Late-Onset Posttransplant Lymphoproliferative Disorders after Solid Organ Transplantation in Adults: A Case Series and Review of the Literature.

The posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of neoplasms that have wide variety of clinical and histological presentations. The management of PTLDs is challenging due to variety of involvement sites and histological types. The length and type of immunosuppression are correlated with the emergence of PTLDs, and most of the cases appear within the first two years after transplant. This case series describes five late-onset PTLDs with rare histological features and multiorgan involvement.

Electrical stimulation or MK-801 in the inferior colliculus improve motor deficits in MPTP-treated mice.

The inferior colliculus (IC) is an important midbrain relay station for the integration of descending and ascending auditory information. Additionally, the IC has been implicated in processing sensorimotor responses. Glutamatergic and GABAergic manipulations in the IC can improve motor deficits as demonstrated by the animal model of haloperidol-induced catalepsy. However, how the IC influences motor function remains unclear. We investigated the effects of either intracollicular deep brain stimulation (DBS) or microinjection of the glutamatergic antagonist MK-801 or the agonist NMDA in C57BL/6J mice chronically treated with saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After DBS or microinjections, the mice were submitted to rotarod and open field tests, respectively. DBS in the IC was effective to increase the time spent on the rotarod in MPTP-treated mice. After unilateral microinjection of MK-801, but not NMDA, MPTP-treated mice increased the distance travelled in the open field (p < 0.05). In conclusion, intracollicular DBS or MK-801 microinjection can improve motor performance in parkinsonian mice suggesting the IC as a new and non-conventional therapeutic target in motor impairment.

Behavioral facilitation after hippocampal lesion: A review.

When parts of the brain suffer from damage, certain functional deficits or impairments are the expected and typical outcome. A myriad of examples show such negative consequences, which afford the daily tasks of neurologists, neuropsychologists, and also behavioral neuroscientists working with experimental brain lesions. Compared to lesion-induced deficits, examples for functional enhancements or facilitation after brain lesions are rather rare and usually not well studied. Here, the mammalian hippocampus seems to provide an exception, since substantial evidence shows that its damage can have facilitatory behavioral effects under certain conditions. This review will address these effects and their possible mechanisms. It will show that facilitatory effects of hippocampal lesions, although mostly studied in rats, can be found in many mammalian species, that is, they are apparently not species-specific. Furthermore, they can be found with various lesion techniques, from tissue ablation, to neurotoxic damage, and from damage of hippocampal structure itself to damage of fiber systems innervating it. The major emphasis of this review, however, lies on the behavioral effects and their interpretations. Thus, facilitatory effects can be found in several learning paradigms, especially active avoidance, and some forms of Pavlovian and instrumental conditioning. These will be discussed in light of pertinent theories of hippocampal function, such as inhibition, spatial cognition, and multiple memory systems theories, which state that facilitatory effects of hippocampal lesions may reflect the loss of interference between hippocampal spatial and striatal procedural cognition. Using the example of the rat sequential reaction time task, it will also be discussed how such lesions can have direct and indirect consequences on certain behavioral readouts. A final note will advocate considering possible functional facilitation also in neurologic patients, especially those with hippocampal damage, since such a strategy might provide new avenues for therapeutic treatments.

Rethinking psychopharmacotherapy: The role of treatment context and brain plasticity in antidepressant and antipsychotic interventions.

Emerging evidence indicates that treatment context profoundly affects psychopharmacological interventions. We review the evidence for the interaction between drug application and the context in which the drug is given both in human and animal research. We found evidence for this interaction in the placebo response in clinical trials, in our evolving knowledge of pharmacological and environmental effects on neural plasticity, and in animal studies analyzing environmental influences on psychotropic drug effects. Experimental placebo research has revealed neurobiological trajectories of mechanisms such as patients' treatment expectations and prior treatment experiences. Animal research confirmed that "enriched environments" support positive drug effects, while unfavorable environments (low sensory stimulation, low rates of social contacts) can even reverse the intended treatment outcome. Finally we provide recommendations for context conditions under which psychotropic drugs should be applied. Drug action should be steered by positive expectations, physical activity, and helpful social and physical environmental stimulation. Future drug trials should focus on fully controlling and optimizing such drug×environment interactions to improve trial sensitivity and treatment outcome.

Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 μL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

On the relationships between ultrasonic calling and anxiety-related behavior in rats

In the present review, the phenomenon of ultrasonic vocalization in rats will be outlined, including the three classes of vocalizations, namely 40-kHz calls of pups, and 22- and 50-kHz calls of juvenile and adult rats, their general relevance to behavioral neuroscience, and their special relevance to research on anxiety, fear, and defense mechanisms. Here, the emphasis will be placed on 40- and 22-kHz calls, since they are typical for various situations with aversive properties. Among other topics, we will discuss whether such behavioral signals can index a certain affective state, and how these signals can be used in social neuroscience, especially with respect to communication. Furthermore, we will address the phenomenon of inter-individual variability in ultrasonic calling and what we currently know about the mechanisms, which may determine such variability. Finally, we will address the current knowledge on the neural and pharmacological mechanisms underlying 22-kHz ultrasonic vocalization, which show a substantial overlap with mechanisms known from other research on fear and anxiety, such as those involving the periaqueductal gray or the amygdala.

On the relationships between ultrasonic calling and anxiety-related behavior in rats.

In the present review, the phenomenon of ultrasonic vocalization in rats will be outlined, including the three classes of vocalizations, namely 40-kHz calls of pups, and 22- and 50-kHz calls of juvenile and adult rats, their general relevance to behavioral neuroscience, and their special relevance to research on anxiety, fear, and defense mechanisms. Here, the emphasis will be placed on 40- and 22-kHz calls, since they are typical for various situations with aversive properties. Among other topics, we will discuss whether such behavioral signals can index a certain affective state, and how these signals can be used in social neuroscience, especially with respect to communication. Furthermore, we will address the phenomenon of inter-individual variability in ultrasonic calling and what we currently know about the mechanisms, which may determine such variability. Finally, we will address the current knowledge on the neural and pharmacological mechanisms underlying 22-kHz ultrasonic vocalization, which show a substantial overlap with mechanisms known from other research on fear and anxiety, such as those involving the periaqueductal gray or the amygdala.

Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety.

Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 µL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

Dorsal hippocampal lesions boost performance in the rat sequential reaction time task.

It is commonly accepted that the hippocampus plays a major role in declarative memory across species and that it is of particular relevance for spatial memory in rodents. However, the interplay between hippocampal function and nondeclarative memory systems, such as procedural stimulus-response (S-R) or sequential learning, is less clear: depending on task requirements, an interaction, dissociation or interference between hippocampal function and other memory systems may occur. This study was conducted to investigate the influence of dorsal ibotenic hippocampal lesions on learning and performance of sequential behavior in a rat version of the serial reaction time task (SRTT). Magnetic resonance imaging (MRI) analyses of the lesions revealed a bilateral volume reduction of ≈ 46% (histological analyses: ≈ 59%) of the total hippocampus. They were largely confined to its dorsal part and led to an expected spatial memory deficits in an object place recognition test as compared to healthy controls, even though sham lesions had the same effect. Our earlier studies on sequential learning had revealed substantial impairments in case of dorsal striatal dopaminergic lesions. In the present study, however, hippocampal lesioned animals unexpectedly showed superior performance throughout SRTT testing and training as compared to controls, which resulted in a higher degree of subsequent automated sequential behavior. Thus, our data reveal the infrequent case where hippocampal lesions lead to long-term improvements in test performance of a type of rather complex procedural behavior. One possible explanation for this effect is that hippocampal activity in rodents can interfere with other memory systems during the acquisition of procedural tasks with very low spatial requirements, as used here. Alternative explanations for the observed superior SRTT performance in lesioned animals, such as hyperactivity or increased exploratory drive are also topic of the discussion.

Time-dependent in-vivo effects of interleukin-2 on neurotransmitters in various cortices: relationships with depressive-related and anxiety-like behaviour.

We investigated the impact of systemically injected IL-2 (2.5 µg/kg, i.p.) on serotonergic and dopaminergic neurotransmission in various cortical areas by in-vivo microdialysis. IL-2 lastingly reduced extracellular 5-HT levels in the medial prefrontal (-75%), occipital (-70%), and temporal cortices (-45%), whereas dopamine was only moderately reduced in the medial prefrontal cortex. Based on the serotonergic time profile, we conducted further experiments to test for acute and delayed (2 h post injection) depressive-related effects of systemic IL-2 (0-5.0 µg/kg) in a forced swim test and delayed effects on anxiety-like behaviour in the elevated plus-maze. IL-2 had dose-dependent effects on depressive-related behaviour after delayed but not acute testing, but no effects on anxiety-like behaviour.

Using bedding in a test environment critically affects 50-kHz ultrasonic vocalizations in laboratory rats.

Rats utter distinct classes of ultrasonic vocalizations depending on their developmental stage, current state, and situational factors. One class, comprising the so-called 50-kHz calls, is typical for situations where rats are anticipating or actually experiencing rewarding stimuli, like being tickled by an experimenter, or when treated with drugs of abuse, such as the psychostimulant amphetamine. Furthermore, rats emit 50-kHz calls when exposed to a clean housing cage. Here, we show that such vocalization effects can depend on subtle details of the testing situation, namely the presence of fresh rodent bedding. Actually, we found that adult males vocalize more in bedded cages than in bare ones. Also, two experiments showed that adult rats emitted more 50-kHz calls when tickled on fresh bedding. Furthermore, ip amphetamine led to more 50-kHz vocalization in activity boxes containing such bedding as compared to bare ones. The analysis of psychomotor activation did not yield such group differences in case of locomotion and centre time, except for rearing duration in rats tested on bedding. Also, the temporal profile of vocalization did not parallel that of behavioural activation, since the effects on vocalization peaked and started to decline again before those of psychomotor activation. Therefore, 50-kHz calls are not a simple correlate of psychomotor activation. A final experiment with a choice procedure showed that rats prefer bedded conditions. Overall, we assume that bedded environments induce a positive affective state, which increases the likelihood of 50-kHz calling. Based on these findings, we recommend that contextual factors, like bedding, should receive more research attention, since they can apparently decrease the aversiveness of a testing situation. Also, we recommend to more routinely measure rat ultrasonic vocalization, especially when studying emotion and motivation, since this analysis can provide information about the subject's status, which may not be detected in its visible behaviour.

Acquisition and performance in a rat sequential reaction time task is not affected by subtotal ventral striatal 6-OHDA lesions.

Based on findings of experiments with humans, non-human primates and rodents, it is commonly accepted that dopaminergic basal ganglia processes play a crucial role in procedural and sequential learning. Primal evidence for this hypothesis came from serial reaction time tasks (SRTT) studies, demonstrating that healthy controls show increased reaction times when visual stimulus presentation switches from a previously learned sequence to random stimulus presentation. This so-called interference effect was reduced in patients with Parkinson's disease. Since ethical and methodical aspects limit neurobiological research in human subjects, we developed a rat version of the human SRTT, which can be used to study experimentally induced brain damage. In the present experiment we investigated the effects of bilateral 6-OHDA lesions of the ventral striatum on sequential learning. The lesions led to subtotal dopaminergic depletions in the ventral striatum (58-60%) and also minor depletions in the medial neostriatum (32-46%). These lesions impaired task acquisition only moderately and did not worsen sequential performance since lesion and control animals showed a comparable interference effect when the trained sequence was tested against random stimulus presentation or violated sequences. In contrast, in an earlier SRTT experiment with medial neostriatal dopaminergic lesions (58-66%), the lesion animals were clearly impaired in their sequential learning as compared to controls. Therefore, we assume that subtotal dopamine loss in the medial neostriatum, rather than the ventral striatum, has a substantial effect on sequential learning.

Alpha-synuclein deficiency affects brain Foxp1 expression and ultrasonic vocalization.

Alpha-synuclein is an abundant protein implicated in synaptic function and plasticity, but the molecular mechanism of its action is not understood. Missense mutations and gene duplication/triplication events result in Parkinson's disease, a neurodegenerative disorder of old age with impaired movement and emotion control. Here, we systematically investigated the striatal as well as the cerebellar transcriptome profile of alpha-synuclein-deficient mice via a genome-wide microarray survey in order to gain hypothesis-free molecular insights into the physiological function of alpha-synuclein. A genotype-dependent, specific and strong downregulation of forkhead box P1 (Foxp1) transcript levels was observed in all brain regions from postnatal age until old age and could be validated by qPCR. In view of the co-localization and heterodimer formation of FOXP1 with FOXP2, a transcription factor with a well established role for vocalization, and the reported regulation of both alpha-synuclein and FOXP2 expression during avian song learning, we performed a detailed assessment of mouse movements and vocalizations in the postnatal period. While there was no difference in isolation-induced behavioral activity in these animals, the alpha-synuclein-deficient mice exhibited an increased production of isolation-induced ultrasonic vocalizations (USVs). This phenotype might also reflect the reduced expression of the anxiety-related GABA-A receptor subunit gamma 2 (Gabrg2) we observed. Taken together, we identified an early behavioral consequence of alpha-synuclein deficiency and accompanying molecular changes, which supports the notion that the neural connectivity of sound or emotion control systems is affected.

New insights into the relationship of neurogenesis and affect: tickling induces hippocampal cell proliferation in rats emitting appetitive 50-kHz ultrasonic vocalizations.

Adult hippocampal cell proliferation (HCP) has been associated with psychopathology, especially depression. However, it is controversial whether a constitutively low rate of HCP is a trait predisposing an individual to psychopathology or whether HCP varies with the subject's affective state. We made use of a so-far neglected measure of affect, namely ultrasonic vocalizations, to gain new insights into the relationship of HCP and affect. Rats emit distinct types of ultrasonic vocalizations, which serve as situation-dependent affective signals. In appetitive situations, rats produce 50-kHz-calls, whereas 22-kHz-calls occur in aversive situations. We applied a standardized protocol of repeated tickling and assessed tickling-induced ultrasonic vocalizations as an index of the animals affect. Stereological quantifications of 5-bromo-2'-deoxyuridine (BrdU) and proliferating-cells-nuclear-antigen (PCNA) immunolabeled cells were used to estimate the rate of cell proliferation in the subventricular zone and the subgranular zone of the dentate gyrus in the hippocampus. The rate of cell proliferation was compared between the groups of tickled vs. non-tickled rats and between subgroups of tickled rats defined by the effect of tickling on ultrasonic vocalizations. Tickling induced ultrasonic vocalizations in a subject-dependent manner. HCP correlated positively with appetitive 50-kHz-calls, but negatively with aversive 22-kHz-calls in individual animals, while cell proliferation in the subventricular zone was not associated with the emission of ultrasonic vocalizations. Repeated tickling did not change HCP in all rats, but increased HCP in the subgroup of rats, which experienced this procedure as appetitive, i.e. in rats emitting high numbers of 50-kHz-calls or low numbers of 22-kHz-calls. Together, these data indicate that the effect of tickling on HCP depends on an interaction between a predisposing trait and stimulation-dependent variations of the subject's affective state.

Individual behavioral differences in recovery from abdominal sepsis in rats.

OBJECTIVE AND DESIGN: In the present study we determined whether individual behavioral differences (high and low locomotor activity) differentially affected recovery from sepsis with high or low mortality. METHODS: Two trials were performed. Trial 1 with high mortality: Rats were randomly assigned to (1) control-A: anesthesia, (2) control-B: sham surgery, (3) sepsis: laparotomy and peritoneal contamination and infection (PCI) with human stool bacteria, (4) sepsis with antibiotic prophylaxis (cefuroxime/ metronidazole), and (5) sepsis with antibiotic plus G-CSF prophylaxis. Trial 2 with low mortality: Comparison of groups 3 and 5. Endpoints were mortality, behavior (open field and social interaction tests), and proinflammatory cytokines (interleukin-6 = IL-6 and macrophage inflammatory protein-2 = MIP-2). RESULTS: The combination of antibiotics plus G-CSF was most effective in reducing mortality in both trials and modified sickness behavior. Behavioral deficits were not statistically significantly improved by G-CSF. However, high versus low responders were differentially affected in both behavioral tests. Furthermore, IL-6 and MIP-2 were increased 24 hours after inoculum only in high responders with untreated sepsis and high mortality. CONCLUSION: Improvement of sickness behavior in sepsis with G-CSF/antibiotic prophylaxis is a promising approach. The course of recovery from sepsis may depend on premorbid individual differences.

Effects of neostriatal 6-OHDA lesion on performance in a rat sequential reaction time task.

Work in humans and monkeys has provided evidence that the basal ganglia, and the neurotransmitter dopamine therein, play an important role for sequential learning and performance. Compared to primates, experimental work in rodents is rather sparse, largely due to the fact that tasks comparable to the human ones, especially serial reaction time tasks (SRTT), had been lacking until recently. We have developed a rat model of the SRTT, which allows to study neural correlates of sequential performance and motor sequence execution. Here, we report the effects of dopaminergic neostriatal lesions, performed using bilateral 6-hydroxydopamine injections, on performance of well-trained rats tested in our SRTT. Sequential behavior was measured in two ways: for one, the effects of small violations of otherwise well trained sequences were examined as a measure of attention and automation. Secondly, sequential versus random performance was compared as a measure of sequential learning. Neurochemically, the lesions led to sub-total dopamine depletions in the neostriatum, which ranged around 60% in the lateral, and around 40% in the medial neostriatum. These lesions led to a general instrumental impairment in terms of reduced speed (response latencies) and response rate, and these deficits were correlated with the degree of striatal dopamine loss. Furthermore, the violation test indicated that the lesion group conducted less automated responses. The comparison of random versus sequential responding showed that the lesion group did not retain its superior sequential performance in terms of speed, whereas they did in terms of accuracy. Also, rats with lesions did not improve further in overall performance as compared to pre-lesion values, whereas controls did. These results support previous results that neostriatal dopamine is involved in instrumental behaviour in general. Also, these lesions are not sufficient to completely abolish sequential performance, at least when acquired before lesion as tested here.

Behavioral and neurochemical consequences of multiple MDMA administrations in the rat: role of individual differences in anxiety-related behavior.

Using the elevated plus-maze (EPM), Wistar rats can be distinguished into high (HA) or low anxiety (LA) subjects. These differences seem to reflect traits, since HA and LA rats vary also in other anxiety-dependent tasks, neurochemical mechanisms, and psychopharmacological reactivity, including lasting consequences after single treatment with 3,4-methylenedioxymethamphetamine (MDMA). Here, we tested whether multiple MDMA treatments also have subject-dependent effects. Based on routine EPM screening, male Wistar rats were divided into HA and LA sub-groups, which received five (i.e. multiple) daily injections of MDMA (5 mg/kg) or saline, followed by a test battery, including a challenge test with MDMA, a retest in the EPM, a novel-object test, and a final neurochemical analysis. Acutely, MDMA led to comparable hyperactivity in HA and LA rats. After multiple MDMA, behavioral sensitization was observed, especially in LA rats. Open arm time during the EPM retest (min 0-5) correlated with that of the initial one only in those rats, which had received a single injection of MDMA. Rats with multiple MDMA, especially LA-rats, showed more open-arm time and locomotion during the subsequent 5-10 min of the retest. In a novel-object test, rats with multiple MDMA, again especially LA subjects, showed more exploratory bouts towards the novel object. Neurochemically, multiple MDMA led to moderately lower serotonin in the ventral striatum, and higher dopamine levels in the frontal cortex as compared to single MDMA; these effects were also moderated by subject-dependent factors. Our data show that low-dosed multiple MDMA can lead to behavioral sensitization and outlasting consequences, which affect behavior in the EPM and a novel object task. Detecting such sequels partly requires consideration of individual differences.

Rat ultrasonic vocalization in aversively motivated situations and the role of individual differences in anxiety-related behavior.

Our previous work has shown that male Wistar rats, although identical in breeder, age and housing conditions, can differ systematically in their anxiety-related behavior as measured in the elevated plus-maze. Since such individual dispositions can affect the responsiveness in other aversively motivated situations, we asked in a 1st experiment whether such rats might also differ in a test of conditioned fear. Based on their levels of spontaneous open arm avoidance in the elevated plus-maze, 20 adult male Wistar rats were divided into those with "high open arm" (HOA) versus "low open arm" (LOA) time. These rats were then tested in a standard fear conditioning paradigm. During the conditioning procedure, they received 6 tone (3 kHz, 20 s) and shock (0.5 mA, 0.5 s) pairings, each followed by a 60 s inter-stimulus interval. Conditioned responses to the tone were tested 24 h thereafter. During both days, freezing behavior and ultrasonic vocalization were measured. Differences in ultrasonic vocalization between HOA and LOA rats were detected during the conditioning day, where vocalization was more likely in LOA rats. Furthermore, LOA rats emitted calls with higher frequency components than HOA rats. On the subsequent day of testing, the number of animals vocalizing, and the rate of vocalization was decreased, and call differences between groups were no longer detectable. In freezing, differences between HOA and LOA rats were observed on the conditioning day, where LOA rats showed more freezing behavior during the tone/shock intervals. Also, on the test day, they showed more freezing behavior during the tone intervals compared to HOA rats. These results indicate that acute and conditioned responses of rats in a conventional fear conditioning paradigm can depend on individual dispositions of anxiety-related behavior as measured with the elevated plus-maze. In a 2nd experiment, we asked whether exposure to an elevated plus-maze would lead to ultrasonic vocalization, which we tested in rats which had been handled or non-handled prior to testing. Most importantly, we found that none of the animals displayed any vocalization in the plus-maze, neither during a 1st nor a repeated test 1 day later. These data are discussed with respect to the presumed role of ultrasonic vocalization in aversively motivated situations, and the mechanisms, which may account for the behavioral differences between HOA and LOA rats in such tests.

Sickness behavior of rats with abdominal sepsis can be improved by antibiotic and G-CSF prophylaxis in clinic modeling randomized trials.

BACKGROUND AND AIM: In clinical sepsis research nearly all immune-modulators have demonstrated no benefit in regard to the 28-day mortality rate. Other endpoints such as quality of life have become more attractive, but clinically relevant animal models analyzing an equivalent to quality of life by measurement of sickness behavior are extremely rare. The concept of clinic modeling randomized trials was used in an animal trial to model clinical complexity and conditions of a randomized clinical trial. METHODS: 80 adult male Wistar rats were randomly assigned to (1) control: anesthesia and sham operation, (2) sepsis: laparotomy and peritoneal infection with human stool bacteria, (3) sepsis with antibiotic prophylaxis: cefuroxime/metronidazole and (4) sepsis with antibiotic plus a cytokine prophylaxis with granulocyte-colony stimulating factor (GCSF). Endpoints were physiological and behavioral parameters. RESULTS: The combination of antibiotics plus G-CSF was most effective in reducing mortality. All infected animals showed reduced open field activity acutely after infection, and recovery was improved during the 9 day follow-up in rats with prophylactic treatments. In the social interaction test, but not in the elevated plus-maze anxiety test, prophylaxis was also efficient, especially with antibiotics and G-CSF. CONCLUSIONS: The results show that improving sickness behavior in septic rats with G-CSF plus antibiotics may be a promising approach.

Open field habituation learning is improved by nicotine and attenuated by mecamylamine administered posttrial into the nucleus accumbens.

Using the paradigm of habituation learning in the open field, we tested the effects of unilateral microinjections of the agonist nicotine (8.0, 40.0, and 80.0 microg) and the nicotine receptor antagonist mecamylamine (0.1, 1.0, 10.0 microg) into the core of the nucleus accumbens. When injected posttrial, that is, immediately after the first exposure to the open field, nicotine dose-dependently enhanced behavioral habituation during the test on the following day, indicating a facilitation of memory, whereas mecamylamine impaired habituation at the highest dose, but not at the two lower doses. When injected 5 h after the learning trial, nicotine (40 microg) and mecamylamine (10 microg) impaired habituation on the subsequent day. A control experiment did not provide evidence for possible proactive effects of mecamylamine. These findings are discussed with respect to the possible behavioral functions of cholinergic, and especially nicotinic, mechanisms in the nucleus accumbens. They may also be relevant for understanding cholinergic-linked psychopathologies such as Alzheimer's disease, since the nucleus accumbens is one of the sites where cholinergic neurons are lost in this neurodegenerative disease.