine, an endogenous agonist of the glycine site on the NMDA receptors, might play a role in the pathophysiology of schizophrenia. The purpose of this study was to determine whether levels of D- and L-serine or D-serine ratio (D-serine/total serine) in cerebrospinal fluid (CSF) were altered in first episode and drug-naive schizophrenic patients. The CSF levels of D- and L-serine in 25 male first episode and drug-naive schizophrenic patients and 17 age-matched male healthy subjects were measured using a column-switching high performance liquid chromatography system. The percentage of D-serine in the total serine of patients was significantly (z = -2.01, p = 0.044) lower than that of controls. This study suggests that synthetic or metabolic pathways of D-serine may be abnormal in the brain of drug-naive schizophrenic patients, supporting the NMDA receptor dysfunction hypothesis of schizophrenia.

Steroids, neuroactive steroids and neurosteroids in psychopathology.

Abstract: The term “neurosteroid” (NS) was introduced by Baulieu in 1981 to name a steroid hormone, dehydroepiandrosterone sulfate (DHEAS), that was found at high levels in the brain long after gonadectomy and adrenalectomy, and shown later to be synthetized by the brain. Later, androstenedione, pregnenolone and their sulfates and lipid derivatives as well as tetrahydrometabolites of progesterone (P) and deoxycorticosterone (DOC) were identified as neurosteroids. The term “neuroactive steroid” (NAS) refers to steroids which, independent of their origin, are capable of modifying neural activities. NASs bind and modulate different types of membrane receptors. The GABA and sigma receptor complexes have been the most extensively studied, while glycine-activated chloride channels, nicotinic acetylcholine receptors, voltage-activated calcium channels, although less explored, are also modulated by NASs. Within the glutamate receptor family, N-methyl-d-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors have also been demonstrated to be a target for steroid modulation. Besides their membrane effects, once inside the neuron oxidation of Ring A reduced pregnanes, THP and THDOC, bind to the progesterone intracellular receptor and regulate gene expression through this path. The involvement of NASs on depression syndromes, anxiety disorders, stress responses to different stress stimuli, memory processes and related phenomena such as long-term potentiation are reviewed and critically evaluated. The importance of context for the interpretation of behavioral effects of hormones as well as for hormonal levels in body fluids is emphasized. Some suggestions for further research are given.

Pharmacogenetics of the serotonin transporter

Abstract: Response to psychopharmacologic drugs is genetically complex, results from an interplay of multiple genomic variations with environmental influences, and depends on the structure or functional expression of gene products, which are direct drug targets or indirectly modify the development and synaptic plasticity of neural networks critically involved in their effects. During brain development, the serotonin (5HT) system, which is commonly targeted by antidepressant, anxiolytic, and antipsychotic drugs, controls neuronal specification, differentiation, and phenotype maintenance. While formation and integration of these neural networks is dependent on the action of multiple proteins, converging lines of evidence indicate that genetically controlled variability in the expression of the 5HT transporter (5HTT) is critical to the development and plasticity of distinct neurocircuits. The most promising finding to date indicate an association between the response time as well as overall response to serotonin reuptake inhibitors (SSRIs) and a common polymorphism (5HTTLPR) within the transcriptional control region of the 5HTT gene (SLC6A4) in patients with depressive disorders. The formation and maturation of serotonergic and associated systems, in turn, are influencing the efficacy of serotonergic compounds in a variety of psychiatric conditions. Based on the notion that complex gene x gene and gene x environment interactions in the regulation of brain plasticity are presumed to contribute to individual differences in psychopharmacologic drug response, the concept of developmental psychopharmacogenetics is emerging.

Apoptotic mechanisms in the pathophysiology of schizophrenia.

Abstract: While schizophrenia is generally considered a neurodevelopmental disorder, evidence for progressive clinical deterioration and subtle neurostructural changes following the onset of psychosis has led to the hypothesis that apoptosis may contribute to the pathophysiology of schizophrenia. Apoptosis (a.k.a. programmed cell death) is a mechanism of cell death that operates in normal neurodevelopment and is increasingly recognized for its role in diverse neuropathological conditions. Activation of apoptosis can lead to rapid and complete elimination of neurons and glia in the central nervous system. Studies also show that in certain settings, pro-apoptotic triggers can lead to non-lethal and localized apoptotic activity that produces neuritic and synaptic loss without causing cell death. Given that the neuropathology of schizophrenia is subtle and includes reduced neuropil (especially synaptic elements), limited and often layer-specific reductions of neurons, as well as neuroimaging data suggesting progressive loss of cortical gray matter in first-episode psychosis, a role for apoptosis in schizophrenia appears plausible. Studies that have examined markers of apoptosis and levels of apoptotic regulatory proteins in postmortem schizophrenia brain tissue will be reviewed in context of this hypothesis. Overall, the data seem to indicate a dysregulation of apoptosis in several cortical regions in schizophrenia, including evidence that the apoptotic vulnerability is increased. Although the exact role of apoptosis in schizophrenia remains uncertain, the potential involvement of non-lethal localized apoptosis is intriguing, especially in earlier stages of the illness.

(+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia

Abstract: Dopaminergic agonists and NMDA-receptor antagonists form the basis for the dopamine and glutamate models of schizophrenia, respectively. In human subjects dopaminergic agonists evoke a psychosis resembling positive symptoms of schizophrenia, while NMDA-receptor antagonists produce both positive and negative symptoms. Consequently, the glutamate model may be considered the most complete of the two models. Alterations in animal behaviour, in response to amphetamine or NMDA-receptor antagonists, are widely used to model schizophrenia. NMDA-receptor antagonist induced social withdrawal in rat is an established model for negative symptoms of schizophrenia. In this study we have set up an automated method, based on video tracking, to assess social behaviour, motor activity and movement pattern in rats. This method was then used to evaluate the effects of amphetamine and the NMDA-receptor antagonist (+)-MK-801, administered as single intraperitoneal injections, on rat behaviour. Amphetamine caused significantly increased motor activity and a tendency towards stimulation of social interactions. (+)-MK-801 also stimulated motor activity, but induced a significant inhibition of social interactions. These results indicate that a single injection of (+)-MK-801 to rats models both positive and negative symptoms of schizophrenia. Amphetamine, in contrast, reflects only the positive symptoms of schizophrenia in this model.

Interface of physical and emotional stress regulation through the endogenous opioid system and μ-opioid receptors

Abstract: Unraveling the pathways and neurobiological mechanisms that underlie the regulation of physical and emotional stress responses in humans is of critical importance to understand vulnerability and resiliency factors to the development of a number of complex physical and psychopathological states. Dysregulation of central stress response circuits have been implicated in the establishment of conditions as diverse as persistent pain, mood and personality disorders and substance abuse and dependence. The present review examines the contribution of the endogenous opioid system and mu-opioid receptors to the modulation and adaptation of the organism to challenges, such as sustained pain and negative emotional states, which threaten its internal homeostasis. Data accumulated in animal models, and more recently in humans, point to this neurotransmitter system as a critical modulator of the transition from acute (warning signals) to sustained (stressor) environmental adversity. The existence of pathways and regulatory mechanisms common to the regulation of both physical and emotional states transcend classical categorical disease classifications, and point to the need to utilize dimensional, "symptom"-related approximations to their study. Possible future areas of study at the interface of "mind" (cognitive-emotional) and "body" (physical) functions are delineated in this context.

Homocysteine and brain atrophy.

Abstract: Homocysteine (Hcy) has been implicated as a risk factor for vascular disease as well as brain atrophy. There is evidence to implicate Hcy in increased oxidative stress, DNA damage, the triggering of apoptosis and excitotoxicity, all important mechanisms in neurodegeneration. Hcy is also prothrombotic and proatherogenic, and causes damage to the vessel wall. It is related to brain atrophy in older individuals, and possibly to white matter hyperintensities (WMH) in the brain. Epidemiological evidence and longitudinal data support Hcy as a risk factor for cognitive impairment and Alzheimer's Disease (AD). This may be due to cerebrovascular as well as direct neurotoxic mechanisms. Its role in Parkinson Disease (PD) is less well supported. High Hcy has been suggested as a mediating factor in alcohol-related brain atrophy. The high prevalence of hyperhomocysteinemia in the population and its easy treatability make Hcy an interesting amino acid for future intervention studies in the prevention of degenerative brain disorders. Intervention studies are necessary to confirm its aetiological role.

Defining stress as a prelude to mapping its neurocircuitry : no help from allostasis

Abstract: The way in which researchers conceptualise and thus define stress shapes the way in which they approach the task of mapping the brain's stress control pathways. Unfortunately, much of the research currently being done on stress neurocircuitry is occurring within a poorly developed conceptual framework, a framework that limits the depth of the questions that our studies ask, and even our ability to fully appreciate and make use of the data that they yield. Consequently, any attempt to improve our conceptual framework merits close attention. In that regard it is notable that in recent years it has been argued that the concept of homeostasis should be supplemented by the concepts of allostasis (literally ‘stability through change’) and allostatic load (in effect, the cost of allostasis). One of the purported benefits of this change has been that it will clarify the concept of stress. A close review of the arguments leads us to conclude that the introduction of the concept of allostasis has largely occurred as a result of misunderstandings and misapprehensions concerning the concept of homeostasis. In terms of understanding how the organism operates, it is not clear that the concepts of ‘allostasis’ or ‘allostatic load’ offer us anything that was not already apparent, or at least readily derivable, from an accurate reading of the original concept of homeostasis. Not surprisingly then, these more recently proposed concepts also offer little help in clarifying our understanding of stress. Indeed, rather than clarifying the concept of stress, the primary effort appears to be directed at subsuming the concept of stress within the concept of allostasis, which has the inadvertent effect of collapsing the study of homeostatic responses and stress responses together. This seems to be out of step with the fact that there is now considerable evidence that the brain does indeed possess certain pathways that merit the title of ‘stress neurocircuitry’. The attempt to subsume the concept of stress within the concept of allostasis is also counter-productive in that it distracts stress researchers from the important task of developing conceptual frameworks that allow us to tackle fundamental issues such as how the organism differentiates stressful from non-stressful challenges.

The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment

Abstract: The development of novel, atypical antipsychotics has been welcomed due to their lower incidence of extrapyramidal side effects. However, as with all pharmacotherapy, patient response is often varied and these novel compounds are not without their own side effect profile, most notably weight gain. Inter-individual variations in response to drug treatment are, in part, due to polymorphisms of the genes encoding drug targets. The importance of the serotonin system in psychiatric symptomatology and several side effects of antipsychotic drugs is well established. Thus genetic polymorphisms of two central 5-HT receptors (5-HT2A and 2C), at which many of the newer antipsychotic drugs act, are prime candidates for pharmacogenetic analysis of the effects of these drugs in the treatment of schizophrenia. To date, much work has focussed on the 5-HT2A receptor subtype. However, pharmacological evidence and recent molecular genetic studies would suggest a role for the 5-HT2C receptor in the consequences of antipsychotic treatment, particularly in relation to the development of both drug-induced dyskinesias and weight gain. This review briefly examines the pharmacology and physiology of the 5HT2C receptor in the context of its genetics, with discussion of known polymorphisms of this receptor gene and its promoter region. Associations between these polymorphisms and the development of schizophrenia, the symptom responses to antipsychotic treatment and side effects of such treatment, notably tardive dyskinesia and weight gain, are assessed and related to the presumed functionality of these polymorphisms. Such studies clearly demonstrate the potential of pharmacogenetics in optimising treatment for the individual patient.

Central acetylcholinesterase inhibitors in the treatment of chronic traumatic brain injury—clinical experience in 111 patients

Abstract: Purpose Theoretically, central acetylcholinesterase inhibitors (CAIs) could alleviate at least some of the main symptoms of chronic traumatic brain injury (TBI). The aim of this report is to describe clinical experience of the treatment of chronic TBI with these drugs. General methods From an outpatient clinic material, 111 patients were selected having chronic stable TBI with at least one of the following target symptoms: fatigue, poor memory, diminished attention or diminished initiation. Patients received in random donepezil, galantamine or rivastigmine. The evaluation of the treatment response was based on the subjective view of the patient. Findings As first treatment, 27 patients received donepezil, 30 galantamine and 54 rivastigmine. Altogether 41 patients tried more than one drug, but only three patients tried all three alternatives. In total, 61% of patients had a marked positive response and 39% a modest or no response. The clearest effect was in almost all responders a better vigilance and attention causing better general function. About half of the patients (55%) wanted to continue therapy with one of these drugs. The therapeutic response became very quickly and at low doses. There were no significant differences between the three drugs either in effect or tolerability. The age, sex, type of injury, severity of TBI or elapsed time after injury did not affect the response. The mean dose in maintenance therapy was 7.2 mg od for donepezil, 5.0 mg bid for galantamine and 2.3 mg bid for rivastigmine. Side effects or inadequate therapeutic response were the main causes for discontinuation with nearly equal frequency. Paradoxical responses were seen in some patients. Conclusions CAIs show a very promising therapeutic potential in the treatment of chronic TBI. There were no significant differences between the three drugs. Large-scale randomised double-blinded placebo-controlled studies are clearly needed.

Cholecystokinin and endogenous opioid peptides: interactive influence on pain, cognition, and emotion.

Abstract: It is well documented that stressful life experiences contribute to the etiology of human mood disorders. Cholecystokinin (CCK) is a neuropeptide found in high concentrations throughout the central nervous system, where it is involved in numerous physiological functions. A role for CCK in the induction and persistence of anxiety and major depression appears to be conspicuous. While increased CCK has been associated with motivational loss, anxiety and panic attacks, an increase in mesocorticolimbic opioid availability has been associated with coping and mood elevation. The close neuroanatomical distribution of CCK with opioid peptides in the limbic system suggests that there may be an opioid-CCK link in the modulation and expression of anxiety or stressor-related behaviors. In effect, while CCK induces relatively protracted behavioral disturbances in both animal and human subjects following stressor applications, opioid receptor activation may change the course of psychopathology. The antagonistic interaction of CCK and opioid peptides is evident in psychological disturbances as well as stress-induced analgesia. There appears to be an intricate balance between the memory-enhancing and anxiety-provoking effects of CCK on one hand, and the amnesic and anxiolytic effects of opioid peptides on the other hand. Potential anxiogenic and mnemonic influences of site-specific mesocorticolimbic CCK and opioid peptide availability, the relative contributions of specific CCK and opioid receptors, as well as the time course underlying neuronal substrates of long-term behavioral disturbances as a result of stressor manipulations, are discussed.

Further evidence for the cholinergic hypothesis of aging and dementia from the canine model of aging

Abstract: Memory decline in human aging and dementia is linked to dysfunction of the cholinergic system. Aging dogs demonstrate cognitive impairments and neuropathology that models human aging and dementia. This paper reviews recent evidence suggesting cholinergic involvement in canine cognitive aging based on studies with the anti-cholinergic drug, scopolamine, and a novel acetylcholinesterase inhibitor, phenserine. In particular, we examine: (1) the cognitive specificity of scopolamine's impairment in dogs, (2) the effect of age on scopolamine impairment and (3) the effect of phenserine on cognitive performance in dogs. Our findings indicate that working memory performance is disrupted by scopolamine at doses that do not disrupt non-cognitive behavior or long-term, semantic-like, memory, as indicated by performance of previously learned discriminations. This pattern of deficits is also seen in human and canine aging. We demonstrate that aged dogs are more sensitive to the impairing effects of scopolamine than young dogs, suggesting a decrease in cholinergic tone with increasing age. Dogs receiving phenserine demonstrate improved learning and memory compared to placebo controls. Our findings suggest that cholinergic decline could result in memory impairment, but that the memory impairment may be secondary to deficits in attention and/or encoding of new information. Together, these results suggest that the canine cholinergic system declines with age and that the aged dog is a unique model for screening therapeutics and for examining the relationship between amyloid pathology and cholinergic dysfunction in age-dependent cognitive decline.

Is quality of life associated with cognitive impairment in schizophrenia

Abstract: Background The subjectively assessed quality of life of schizophrenia patients is mostly lower than healthy subjects, and cognitive impairment is an integral feature of schizophrenia. The aims of the present study were to compare the quality of life and neurocognitive functioning between the patients with schizophrenia and the healthy subjects, and to examine the relationships between quality of life and neurocognitive functions among the patients with schizophrenia. Methods Thirty-eight patients with schizophrenia (15 women and 23 men) and 31 healthy individuals (18 women and 13 men) were included in the study. All participants were administered World Health Organization Quality of Life–Brief Form (WHOQOL-BREF) to assess their quality of life, and Digit Span Test (DST) and Controlled Oral Word Association Test (COWAT) for cognitive functions. Results The patients with schizophrenia demonstrated lower scores in physical ( F =25.6, p =0.0001), psychological ( F =15.85, p =0.0001) and social ( F =37.7, p =0.0001) domains compared to control group. The patients with schizophrenia showed significantly lower scores on COWAT compared to healthy subjects ( F =4.22, p =0.04). The social domain scores of WHOQOL correlated to DST total scores ( r =0.45, p =0.007), DST forwards scores ( r =0.54, p =0.001) and COWAT total scores ( r =0.40, p =0.04) in patients with schizophrenia but not in the control group. The patients with lower level of cognitive functioning had lower scores on social domain of WHOQOL-BREF ( z =−2.01, p =0.04). Conclusion Our results confirm that the cognitive deficits in executive function and working memory appear to have direct impact on the patients’ perceived quality of life especially in social domain which can either be a cause or a consequence of social isolation of patients with schizophrenia.

Mitochondrial aging and dysfunction in Alzheimer's disease

Abstract: Disruptions in energy metabolism have been suggested to be a prominent feature, perhaps even a fundamental component, of Alzheimer's disease (AD). These abnormalities in cerebral metabolism precede the onset of neurological dysfunction as well as gross neuropathology of AD. These changes may stem from inhibition of mitochondrial enzymes including pyruvate dehydrogenase, cytochrome c oxidase, and α-ketoglutarate dehydrogenase. Several lines of evidence also suggest a role for oxidative stress in the neuropathology associated with the disease state. Because mitochondria are the major site of free radical production in cells, they are also a primary target for oxidative damage and subsequent dysfunction. This link between mitochondrial dysfunction and the pathophysiology of AD is supported by several lines of evidence.

The influence of Serotonin Transporter Promoter Polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments

Abstract: The definition of a genetic liability profile for specific antidepressant treatment will soon be available offering considerable help in early detection of effective therapy in affective disorders. The search for genetic factors predisposing to drug response or side-effects in affective disorders started only in the last few years. The efficacy of antidepressant action was associated with several polymorphisms, located on coding genes of proteins thought to be involved in the different mechanisms of action of antidepressant treatments. Among these, gene variants in sequences of serotonin pathway proteins were candidate, both for the well known evidence of its involvement in the development of depressive symptomathology and for the wide-world use of selective serotonin reuptake inhibitors as first choice treatment of depression. A polymorphism in the promoter region of the serotonin transporter (SERTPR) was independently associated with efficacy for a range of treatments, other polymorphism located on the tryptophan hydroxylase gene, 5-HT2a receptor and G-protein beta 3 showed some association, while other candidate genes were not associated with treatment efficacy. Possible liability genes controlling at least to some extent both acute and long-term treatment were identified, and the further objective is to identify other candidate genes in order to define individualized treatments according to genetic profile in a future. The present paper reviews the pharmacogenetic studies published to date, focusing the attention on the serotonergic pathway.

The central nervous system in animal models of hyperhomocysteinemia

Abstract: Growing epidemiological evidence of associations between mildly elevated plasma homocysteine with age-related cognitive impairment, neurodegenerative and cerebrovascular disease has stimulated interest in the role of homocysteine in neurological and neuropsychiatric disorders. Homocysteine is an intermediate in the folate, vitamin B12 and B6 dependent pathways of one-carbon and sulfur amino acid metabolism. Impairments of these pathways may cause CNS dysfunction by promoting the intracellular generation of homocysteine, which is postulated to have vasotoxic and neurotoxic properties. It might also inhibit the methylation of myelin basic protein and membrane phospholipids, or disrupt biogenic amine metabolism and many other vital CNS reactions. However, it is unclear which, if any, of these putative mechanisms underlies the epidemiological associations. Genetic mouse models of hyperhomocysteinemia suggest that the primary metabolic disturbances rather than homocysteine per se may be important in determining neurological outcomes. However, severe and early developmental abnormalities in these mice limit their usefulness for understanding the relation of hyperhomocysteinemia to adult CNS disorders. Pharmacologic and dietary studies on homocysteine in rodents have reported heightened neuronal sensitivity to neurotoxic insults, neurochemical abnormalities and cerebrovascular dysfunction. Such studies are consistent with a causal relationship, but they fail to distinguish between effects that might result from a dietary imbalance and those that might be caused by homocysteine per se. Future work should be directed towards refining these models in order to distinguish between the effects of homocysteine and its determinants on neurological and behavioral outcomes that represent different CNS disorders.

The perfect time to be stressed: a differential modulation of human memory by stress applied in the morning or in the afternoon.

Abstract: We measured the effects of a stressful experience on memory for emotionally arousing and neutral material learned after exposure to a stressor which induces a significant increase in corticosteroid stress hormones. Because memory performance can be influenced by circadian changes in corticosteroid levels, subjects were tested either in the morning or in the afternoon. Nineteen healthy men (9 in the morning group and 10 in the afternoon group) were submitted to a psychological stress task before viewing a story composed of emotionally negative and neutral segments, while another 20 healthy males (10 in the morning group and 10 in the afternoon group) viewed the story without being exposed to the psychological stressor. Salivary cortisol levels were measured before and after the stressor. Memory performance was assessed by a one week post learning delayed recall. Results show that stress-induced increases in salivary cortisol levels impaired delayed free recall of emotionally arousing material in the morning group, but not in the afternoon group. There was no effect of stress on memory for neutral material. Altogether, these findings suggest that stressing participants in the morning, at a time of high circulating levels of corticosteroids, over stimulated the corticosteroid receptors in the brain, impairing declarative memory for emotionally arousing material unrelated to the stressor. These findings suggest that the experimental context, i.e., time of day at which the experiment occurs, the nature of the to-be-remembered material (remembering the stressful event itself or material unrelated to the stressor) and the valence of the to-be-remembered material (emotionally arousing vs. neutral), modulates the effects of stress on human declarative memory.

Antidepressant action of agomelatine (S 20098) in a transgenic mouse model.

Abstract: The aim of this study was to evaluate the efficacy of agomelatine (S 20098) to accelerate reversal of the neuroendocrinological, behavioural and cyclical changes seen in a transgenic mouse model of the neuroendocrine characteristics of depression. The effects of agomelatine were assessed in transgenic mice with low glucocorticoid receptor (GR) function, after acute stress or induced phase shift, and compared to desipramine and melatonin. Mice were injected 2 h before the onset of the dark period with agomelatine (10 mg/kg, i.p.), desipramine (10 mg/kg, i.p.), melatonin (10 mg/kg, i.p.) or vehicle (hydroxy-ethyl-cellulose (HEC) 1%) each day for 21 to 42 days. Agomelatine was effective in reversing the transgenic mouse behavioural changes noted in the Porsolt forced swim test as well as in the elevated plus maze. Both the number of open arm entries and the total time spent in open arms of the elevated plus maze is greatly increased in transgenic mice. The mean time spent in open arms is exquisitely sensitive to reversal by agomelatine and desipramine. Agomelatine also markedly accelerated readjustment of circadian cycles of temperature and activity following an induced phase shift. This action of agomelatine was superior to that of melatonin while desipramine was without effect. The accelerating effect of agomelatine was particularly notable if treatment was started 3 weeks prior to the induced phase shift. Agomelatine treatment did not cause any major change in corticosterone or adrenocorticotropic hormone (ACTH) concentrations nor in vasopressin (AVP), corticotropin-releasing hormone (CRH), GR and mineralocorticoid receptor (MR) mRNAs levels, which make it unlikely that the mechanism of agomelatine action is related to hypothalamic-pituitary-adrenocortical (HPA) axis changes. The present study shows that agomelatine displays some characteristics of antidepressant drug action in the transgenic mouse model, effects that could be partially related to its chronobiotic properties.

Association between Ala-9Val polymorphism of Mn-SOD gene and schizophrenia.

Abstract: Reactive oxygen species (ROS) have been suggested to play an important role in physiopathology of schizophrenia. The major intracellular antioxidant enzymes, copper–zinc superoxide dismutase in the cytoplasm and manganese superoxide dismutase (Mn-SOD) in the mitochondria, rapidly and specifically reduce superoxide radicals to hydrogen peroxide. Polymorphisms in the genes encoding antioxidant enzymes should therefore result in predisposition to schizophrenia. The present study was performed to assess whether there is a genetic association between a functional polymorphism (Ala–9Val) in the human Mn-SOD gene in schizophrenic patients (n=153) and healthy controls (n=196) using a PCR/RFLP method. Significant differences in the genotypic distribution between schizophrenics and controls were observed. Genotypic distribution with 14 (9.2%) Ala/Ala, 106 (69.3%) Ala/Val and 33 (21.6%) Val/Val subjects in schizophrenia was different from those of controls with 46 (23.5%), 83 (42.3%) and 67 (34.2%), respectively (p<0.0001). When the patients with schizophrenia were divided into the subgroups as disorganized, paranoid and residual, there was a significant difference in genotypic distribution among the subgroups (χ2=11.35, df=4, p=0.023). This association between –9Ala Mn-SOD allele and schizophrenia suggests that –9Ala variant may have a contribution in the physiopathogenesis of schizophrenia. Further investigations are warranted in larger populations with other susceptible genes that might be associated with schizophrenia.

Optimized voxel-based morphometry of gray matter volume in first-episode, antipsychotic-naïve schizophrenia

Abstract: This study examined gray matter (GM) volume abnormalities in first-episode, antipsychotic-naive Indian schizophrenia patients. Magnetic resonance images of 18 schizophrenia patients and 18 matched healthy comparison subjects were analyzed by optimized voxel-based morphometry. Schizophrenia patients had significantly smaller global GM and greater global CSF volumes and smaller regional GM volume in superior frontal, inferior frontal, cingulate, post-central, superior temporal and parahippocampal gyri, inferior parietal lobule, insula, caudate nuclei, thalamus and cerebellum. Findings suggest limbic, heteromodal cortical, striatal, thalamic and cerebellar abnormalities in schizophrenia.

Attention deficit hyperactivity disorder and borderline personality disorder

Abstract: To evaluate the association between attention deficit hyperactivity disorder (ADHD) and the diagnosis of borderline personality disorder (BPD) in adulthood, a systematic review of published follow-up data, mainly from observational studies was done. Electronic databases Medline, PsychInfo and PSYNDEXplus were searched from their earliest entries. All studies suggested significant relationships between ADHD and BPD. From a phenomenological point of view there seem to exist some similarities between these two disorders: deficits in affect regulation and impulse control, substance abuse, low self esteem and disturbed interpersonal relationship are common in both conditions. From a neuropsychological point of view dissociation in BPD might be regarded as a special form of behavioral inhibition and sustained attention comparable to ADHD. Possible therapeutic strategies of comorbid ADHD and BPD are discussed.

Membrane phospholipid composition, alterations in neurotransmitter systems and schizophrenia

Abstract: This review addresses the relationship between modifications in membrane phospholipid composition (MPC) and alterations in dopaminergic, serotonergic and cholinergic neurotransmitter systems in schizophrenia. The main evidence in support of the MPC hypothesis of schizophrenia comes from post-mortem and platelet studies, which show that in schizophrenia, certain omega-3 and omega-6 polyunsaturated fatty acid (PUFA) levels are reduced. Furthermore, examination of several biochemical markers suggests abnormal fatty acid metabolism may be present in schizophrenia. Dietary manipulation of MPC with polyunsaturated fatty acid diets has been shown to affect densities of dopamine, serotonin and muscarinic receptors in rats. Also, supplementation with omega-3 fatty acids has been shown to improve mental health rating scores, and there is evidence that the mechanism behind this involves the serotonin receptor complex. This suggests that a tight relationship exists between essential fatty acid status and normal neurotransmission, and that altered PUFA levels may contribute to the abnormalities in neurotransmission seen in schizophrenia.

Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses

Abstract: In the recent years, elevated homocysteine plasma levels have been reported to represent a risk factor not only for atherosclerosis, but also to be associated with dementia, depression and-in a gender-specific manner-schizophrenia. Here, we explored a possible association between homocysteinemia and psychiatric disorders. Fasting homocysteine, vitamin B12 and folate were determined in an ethnically homogeneous female population with different psychiatric disorders. Homocysteine was not elevated in females suffering from schizophrenia (mean, 11.6+/-5.8 micromol/l). As shown previously, increased homocysteine concentrations were associated not only with dementia of different aetiology (mean, 17.2+/-6.7 micromol/l; chi2=23.39, p<0.001, compared to the schizophrenia group), but also with depressive disorders (mean, 12.9+/-3.8 micromol/l; chi2=6.88, p=0.009). B12 and folate levels did not differ between different diagnostic groups. To further explore the connection between homocysteinemia and affective psychoses, a case-control study examining the C677T and the A1298C variants of methylenetetrahydrofolate reductase was conducted. The latter polymorphism not only was associated with affective psychoses in general, but also when divided in unipolar depression and bipolar affective disorder. In conclusion, we suggest that in females homocysteinemia is an unspecific risk factor for organic brain disorders like dementia, and possibly depression, but not for schizophrenia.