Metallic taste in cancer patients treated with chemotherapy.

BACKGROUND: Metallic taste is a taste alteration frequently reported by cancer patients treated with chemotherapy. Attention to this side effect of chemotherapy is limited. This review addresses the definition, assessment methods, prevalence, duration, etiology, and management strategies of metallic taste in chemotherapy treated cancer patients. METHODS: Literature search for metallic taste and chemotherapy was performed in PubMed up to September 2014, resulting in 184 articles of which 13 articles fulfilled the inclusion criteria: English publications addressing metallic taste in cancer patients treated with FDA-approved chemotherapy. An additional search in Google Scholar, in related articles of both search engines, and subsequent in the reference lists, resulted in 13 additional articles included in this review. Cancer patient forums were visited to explore management strategies. FINDINGS: Prevalence of metallic taste ranged from 9.7% to 78% among patients with various cancers, chemotherapy treatments, and treatment phases. No studies have been performed to investigate the influence of metallic taste on dietary intake, body weight, and quality of life. Several management strategies can be recommended for cancer patients: using plastic utensils, eating cold or frozen foods, adding strong herbs, spices, sweetener or acid to foods, eating sweet and sour foods, using 'miracle fruit' supplements, and rinsing with chelating agents. INTERPRETATION: Although metallic taste is a frequent side effect of chemotherapy and a much discussed topic on cancer patient forums, literature regarding metallic taste among chemotherapy treated cancer patients is scarce. More awareness for this side effect can improve the support for these patients.

To like or not to like: neural substrates of subjective flavor preferences.

Flavor preferences vary; what one enjoys may be disgusting to another. Previous research has indicated several brain regions associated with flavor preferences. However, by using different stimuli or different internal states to obtain differences in liking, results of these studies may be confounded. Therefore, we used one target stimulus (grapefruit juice) and fMRI to compare brain activation patterns between participants that either liked (n=16) or disliked (n=18) this stimulus. Our first aim was to investigate whether differential neural activation exists that accounts for the difference in subjective flavor preference for the target stimulus. Secondly, multivariate analysis was used to investigate whether differences in subjective liking for the target revealed similar activation patterns as differences in general liking for a sweet and bitter solution. A direct comparison of likers and dislikers of the target stimulus revealed only small differences in activations in orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC). However, when using multivariate analysis, a broader activation pattern (including OFC, dACC, pregenual anterior cingulate, anterior insula and ventral striatum) was identified that discriminated likers from dislikers with an 88% success rate. Interestingly though, little overlap was found between this pattern and the pattern that discriminates liking for the sweet and bitter solutions and lesser voxels contributed to the former compared with the latter. These differences between patterns discerning innate versus learned preferences may suggest that different mechanisms are at work and highlight the importance of elucidating the neural processes of how subjective preferences are learned and acquired.

Love is more than just a kiss: a neurobiological perspective on love and affection.

Love, attachment, and truth of human monogamy have become important research themes in neuroscience. After the introduction of functional Magnetic Resonance Imaging (fMRI) and Positron Emission Tomography (PET), neuroscientists have demonstrated increased interest in the neurobiology and neurochemistry of emotions, including love and affection. Neurobiologists have studied pair-bonding mechanisms in animal models of mate choice to elucidate neurochemical mechanisms underlying attachment and showed possible roles for oxytocin, vasopressin, and dopamine and their receptors in pair-bonding and monogamy. Unresolved is whether these substances are also critically involved in human attachment. The limited number of available imaging studies on love and affection is hampered by selection bias on gender, duration of a love affair, and cultural differences. Brain activity patterns associated with romantic love, shown with fMRI, overlapped with regions expressing oxytocin receptors in the animal models, but definite proof for a role of oxytocin in human attachment is still lacking. There is also evidence for a role of serotonin, cortisol, nerve growth factor, and testosterone in love and attachment. Changes in brain activity related to the various stages of a love affair, gender, and cultural differences are unresolved and will probably become important research themes in this field in the near future. In this review we give a resume of the current knowledge of the neurobiology of love and attachment and we discuss in brief the truth of human monogamy.

Increased limbic phosphorylated extracellular-regulated kinase 1 and 2 expression after chronic stress is reduced by cyclic 17beta-estradiol administration.

Chronic stress induced neuronal changes that may have consequences for subsequent stress responses. For example, chronic stress in rats rearranges dendritic branching patterns and disturbs the phosphorylation of extracellular-regulated kinase 1 and 2 (ERK) 1/2 throughout the limbic system. Stress-induced psychopathology occurs more often in women, however, most of studies have been done in male rats. Therefore, we studied the effect of stress in female rats. Other studies show that estradiol can modulate neuronal plasticity and might protect against stress-induced aberrations. To investigate the role of estradiol in stress responses we manipulated the hormone levels. Ovariectomized rats were cyclically treated with vehicle or with 17beta-estradiol-benzoate (1x in 4 days, 10 microg/250 g, s.c.) and subjected to either acute (3 days) or chronic (22 days) stress. In ovariectomized rats, the number of c-Fos positive cells in the infralimbic and prelimbic cortex of the prefrontal cortex and in the medial and basolateral amygdala was increased after acute stress. Moreover, acute stress reduced the number of phosphorylated ERK1/2 positive neurons in the prefrontal cortex of ovariectomized rats. Chronic stress, on the other hand, abolished normal patterns of c-Fos immunoreactivity in the prefrontal cortex and amygdala and increased the prefrontocortical phosphorylation of ERK1/2 in ovariectomized rats. Cyclic estradiol treatment preserved the neuronal reactivity in the infralimbic cortex after chronic stress and prevented sustained accumulation of phosphorylated ERK1/2. Therefore, cyclic estradiol administration apparently preserves the integrity of signal transduction cascades in limbic structures, which may protect against the harmful consequences of recurrent stress.

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 SSRI's 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.

Pair-housing of male and female rats during chronic stress exposure results in gender-specific behavioral responses.

UNLABELLED: Social support has a positive influence on the course of a depression and social housing of rats could provide an animal model for studying the neurobiological mechanisms of social support. Male and female rats were subjected to chronic footshock stress for 3 weeks and pair-housing of rats was used to mimic social support. Rats were isolated or housed with a partner of the opposite sex. A plastic tube was placed in each cage and subsequently used as a 'safe' area in an open field test. Time spent in the tube was used as a measurement of anxiety levels. Chronic stress increased adrenal weights in all groups, except for isolated females who showed adrenal hypertrophy in control conditions. In isolated males, chronic stress resulted in an increase in the time the animals spent in the tube. While stress did not affect this parameter in socially housed males, males with a stressed partner showed a similar response as isolated stressed males. Even though adrenal weights showed that isolated females were more affected by stress, after chronic stress exposure, they spent less time in the tube than socially housed females. Socially housed stressed females spent less time in the 'safe' tube compared to control counterparts, indicating that stress has a gender-specific behavioral effect. IN CONCLUSION: pair-housing had a stress-reducing effect on behavior in males. Isolation of females was stressful by itself. Pair housing of females was not able to prevent stress-induced behavioral changes completely, but appeared to reduce the effects of chronic stress.

Immunohistochemical changes induced by repeated footshock stress: revelations of gender-based differences.

As a growing literature has proven, adverse experiences, particularly when severe and persistent, play a pivotal role in the development of neuronal dysfunctions and psychopathology. In the present study, the neurochemical changes induced by acute and repeated footshock exposure were investigated at the molecular and cellular level, using c-fos and phospho-ERK1/2 immunoreactivity and gene expression arrays. Marked gender-related differences were found following both acute and prolonged footshock exposure. Acute aversive conditioning resulted in significant immunohistochemical changes that might be critically involved in the modulation of fear-related responses, especially in males. Prolonged footshock exposure, on the contrary, was associated with sustained hypothalamic-pituitary-adrenal axis hyperactivity, differential gender-related patterns of cortical-limbic activity, and abnormal neuronal plasticity, especially in medial prefrontocortical regions. These data may provide additional insights into the understanding of the neural circuits underlying the effects of acute and repeated footshock exposure as well as clarify some of the mechanisms involved in the development of stress-related neuronal abnormalities.

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.

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.

Selective chronic stress-induced in vivo ERK1/2 hyperphosphorylation in medial prefrontocortical dendrites: implications for stress-related cortical pathology?

Stress has been shown to affect brain structural plasticity, promote long-term changes in multiple neurotransmitter systems and cause neuronal atrophy. However, the mechanisms involved in these stress-related neural alterations are still poorly understood. Mitogen-activated protein kinase (MAPK) cascades play a crucial role in the transduction of neurotrophic signal from the cell surface to the nucleus and are implicated in the modulation of synaptic plasticity and neuronal survival. An intriguing possibility is that stress might influence brain plasticity through its effects on selective members of such intracellular signalling cascades responsible for the transduction of neurotrophin signals. Here, we have investigated the effects of stress on the expression of three members of the MAPK/extracellular-regulated kinase (ERK) pathway such as phospho-ERK1, phospho-ERK2 and phospho-cAMP/calcium-responsive element-binding protein (CREB) in the adult rat brain. Male rats were subjected to mild footshocks and the patterns of protein expression were analysed after 21 consecutive days of stress. We found that chronic stress induced a pronounced and persistent ERK1/2 hyperphosphorylation in dendrites of the higher prefrontocortical layers (II and III) and a reduction of phospho-CREB expression in several cortical and subcortical regions. We hypothesized that defects in ERK signalling regulation combined with a reduced phospho-CREB activity may be a crucial mechanism by which sustained stress may induce atrophy of selective subpopulations of vulnerable cortical neurons and/or distal dendrites. Thus, ERK-mediated cortical abnormalities may represent a specific path by which chronic stress affects the functioning of cortical structures and causes selective neural network defects.

Considering depression as a consequence of activation of the inflammatory response system.

This paper summarizes the possible interrelation between peripheral and/or cerebral inflammation and depression. Often, depression is regarded as a consequence of life events, including disabling diseases. The question addressed here is whether activation of the inflammatory response system (IRS) can cause depression. Epidemiological studies suggest that depression can be precipitated by bacterial or viral infections. In depressed patients, peripheral markers of the IRS are often increased. There is some evidence that some forms of depression are caused by a viral infection of the limbic system. More consistent are the observations that depression in diseases with active cerebral inflammatory processes (e.g. multiple sclerosis, Alzheimer's disease) may concur. Direct evidence of a relation between depression and inflammation was found in post-mortem brain material of patients with a vascular depression. In both inflammatory brain diseases and in depression, a state-dependent increased hypothalamus-pituitary-adrenal axis activity is seen. Animals studies have shown that intact cerebral serotonin systems are required for the activation of the IRS following an endotoxin challenge and that long-term treatment with antidepressants may change such a response. Gender differences between the prevalence of depression and inflammatory diseases are similar, as more females are affected. We hypothesize that cerebral or peripheral activation of the IRS may contribute to the course of some antidepressant treatment-resistant depressions. Clinical trials combining antidepressants and drugs that reduce the activation of the IRS may provide evidence for such proposed depression subtypes.

Donor brain death reduces survival after transplantation in rat livers preserved for 20 hr.

BACKGROUND: Eighty percent of donor organs come from donors who have suffered brain trauma (brain-dead donors). This unphysiological state alters the hemodynamic and hormonal status of the organ donor. This can cause organ injury, which has been suggested to alter the immunological or inflammatory status of the organ after transplantation, and may lead to increased sensitivity of the organ to preservation/transplantation injury. In this study we asked the question: does brain death cause injury to the liver that decreases successful liver preservation? METHODS: The rat liver transplant model was used to compare survival in rats receiving a liver from a brain-dead donor versus a non-brain-dead donor. Brain death was induced by inflation of a cranially placed balloon catheter. The rats were maintained normotensive with fluid infusion for 6 hr. The livers were flushed with University of Wisconsin (UW) solution and immediately transplanted or cold stored for 20 hr before transplantation. RESULTS: Recipient survival with immediately transplanted livers or those stored for 20 hr was 100% with livers from non-brain-dead donors. However, survival decreased when livers were procured from brain-dead donors. Survival was 75% (6/8) when storage time was 0 hr and 20% (2/10) when the liver was cold stored for 20 hr before transplantation. CONCLUSION: This study shows that brain death induces alterations in the donor liver that make it more sensitive to preservation/reperfusion injury than livers from donors without brain death. The mechanism of injury to the liver caused by brain death is not known. Because most livers used clinically for transplantation come from brain-dead donors, it is possible that poor function of these livers is due to the intrinsic condition of the donor organ, more than the quality of the preservation. Methods to treat the brain-dead donor to improve the quality of the liver may be needed to allow better preservation of the organ and to give better outcome after liver transplantation.

Urinary free cortisol excretion in elderly persons with minor and major depression.

Several studies have found that cortisol hypersecretion may occur in severely depressed patients, characterized by melancholic features. On the other hand, illness chronicity seems to be related to low, rather than high, cortisol levels. This study aims to trace factors associated with 24-h urinary free cortisol levels in a sample of 23 elderly persons with major or minor depression and 21 non-depressed control subjects. Depressive episodes were subdivided according to severity and chronicity (i.e. length and recurrence). None of the depressed persons showed unusually high 24-h cortisol levels, and cortisol excretion was not elevated as compared with that in the control group, regardless of subtype of depression. The results suggest, however, that hyposecretion of cortisol may be a feature of chronic depressive episodes, especially in males.

Migraine and function of the immune system: a meta-analysis of clinical literature published between 1966 and 1999.

Mechanisms underlying migraine precipitation are largely unknown. A role of the immune system in migraine precipitation is a matter of debate because of the association of atopic disorders and migraine. Recently, it was demonstrated that migraineurs benefit from eradication of a Helicobacter pylori infection, which substantiates a possible role for (sub-clinical) infections in precipitation of migraine. Since 1966, about 45 clinical investigations have reported on alterations of immune function in migraine patients, which we present in this review. Changes of serum levels of complement and immunoglobulins, histamine, cytokines and immune cells were found in some of these studies but in most cases not corroborated by others. Migraineurs suffering from comorbid atopic disorders show elevated plasma IgE levels but not patients without a type I hypersensitivity. Histamine plasma levels are chronically elevated in migraineurs, and interictally decreased lymphocyte phagocytotic function and increased plasma tumor necrosis factor alpha (TNFalpha) levels were found, and may be related to increased infection susceptibility. The cause of this increased susceptibility is unclear but most likely is a result of chronic stress, a well-known suppressor of the immune system. Stress relief enhances immune activity and triggers a burst of circulating vasoactive compounds that function as mediators of inflammation and potential precipitators of a migraine attack in vulnerable subjects. In conclusion, in the clinical literature of the past decades, there is no clear-cut evidence of an immune dysfunction in migraineurs, but we cannot totally exclude the possibility of an altered immune function in migraineurs. Discrepancies in the literature most likely are caused by the divergent patterns of sample collection relative to the time of the attack. We propose stringent definition of sample collection times for future studies of immune function in migraine patients.

Clozapine-induced Fos-protein expression in rat forebrain regions: differential effects of adrenalectomy and corticosterone supplement.

Unlike classical antipsychotic drugs, clozapine activates the hypothalamo-pituitary-adrenal axis and induces a specific regional pattern of Fos-protein expression in the rat forebrain. Whether corticosterone plays a role in the clozapine-induced Fos response is the subject of this study. Some rats were adrenalectomized and in a number, including intact animals, a corticosterone pellet (100 mg s.c.) was implanted; after 1 week, a single dose of clozapine (20 mg kg(-1) i.p.) was administered. The clozapine-induced Fos response was not affected by adrenalectomy, apart from the nucleus accumbens shell, the subfornical organ and the supraoptic nucleus; there was an increased response in the nucleus accumbens shell, while other regions showed less Fos immunoreactivity. Implantation of the corticosterone pellet in both sham-operated and adrenalectomized animals, reduced the clozapine-induced Fos responses strongly in the hypothalamic paraventricular nucleus, the subfornical organ and possibly in the prefrontal cortex; in the supraoptic nucleus, this effect was seen only in intact animals. The effect of clozapine on plasma corticosterone levels was also diminished by supplemental corticosterone treatment. These results imply that the effects of clozapine are partially dependent upon hypothalamo-pituitary-adrenal axis integrity and activation. The efficacy of clozapine in the treatment of polydipsia and hyponatremia in chronic psychiatric patients may involve clozapine-mediated activation of the cellular activity in the subfornical organ.

Physiological and anatomic evidence for regulation of the heart by suprachiasmatic nucleus in rats.

The suprachiasmatic nucleus (SCN) is the mammalian biological clock that generates the daily rhythms in physiology and behavior. Light can phase shift the rhythm of the SCN but can also acutely affect SCN activity and output, e.g., output to the pineal. Recently, multisynaptic SCN connections to other organs were also demonstrated. Moreover, they were shown to affect those organs functionally. The aim of the present study was to investigate the role of the SCN in the regulation of the heart. First, we demonstrated that heart rate (HR) in SCN-intact, but not SCN-lesioned (SCNx), male Wistar rats had a clear circadian rhythm, which was not caused by locomotor activity. Second, we demonstrated that light at night reduces HR in intact but not in SCNx rats. Finally, we demonstrated the presence of a multisynaptic autonomic connection from SCN neurons to the heart with the retrograde pseudorabies virus tracing technique. Together, these results demonstrate that the SCN affects the heart in rats and suggest that this is mediated by a neuronal mechanism.

Trigeminal nociception-induced cerebral Fos expression in the conscious rat.

Little is known about trigeminal nociception-induced cerebral activity and involvement of cerebral structures in pathogenesis of trigeminovascular headaches such as migraine. Neuroimaging has demonstrated cortical, hypothalamic and brainstem activation during the attack and after abolition with sumatriptan. This has led to the conclusion that the dorsal raphe and locus coeruleus may initiate events that generate migraneous headache. Using a conscious rat model of trigeminal nociception and cerebral Fos expression as histochemical markers of neuronal activity, we characterized the pattern of brain activity after noxious trigeminal stimulation with capsaicin (250 and 1000 nm). A significantly increased Fos immunoreactivity was found in the trigeminal nucleus caudalis (layers I and II), the area postrema, the nucleus of the solitary tract, the parvicellular reticular nucleus, the locus coeruleus, the parabrachial nucleus and the raphe nuclei. In addition, the ventrolateral periaqueductal grey, the intralaminar thalamic and various hypothalamic areas, showed an enhanced Fos expression after the intracisternal administration of capsaicin. Other responding areas were the amygdala, the upper lip and forelimb regions of the primary somatosensory cortex, and the insula. Many of these areas participate in (anti)-nociception, although we cannot exclude the possibility that in conscious animals the pain-associated physiological and behavioural responses that are an intrinsic and necessary part of coping with pain have generated the increased Fos expression. Trigeminal stimulation-induced locus coeruleus, dorsal raphe and hypothalamic activation are opposed to a suggested pathogenic role of these nuclei in migraine and cluster headache, respectively.

Limited participation of 5-HT(1A) and 5-HT(2A/2C) receptors in the clozapine-induced Fos-protein expression in rat forebrain regions.

Through the development of tolerance following long-term clozapine treatment, we investigated whether 5-HT(1A) and 5-HT(2A/2C) receptors participate in the clozapine-induced Fos-protein expression in the rat forebrain. Tolerance exists when the acutely increased Fos responses to a challenge dose of the 5-HT(1A) and 5-HT(2A/2C) agonists 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane-hydrochloride (DOI) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), respectively, given simultaneously to rats, are attenuated after 3-week clozapine (20 mg kg(-1) day(-1) i.p.) pretreatment. As compared to the acute effects of clozapine, the Fos responses to concomitant administration of the 5-HT receptor agonists DOI (2.5 mg kg(-1) i.p. ) and 8-OH-DPAT (2.5 mg kg(-1) i.p.) were more pronounced in the prefrontal cortex, the nucleus accumbens core and the dorsomedial and ventromedial striatum, areas in which clozapine (20 mg kg(-1) i. p.) exhibited marginal effects. In the hypothalamic paraventricular nucleus, both clozapine and DOI/8-OH-DPAT induced a remarkably high number of Fos-positive nuclei. Long-term clozapine pretreatment attenuated the acutely induced Fos expression of the 5-HT receptor agonists in the nucleus accumbens core, the dorsomedial and ventromedial parts of the striatum and the lateral septum, indicating (partial) common sites of action of the agents in these brain regions. No tolerance was found in the nucleus accumbens shell and the hypothalamic paraventricular nucleus and the central amygdala, suggesting that the clozapine-induced Fos responses, though distinct in these regions, are independent of 5-HT receptors. The prefrontal cortex and the dorsolateral striatum indicated only a tendency towards tolerance. In addition, the involvement of the tested 5-HT receptor agonists in the clozapine-enhanced release of plasma corticosterone became apparent. The present results indicate that the clozapine-induced patterns of Fos expression in the rat forebrain can only be in part attributed to an interaction with 5-HT(1A/2A/2C) receptors.

Effects of brain death and hemodynamic status on function and immunologic activation of the potential donor liver in the rat.

OBJECTIVE: To assess the effect on the function and immunologic status of potential donor livers of the duration of brain death combined with the presence and absence of hemodynamic instability in the donor. SUMMARY BACKGROUND DATA: Brain death, regarded as a given condition in organ transplantation, could have significant effects on the donor organ quality. METHODS: Brain death was induced in Wistar rats. Short or long periods of brain death in the presence or absence of hemodynamic instability were applied. Sham-operated rats served as controls. Organ function was studied by monitoring standard serum parameters. The inflammatory status of the liver was assessed by determining the immediate early gene products, the expression of cell adhesion molecules, and the influx of leukocytes in the liver. RESULTS: Progressive organ dysfunction was most pronounced in hemodynamically unstable brain-dead donors. Irrespective of hemodynamic status, a progressive inflammatory activation could be observed in brain-dead rats compared with controls. CONCLUSIONS: Brain death causes progressive liver dysfunction, which is made worse by the coexistence of hemodynamic instability. Further, brain death activates the inflammatory status of the potential donor liver, irrespective of the presence of hypotension. The changes observed may predispose the graft to additional damage from ischemia and reperfusion in the transplant procedure.

Intracisternal octreotide does not ameliorate orthodromic trigeminovascular nociception.

Octreotide is a long-acting somatostatin analogue that has been effectively used to treat migraine. Octreotide poorly penetrates the blood-brain barrier, but has potential central target sites in the trigeminal nucleus caudalis, which is the primary central relay station for trigeminal nociceptive information in the brain. We studied the effect of intracisternally applied octreotide in a model of trigeminovascular stimulation in the unrestrained rat using intracisternal capsaicin infusion to stimulate intracranial trigeminal nerves. Fos expression in the outer layers of the trigeminal nucleus caudalis (TNC I-II) and behavioural analysis were used to measure the effects of octreotide on capsaicin-induced trigeminovascular activation. Increases of head grooming and scratching behaviour are an indication of octreotide-induced trigeminal activation. However, octreotide did not alter the average capsaicin-induced Fos expression in the TNC I-II and capsaicin sensitive behaviours were not modified by octreotide pretreatment. This argues against a role for central (TNC I-II) somatostatin receptors in the processing of the nociceptive trigeminovascular signals.