den Johan Boer

Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA

Highly prevalent stress-related disorders such as major depression (MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic variations in genes coding for serotonin transporter (5-HTT), catechol-O-methyl transferase (COMT) and monoamine oxidase A (MAOA) as well as sex differences influence the regulation of hypothalamic–pituitary–adrenal (HPA)-axis response to acute psychological and endocrine challenges. In our sample, the effects of COMT on the release of adrenocorticotrophin hormone (ACTH) depend on the presence of the low-expression MAOA variant in the same individual. By including individuals varying in their degree of susceptibility to MD, we showed evidence of interactions between 5-HTT and MD susceptibility in baseline cortisol, and between MAOA and MD susceptibility in baseline ACTH measures, indicating a role for these genotypes in stable-state endocrine regulation. Collectively, these results indicate that the simultaneous investigation of multiple monoaminergic genes in interaction with gender have to be measured to understand the endocrine regulation of stress. These findings point towards a genetic susceptibility to stress-related disorders.

Molecular correlates of impaired prefrontal plasticity in response to chronic stress.

Disturbed adaptations at the molecular and cellular levels following stress could represent compromised neural plasticity that contributes to the pathophysiology of stress‐induced disorders. Evidence illustrates atrophy and cell death of stress‐vulnerable neurones in the prefrontal cortex. Reduced plasticity may be realized through the destabilized function of selective proteins involved in organizing the neuronal skeleton and translating neurotrophic signals. To elucidate the mechanisms underlying these effects, rats were exposed to chronic footshock stress. Patterns of c‐fos, phospho‐extracellular‐regulated protein kinases 1/2 (ERK1/2), calcineurin and phospho‐cyclic‐AMP response‐element binding protein (CREB) expression were subsequently investigated. The results indicate chronic stress‐induced impairments in prefrontal and cingulate signal transduction cascades underlying neuronal plasticity. The medial prefrontal cortex, demonstrated functional hyperactivity and dendritic phospho‐ERK1/2 hyperphosphorylation, while reduced c‐fos and calcineurin immunoreactivity occurred in the cingulate cortex. Significantly reduced phospho‐CREB expression in both cortical regions, considering its implication in brain‐derived neurotrophic factor (BDNF) transcription, suggests reduced synaptic plasticity. This data confirms the damaging effect of stress on cortical activity, on a molecular level. Due to the association of these markers in the regulation of BDNF signalling, these findings suggest a central role for intracellular neurotrophin transduction members in the pathways underlying cellular actions of stress in the brain.

Acute and chronic effects of citalopram on postsynaptic 5-hydroxytryptamine(1A) receptor-mediated feedback: a microdialysis study in the amygdala

Microdialysis was used to assess the involvement of postsynaptic 5‐hydroxytryptamine1A (5‐HT1A) receptors in the regulation of extracellular 5‐HT in the amygdala. Local infusion of the 5‐HT1A receptor agonist flesinoxan (0.3, 1, 3 µm) for 30 min into the amygdala maximally decreased 5‐HT to 50% of basal level. Systemic administration of citalopram (10 µmol/kg) increased 5‐HT to 175% of basal level. Local infusion of 1 µm of the 5‐HT1A receptor antagonist WAY 100.635 into the amygdala augmented the effect of citalopram to more than 500% of basal 5‐HT level. 5‐HT1A receptor responsiveness after chronic citalopram treatment was determined in two ways. First, by local infusion of 1 µm flesinoxan for 30 min into the amygdala, which showed a significant 63% reduction in response (area under the concentration–time curve; AUC) for the citalopram group compared to the saline group. Second, by systemic administration of citalopram (10 µmol/kg), which increased 5‐HT to 350% of basal level. The effect was larger than in untreated animals, but more important, local infusion of 1 µm WAY 100.635 into the amygdala now failed to augment the effect of citalopram. Both the flesinoxan and WAY 100.635 data suggest an involvement of postsynaptic 5‐HT1A receptor‐mediated feedback in the amygdala, which diminishes following chronic citalopram treatment.

Decision making performance in obsessive compulsive disorder

BACKGROUND Neuro-imaging studies in OCD report the orbitofrontal cortex to be functionally abnormal. As these areas are presumed to be involved in decision making, studying this behavior in OCD may provide further insight into the cognitive deficits accompanying the disorder. METHODS Performance of 27 drug-free OCD patients and 26 healthy volunteers was compared on the decision making task of Bechara et al. [Cognition, 50 (1994) 7-15]. RESULTS OCD patients and volunteers displayed comparable decision-making behavior. Within OCD patients, risk taking was independently related to both anxiety and OCD severity. LIMITATIONS Results must be regarded as preliminary, due to the limited number of OCD patients included and the lack of a clinical control group. CONCLUSIONS Although VMpfc function is not generally impaired, it seems to be involved in OCD; possibly in another way than could be measured with this task. CLINICAL RELEVANCE Clarification of cognitive distortions underlying OCD may guide development of new strategies for cognitive-behavioral therapy.

Chronic but not acute foot-shock stress leads to temporary suppression of cell proliferation in rat hippocampus.

Stressful experiences, especially when prolonged and severe are associated with psychopathology and impaired neuronal plasticity. Among other effects on the brain, stress has been shown to negatively regulate hippocampal neurogenesis, and this effect is considered to be exerted via glucocorticoids. Here, we sought to determine the temporal dynamics of changes in hippocampal neurogenesis after acute and chronic exposure to foot-shock stress. Rats subjected to a foot-shock procedure showed strong activation of the hypothalamic-pituitary-adrenal (HPA) axis, even after exposure to daily stress for 3 weeks. Despite a robust release of corticosterone, acute foot-shock stress did not affect the rate of hippocampal cell proliferation. In contrast, exposure to foot-shock stress daily for 3 weeks led to reduced cell proliferation 2 hours after the stress procedure. Interestingly, this stress-induced effect did not persist and was no longer detected 24 hours later. Also, while chronic foot-shock stress had no impact on survival of hippocampal cells that were born before the stress procedure, it led to a decreased number of doublecortin-positive granule neurons that were born during the chronic stress period. Thus, whereas a strong activation of the HPA axis during acute foot-shock stress is not sufficient to reduce hippocampal cell proliferation, repeated exposure to stressful stimuli for prolonged period of time ultimately results in dysregulated neurogenesis. In sum, this study supports the notion that chronic stress may lead to cumulative changes in the brain that are not seen after acute stress. Such changes may indicate compromised brain plasticity and increased vulnerability to neuropathology.

Unique patterns of FOS, phospho-CREB and BrdU immunoreactivity in the female rat brain following chronic stress and citalopram treatment

Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined. Here we show that chronic footshock stress (21 days) promotes HPA axis hyperactivity (as seen by the increased FOS-ir in the paraventricular hypothalamic nucleus (PVN), plasma corticosterone and adrenal hypertrophy), reduces hippocampal BrdU immunoreactivity and suppresses cortical-limbic CREB phosphorylation in female rats. Long-term citalopram treatment, in contrast, attenuates stress-induced elevation of corticosterone levels and adrenal hypertrophy, although it does not reverse footshock-mediated induction of FOS-ir in the PVN, inhibition of CREB phosphorylation and reduction of hippocampal BrdU-labeling. Moreover, citalopram administration was also associated with significant hypophagic effects and inhibition of CREB phosphorylation. These data suggest that, in female rats, normalization of chronic stress-induced HPA axis abnormalities may represent an initial phase of citalopram-mediated therapeutic actions and despite this SSRIs apparent lack of effects on neuroplasticity, we cannot exclude the possibility that some neurochemical adaptations occur in a later stage which may require more than 3 weeks of treatment to manifest.

Gender-specific effects of social housing on chronic stress-induced limbic Fos expression.

Stress plays an important role in the development of affective disorders. Women show a higher prevalence for these disorders then men. The course of a depressive episode is thought to be positively influenced by social support. We have used a chronic mild stress model in which rats received footshocks daily for 3 weeks. Since rats are social animals we hypothesised that social housing, as a possible model for human social support, might reduce the adverse effects of chronic stress. Brain activity after chronic stress was measured in several limbic brain areas with the neuronal activation marker c-fos. High behavioural activity due to housing rats under reversed light-dark conditions could be responsible for the observed high within group variability in some limbic regions. FOS- (ir) in the paraventricular nucleus of the hypothalamus (PVN) was increased in all stress-exposed groups, except for the socially housed females who showed increased FOS-ir in control condition. Individually housed males and socially housed females showed increased FOS-ir in the dorsal raphe (DRN). Amygdala nuclei were differentially affected by stress, gender and housing conditions. Also the mesolimbic dopaminergic system showed gender specific responses to stress and housing conditions. These results indicate that social support can enhance stress coping in female rats, whereas in males rats, group housing appears to increase the adverse effects of chronic stress, although the neurobiological mechanism is not simply a reduction or enhancement of stress-induced brain activation.

Neural correlates of perception of emotional facial expressions in out-patients with mild-to-moderate depression and anxiety. A multicenter fMRI study

BACKGROUND Depression has been associated with limbic hyperactivation and frontal hypoactivation in response to negative facial stimuli. Anxiety disorders have also been associated with increased activation of emotional structures such as the amygdala and insula. This study examined to what extent activation of brain regions involved in perception of emotional faces is specific to depression and anxiety disorders in a large community-based sample of out-patients. METHOD An event-related functional magnetic resonance imaging (fMRI) paradigm was used including angry, fearful, sad, happy and neutral facial expressions. One hundred and eighty-two out-patients (59 depressed, 57 anxiety and 66 co-morbid depression-anxiety) and 56 healthy controls selected from the Netherlands Study of Depression and Anxiety (NESDA) were included in the present study. Whole-brain analyses were conducted. The temporal profile of amygdala activation was also investigated. RESULTS Facial expressions activated the amygdala and fusiform gyrus in depressed patients with or without anxiety and in healthy controls, relative to scrambled faces, but this was less evident in patients with anxiety disorders. The response shape of the amygdala did not differ between groups. Depressed patients showed dorsolateral prefrontal cortex (PFC) hyperactivation in response to happy faces compared to healthy controls. CONCLUSIONS We suggest that stronger frontal activation to happy faces in depressed patients may reflect increased demands on effortful emotion regulation processes triggered by mood-incongruent stimuli. The lack of strong differences in neural activation to negative emotional faces, relative to healthy controls, may be characteristic of the mild-to-moderate severity of illness in this sample and may be indicative of a certain cognitive-emotional processing reserve.

Future antidepressants: what is in the pipeline and what is missing?

Monoamine reuptake inhibitors still reign in the treatment of major depression, but possibly not for long. While medicinal chemists have been able to reduce the side effects of these drugs, their delayed onset of action and considerable non-response rate remain problematic. Of late, serious questions have been raised regarding the efficacy of monoamine reuptake inhibitors.The present review presents an inventory of what is (and until recently was) in the antidepressant pipeline of pharmaceutical companies. Novel antidepressant compounds can be categorised into four groups depending on their target(s): (i) monoamine receptors; (ii) non-monoamine receptors; (iii) neuropeptide receptors; and (iv) hormone receptors. Other possible targets include components of post-receptor intracellular processes and elements of the immune system; to date, however, compounds specifically aimed at these targets have not been the subject of clinical trials.Development of several compounds targeted at monoamine receptors has recently been discontinued. At least five neurokinin-1 (NK1) receptor antagonists were until recently in phase II of clinical testing. However, the apparent interest in the NK1 receptor should not be interpreted as representing a departure from the monoamine hypothesis since neurokinins also modulate monoaminergic systems.In the authors’ view, development of future antidepressants will continue to rely on the serendipity-based monoamine hypothesis. However, an alternative approach, based on the hypothesis that chronic stress precipitates depressive symptoms, might be more productive. Unfortunately, clinical results using drugs targeted at components of the HPA axis have not been very encouraging to date. In the short run, the authors believe that augmentation strategies offer the best hope for improving the efficacy of antidepressant treatment. Several approaches to improve the efficacy of SSRIs are conceivable, such as concurrent blockade of monoamine autoreceptors and the addition of antipsychotics, neuromodulators or hormones (HPA axis and gender related). In the long-term, however, construction of a scientifically verified conceptual framework will be needed before more effective antidepressants can be developed. It can be argued that it is not depression itself that should be treated, but rather that its duration should be reduced by pharmacological means. Animal models that take this concept into consideration and identify mechanisms for acceleration of recovery from the effects of stress need to be developed.

Neuropsychological investigation into the carcinoid syndrome

RationaleIn patients suffering from metastatic carcinoid tumors, chronic disturbances of serotonergic metabolism are frequently present. Serotonin is supposed to influence a range of cognitive functions.ObjectivesThe present study evaluated the cognitive performance of carcinoid patients.MethodsIn 14 patients with proven carcinoid syndrome, neuropsychological functioning was studied. Visual search, sustained attention, set shifting ability and spatial working memory were assessed using tests from the CANTAB neuropsychological battery. This was compared with the performance of matched healthy controls.ResultsPlasma tryptophan levels were lower than controls. Patients showed an enhanced ability to learn new stimulus–response associations. Sustained visual attention, however, was impaired.ConclusionCognitive patterns were different from those found in depressive patients and partly mimicked those found in tryptophan depletion experiments. Further investigation has to point out the role of serotonergic changes in the accomplishment of affective states.