Effects of aspirin dose escalation on platelet function and urinary thromboxane and prostacyclin levels in normal dogs.

Established "low" aspirin dosages inconsistently inhibit platelet function in dogs. Higher aspirin dosages consistently inhibit platelet function, but are associated with adverse effects. The objectives of this study were to use an escalation in dosage to determine the lowest aspirin dosage that consistently inhibited platelet function without inhibiting prostacyclin synthesis. Eight dogs were treated with five aspirin dosages: 0.5 mg/kg q24h, 1 mg/kg q24h, 2 mg/kg q24h, 4 mg/kg q24h and 10 mg/kg q12h for 7 days. Utilizing aggregometry and a whole-blood platelet function analyzer (PFA-100), platelet function was evaluated before and after treatment. Urine 11-dehydro-thromboxane-B2 (11-dTXB2 ) and 6-keto-prostaglandin-F1α (6-keto-PGF1α ), were measured. Compared to pretreatment, there were significant post-treatment decreases in the maximum aggregometry amplitude and increases in the PFA-100 closure times for all dosages expect 0.5 mg/kg q24h. There was no difference in amplitude or closure time among the 2 mg/kg q24h, 4 mg/kg q24h, and 10 mg/kg q12h dosages. Compared to pretreatment values, there was a significant decrease in urinary 11-dTXB2 -to-creatinine and 6-keto-PGF1α -to-creatinine ratios, but there was no dose-dependent decrease for either metabolite. An aspirin dosage of 2 mg/kg q24h consistently inhibits platelet function without decreasing prostacyclin synthesis significantly more than lower aspirin dosages.

The effects of clopidogrel and omeprazole on platelet function in normal dogs.

Omeprazole is used concurrently with clopidogrel to reduce gastrointestinal adverse effects. In humans, the concurrent use of these two drugs can reduce the antiplatelet efficacy of clopidogrel. Our objective was to determine the effects of omeprazole and clopidogrel on platelet function in healthy dogs. A crossover study utilized turbidimetric aggregometry (ADP and collagen) and the PFA-100® with the collagen/ADP cartridge to evaluate platelet function in eight healthy dogs during the administration of clopidogrel (1 mg/kg/24 h p.o.), omeprazole (1 mg/kg/24 h p.o.), and a combination of clopidogrel and omeprazole. Drug metabolite concentrations were also measured. Compared to pretreatment, on Days 3 and 5, with ADP as the agonist, there was a significant decrease in maximum amplitude on aggregometry for both clopidogrel and clopidogrel/omeprazole groups. The following revealed no significant differences between clopidogrel and clopidogrel/omeprazole groups when compared on Days 3 and 5: maximum amplitude on aggregometry with ADP or collagen agonists, and PFA-100® closure times. When compared to the clopidogrel group, clopidogrel metabolite concentrations in the clopidogrel/omeprazole group were significantly higher on Days 3 and 5. The concurrent administration of omeprazole and clopidogrel in healthy dogs was associated with an increase in the plasma concentration of an inactive metabolite of clopidogrel, but does not significantly alter the antiplatelet effects of clopidogrel.

Effects of oral cyclosporine on canine T-cell expression of IL-2 and IFN-gamma across a 12-h dosing interval.

The duration of immunosuppressive effects following oral cyclosporine in dogs is unknown. This study used flow cytometry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to evaluate the effects of high-dose oral cyclosporine across a 12-h dosing interval. Expression of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) was compared before and after 8 days of cyclosporine at 10 mg/kg every 12 h in six healthy dogs. Samples were collected at 0, 2, 4, and 8 h postdosing for analysis of unactivated and activated T-cell and whole blood cytokine expression using flow cytometry and qRT-PCR, respectively, and at 0, 2, 4, 6, 8, and 10 h postdosing for measurement of cyclosporine concentrations. Flow cytometry and qRT-PCR both demonstrated significant marked reductions in IL-2 and IFN-γ levels at 0, 2, 4, and 8 h after dosing compared to pretreatment levels (P < 0.05) for activated samples, with less consistent effects observed for unactivated samples. Both flow cytometry and qRT-PCR are viable techniques for measuring cyclosporine pharmacodynamics in dogs, yielding comparable results with activated samples. Two hours postdrug administration is the preferred time for concurrent assessment of peak drug concentration and cytokine expression, and T-cell activation is needed for optimal results.

Physical exercise intervention in depressive disorders: meta-analysis and systematic review.

Previous meta-analyses investigating the effect of exercise on depression have included trials where the control condition has been categorized as placebo despite the fact that this particular placebo intervention (e.g., meditation, relaxation) has been recognized as having an antidepressant effect. Because meditation and mindfulness-based interventions are associated with depression reduction, it is impossible to separate the effect of the physical exercise from the meditation-related parts. The present study determined the efficacy of exercise in reducing symptoms of depression compared with no treatment, placebo conditions or usual care among clinically defined depressed adults. Of 89 retrieved studies, 15 passed the inclusion criteria of which 13 studies presented sufficient information for calculating effect sizes. The main result showed a significant large overall effect favoring exercise intervention. The effect size was even larger when only trials that had used no treatment or placebo conditions were analyzed. Nevertheless, effect size was reduced to a moderate level when only studies with high methodological quality were included in the analysis. Exercise may be recommended for people with mild and moderate depression who are willing, motivated, and physically healthy enough to engage in such a program.

Pharmacokinetic evaluation of oral dantrolene in the dog.

The pharmacokinetics of dantrolene and its active metabolite, 5-hydroxydantrolene, after a single oral dose of either 5 or 10 mg/kg of dantrolene was determined. The effects of exposure to dantrolene and 5-hydroxydantrolene on activated whole-blood gene expression of the cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ) were also investigated. When dantrolene was administered at a 5 mg/kg dose, peak plasma concentration (Cmax ) was 0.43 µg/mL, terminal half-life (t1/2 ) was 1.26 h, and area under the time-concentration curve (AUC) was 3.87 µg·h/mL. For the 10 mg/kg dose, Cmax was 0.65 µg/mL, t1/2 was 1.21 h, and AUC was 5.94 µg·h/mL. For all calculated parameters, however, there were large standard deviations and wide ranges noted between and within individual dogs: t1/2 , for example, ranged from 0.43 to 6.93 h, Cmax ratios ranged from 1.05 to 3.39, and relative bioavailability (rF) values ranged from 0.02 to 1.56. While activated whole-blood expression of IL-2 and IFN-γ as measured by qRT-PCR was markedly suppressed following exposure to very high concentrations (30 and 50 µg/mL, respectively) of both dantrolene and 5-hydroxydantrolene, biologically and therapeutically relevant suppression of cytokine expression did not occur at the much lower drug concentrations achieved with oral dantrolene dosing.

Physical exercise ameliorates deficits induced by traumatic brain injury.

The extent and depth of traumatic brain injury (TBI) remains a major determining factor together with the type of structural insult and its location, whether mild, moderate or severe, as well as the distribution and magnitude of inflammation and loss of cerebrovascular integrity, and the eventual efficacy of intervention. The influence of exercise intervention in TBI is multiple, ranging from anti-apoptotic effects to the augmentation of neuroplasticity. Physical exercise diminishes cerebral inflammation by elevating factors and agents involved in immunomodulatory function, and buttresses glial cell, cerebrovascular, and blood-brain barrier intactness. It provides unique non-pharmacologic intervention that incorporate different physical activity regimes, whether dynamic or static, endurance or resistance. Physical training regimes ought necessarily to be adapted to the specific demands of diagnosis, type and degree of injury and prognosis for individuals who have suffered TBI.

Physical exercise alleviates debilities of normal aging and Alzheimer's disease.

Both healthy aging and the pathologic incidence of disorders associated with aging involve an array of debilities. Physical exercise harnesses implicit and inherent biologic characteristics amenable to the putative interventional influences under clinical, institutional or laboratory conditions. The neurodegenerative and pathophysiologic progressions that constitute Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), normal aging, and different animal models of AD have shown the existence of several putative mechanisms. A large variety of moderating factors have demonstrated that the ever-proliferating plethora of neurotrophic factors, neurogenesis as observed through generality of expression and neuronal arborization. The insistent efficacy of brain vascular angiogenesis may delay also the comorbid incidence of depressive disorders with dementia pathology. The pathogenesis of aging may be contained by selective treatments: these diverse conditions, linked to the basis of the aging concept, have been shown, to greater or lesser extents, to respond to a variety of scheduled applications of physical exercise. The range of reports that provide accounts of the mechanisms mediating the positive progressive response to exercise intervention is far-ranging; these studies indicate that subtle changes at molecular, neuronal, vascular and epigenetic levels may exert notable consequence at functional expression and, perhaps most essentially, offer convincing expectancy of significant benefits.

Exercise alleviates Parkinsonism: clinical and laboratory evidence.

The present review examines the putative benefits for individuals afflicted with Parkinsonism, whether in the clinical setting or in the animal laboratory, accruing from different exercise regimes. The tendency for patients with Parkinson's disease (PD) to express either normal or reduced exercise capacity appears regulated by factors such as fatigue, quality-of-life and disorder severity. The associations between physical exercise and risk for PD, the effects of exercise on idiopathic Parkinsonism and quality-of-life, the effects of exercise on animal laboratory models of Parkinsonism and dopamine (DA) loss following neurotoxic insults, and the effects of exercise on the DA precursor, L-Dopa, efficacy are examined. It would appear to be case that in view of the particular responsiveness of the dopaminergic neurons to exercise, the principle of 'use it or lose' may be of special applicability among PD patients.

Transcription factor loading on the MMTV promoter: a bimodal mechanism for promoter activation.

The mouse mammary tumor virus (MMTV) promoter attains a phased array of six nucleosomes when introduced into rodent cells. This architecture excludes nuclear factor 1/CCAAT transcription factor (NF1/CTF) from the promoter before glucocorticoid treatment and hormone-dependent access of nucleolytic agents to promoter DNA. In contrast, when the promoter was transiently introduced into cells, NF1/CTF was bound constitutively and nucleolytic attack was hormone-independent. Thus, induction at this promoter was a bimodal process involving receptor-dependent remodeling of chromatin that allows NF1/CTF loading and direct receptor-mediated recruitment of additional transcription factors.

Affective personality as cognitive-emotional presymptom profiles regulatory for self-reported health predispositions.

Three studies that examined the links between affective personality, as constructed from responses to the Positive Affect (PA) and Negative Affect (NA) Scale (PANAS), and individuals' self-report of self-esteem, intrinsic motivation and Beck's Depression Inventory (BDI) depression in high school students and persons in working occupations are described. Self-report estimations of several other neuropsychiatric and psychosocial variables including, the Uppsala Sleep Inventory (USI), the Hospital Anxiety and Depression (HAD) test, Dispositional optimism, Locus of control, the Subjective Stress Experience test (SSE) and the Stress-Energy (SE) test, were also derived. Marked effects due to affective personality type upon somatic and psychological stress, anxiety and depression, self-esteem, internal and external locus of control, optimism, stress and energy, intrinsic motivation, external regulation, identified regulation, major sleep problems, problems falling asleep, and psychophysiological problems were observed; levels of self-esteem, self-motivation and BDI-depression all produced substantial effects on health and well-being. Regression analyses indicated PA was predicted by dispositional optimism (thrice), energy (thrice), and intrinsic motivation, and counter predicted by depression (twice) and stress (twice); and NA by anxiety (twice), stress (twice), psychological stress, identified regulation, BDI depression and psychophysiological problems, and counter predicted by internal locus of control and self-esteem. BDI-depression was predicted by negative affect, major sleep problems and psychophysiological problems (Study III), self-esteem by dispositional optimism and energy, and counter predicted by anxiety, depression and stress (Study I), and intrinsic motivation by dispositional optimism, energy, PA and self-esteem (Study II). These convergent findings are interpreted from a perspective of the cognitive-emotional expressions underlying behavioural or presymptomatic profiles presenting predispositions for health or ill health.

Focusing on symptoms rather than diagnoses in brain dysfunction: conscious and nonconscious expression in impulsiveness and decision-making.

Symptoms and syndromes in neuropathology, whether expressed in conscious or nonconscious behaviour, remain imbedded in often complex diagnostic categories. Symptom-based strategies for studying brain disease states are driven by assessments of presenting symptoms, signs, assay results, neuroimages and biomarkers. In the present account, symptom-based strategies are contrasted with existing diagnostic classifications. Topics include brain areas and regional circuitry underlying decision-making and impulsiveness, and motor and learned expressions of explicit and implicit processes. In three self-report studies on young adult and adolescent healthy individuals, it was observed that linear regression analyses between positive and negative affect, self-esteem, four different types of situational motivation: intrinsic, identified regulation, extrinsic regulation and amotivation, and impulsiveness predicted significant associations between impulsiveness with negative affect and lack of motivation (i.e., amotivation) and internal locus of control, on the one hand, and non-impulsiveness with positive affect, self-esteem, and high motivation (i.e., intrinsic motivation and identified regulation), on the other. Although presymptomatic, these cognitive-affective characterizations illustrate individuals' choice behaviour in appraisals of situations, events and proclivities essentially of distal perspective. Neuropathological expressions provide the proximal realities of symptoms and syndromes with underlying dysfunctionality of brain regions, circuits and molecular mechanisms.

In vivo effects of aspirin and cyclosporine on regulatory T cells and T-cell cytokine production in healthy dogs.

Cyclosporine and aspirin are routinely used in combination to treat immune-mediated hemolytic anemia (IMHA) in dogs. Cyclosporine is a potent immunosuppressive agent that targets T cell production of the cytokines IL-2 and IFN-γ. Low-dose aspirin is often used to inhibit platelet function in dogs with IMHA, since these animals are prone to life-threatening thromboembolic disease. In rodents and humans, aspirin and cyclosporine have both been shown to variably affect T cell cytokine production, and also numbers of circulating regulatory T cells (Tregs). In dogs, it has not yet been determined if concurrent aspirin alters the effects of cyclosporine on T-cell cytokine expression, or if either drug influences Treg numbers. In a crossover study, seven healthy young adult dogs were given either oral high-dose cyclosporine (10 mg/kg Q12 h), oral low-dose aspirin (1 mg/kg Q24 h), oral high-dose aspirin (10 mg/kg Q12 h), or combined low-dose aspirin with cyclosporine, each for 8 days, with a washout of at least 2 weeks after each treatment. Activated T cell cytokine expression (IL-2 & IFN-γ) and percent CD4 + CD25 + FOXP3+ Tregs were evaluated using flow cytometry, both prior to and on the last day of treatment. The difference between pre- and post-treatment values for each group, as well as the difference between treatment groups, was evaluated. Cyclosporine significantly decreased IL-2 and IFN-γ expression when used alone or in combination with low-dose aspirin. High-dose aspirin, but not low-dose aspirin, also significantly decreased IL-2 expression, although the decrease was not as marked as that seen with cyclosporine alone or in combination with aspirin. Neither low-dose nor high-dose aspirin significantly affected IFN-γ expression. No drug or drug combination affected Treg numbers. Low-dose aspirin given with cyclosporine creates the same degree of T-cell cytokine suppression as does cyclosporine alone, suggesting that the two drugs can be used concurrently without significantly altering the immunosuppressive mechanism of action of cyclosporine.

Evaluation of SNAP cPL, Spec cPL, VetScan cPL Rapid Test, and Precision PSL Assays for the Diagnosis of Clinical Pancreatitis in Dogs.

BACKGROUND: The sensitivity, specificity, and agreement of 4 diagnostic assays (SNAP canine pancreatic lipase (cPL), specific cPL (Spec cPL), VetScan cPL Rapid Test, and Precision PSL) for pancreatitis in dogs have not been directly compared. HYPOTHESIS/OBJECTIVES: To determine the level of agreement among each of the 4 assays and a clinical suspicion score, level of agreement among the assays, and sensitivity and specificity of each assay in a clinically relevant patient group. ANIMALS: Fifty client-owned dogs with clinical signs of gastrointestinal disease. METHODS: Prospective study. History, physical examination, complete blood count, serum biochemistry, abdominal ultrasound examination, and the 4 diagnostic assays for pancreatitis were performed. Intraclass correlation coefficients (ICC) were used to determine the level of agreement between each assay and a clinical suspicion score determined by a panel of 5 board-certified veterinary internists. RESULTS: The ICC between the clinical suspicion score and the 4 assays were SNAP cPL, 0.61; Spec cPL, 0.68; VetScan cPL Rapid Test, 0.68; and Precision PSL, 0.60. The sensitivities of the assays ranged from 73.9 to 100.0%, whereas the specificities were SNAP cPL, 71.1-77.8%; Spec cPL, 74.1-81.1%; VetScan cPL Rapid Test, 76.9-83.8%; and Precision PSL, 64.0-74.3%. CONCLUSIONS AND CLINICAL IMPORTANCE: A good to excellent level of agreement was demonstrated among the 4 assays. The previously unreported sensitivity and specificity of the VetScan cPL Rapid Test were 73.9-83.3% and 76.9-83.8%, respectively. Results of any of the 4 diagnostic assays alone, in the absence of supporting clinical findings, are insufficient to establish a diagnosis of clinical pancreatitis in dogs.

Short-term tissue decomposition alters stable isotope values and C:N ratio, but does not change relationships between lipid content, C:N ratio, and Δδ13C in marine animals.

Measures (e.g. δ15N, δ13C, %C, %N and C:N) derived from animal tissues are commonly used to estimate diets and trophic interactions. Since tissue samples are often exposed to air or kept chilled in ice over a short-term during sample preparation, they may degrade. Herein, we hypothesize that tissue decomposition will cause changes in these measures. In this study, we kept marine fish, crustacean and mollusc tissues in air or ice over 120 h (5 days). We found that tissue decomposition in air enriched δ15N (range 0.6‰ to 1.3‰) and δ13C (0.2‰ to 0.4‰), decreased %N (0.47 to 3.43 percentage points from staring values of ~13%) and %C (4.53 to 8.29 percentage points from starting values of ~43%), and subsequently increased C:N ratio (0.14 to 0.75). In air, while such changes to δ13C were relatively minor and therefore likely tolerable, changes in δ15N, %N, %C and C:N ratio should be interpreted with caution. Ice effectively reduced the extent to which decomposition enriched δ15N (≤ 0.4‰) and δ13C (≤ 0.2‰), and eliminated decomposition in C:N ratio, %N and %C. In our second experiment, for fish tissues in either air or ice over 120 h, we observed no effects of decomposition on relationships between lipid content, C:N ratio, and Δδ13C (change in δ13C after lipid removal), which are employed to correct δ13C for samples containing lipid. We also confirmed that lipid in tissues caused large errors when estimating δ13C (mean ± standard error = -1.8‰ ± 0.1‰, range -0.6‰ to -3.8‰), and showed both lipid extraction and mathematical correction performed equally well to correct for lipids when estimating δ13C. We, therefore, recommend that specimens of marine animals should be kept in ice during sample preparation for a short-term, as it is an effective means for minimizing changes of the stable isotope measures in their tissue.

Nucleosome-mediated disruption of transcription factor-chromatin initiation complexes at the mouse mammary tumor virus long terminal repeat in vivo.

Glucocorticoid induction of mouse mammary tumor virus (MMTV) is short lived, returning to base levels within 24 h despite the continued presence of hormone. MMTV DNA sequences assembled as chromatin require hormone for binding by nuclear factor 1 (NF1) and octamer proteins (OCT). However, in the same cells, NF1 and OCT factors are bound to transiently introduced DNA in the absence of hormone. In contrast, recruitment of the TATA-binding protein and a novel DNA-binding protein, which we have designated FDT, for factor downstream of the TATA-binding protein, is hormone dependent for both stable and transient templates. Furthermore, transient DNA templates, but not nucleosomal templates, retain these transcription factors over the course of 24 h. This finding suggests that MMTV chromatin structure contributes to activation and cessation of transcription in vivo.

Transcription factor access is mediated by accurately positioned nucleosomes on the mouse mammary tumor virus promoter.

A fragment of the mouse mammary tumor virus (MMTV) promoter was reconstituted from pure histones into a dinucleosome with uniquely positioned octamer cores. Core boundaries for the in vitro-assembled dinucleosome corresponded to the observed in vivo phasing pattern for long terminal repeat nucleosomes A and B. Nuclear factor 1 (NF1), a constituent of the MMTV transcription initiation complex, was excluded from the assembled dinucleosome, whereas the glucocorticoid receptor was able to bind. During transcription of MMTV in vivo, displacement of nucleosome B was necessary to permit assembly of the initiation complex. These results indicate that the nucleoprotein structure of the promoter can provide differential access to sequence-specific DNA-binding proteins and that active chromatin remodeling can occur during transcription activation.

Mouse mammary tumor virus chromatin in human breast cancer cells is constitutively hypersensitive and exhibits steroid hormone-independent loading of transcription factors in vivo.

We have stably introduced a reporter gene under the control of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) into human T47D breast cancer cells to study the action of the progesterone receptor (PR) on transcription from a chromatin template. Unexpectedly, the chromatin organization of the MMTV LTR in these human breast cancer cells differed markedly from what we have observed previously. The region adjacent to the transcription start site (-221 to -75) was found to be constitutively hypersensitive to restriction enzyme cleavage in the absence of hormone. This region is normally encompassed within the second nucleosome of a phased array of six nucleosomes that is assembled when the MMTV LTR is stably maintained in mouse cells. Characteristically, in these rodent cells, the identical DNA sequences show increased restriction enzyme cleavage only in the presence of glucocorticoid. The increased access of restriction enzymes observed in the human PR+ cells was not observed in adjacent nucleosomes and was unaffected by treatment with the progesterone antagonist RU486. In addition, exonuclease III-dependent stops corresponding to the binding sites for nuclear factor 1 and the PR were observed before and after hormone treatment. These results indicate that MMTV chromatin replicated in these cells is organized into a constitutively open architecture and that this open chromatin state is accompanied by hormone-independent loading of a transcription factor complex that is normally excluded from uninduced chromatin.

Histone H1 phosphorylation by Cdk2 selectively modulates mouse mammary tumor virus transcription through chromatin remodeling.

Transcriptional activation of the mouse mammary tumor virus (MMTV) promoter by ligand-bound glucocorticoid receptor (GR) is transient. Previously, we demonstrated that prolonged hormone exposure results in displacement of the transcription factor nuclear factor 1 (NF1) and the basal transcription complex from the promoter, the dephosphorylation of histone H1, and the establishment of a repressive chromatin structure. We have explored the mechanistic link between histone H1 dephosphorylation and silencing of the MMTV promoter by describing the putative kinase responsible for H1 phosphorylation. Both in vitro kinase assays and in vivo protein expression studies suggest that in hormone-treated cells the ability of cdk2 to phosphorylate histone H1 is decreased and the cdk2 inhibitory p21 protein level is increased. To address the role of cdk2 and histone H1 dephosphorylation in the silencing of the MMTV promoter, we used potent cdk2 inhibitors, Roscovitine and CVT-313, to generate an MMTV promoter which is associated predominantly with the dephosphorylated form of histone H1. Both Roscovitine and CVT-313 block phosphorylation of histone H1 and, under these conditions, the GR is unable to remodel chromatin, recruit transcription factors to the promoter, or stimulate MMTV mRNA accumulation. These results suggest a model where cdk2-directed histone H1 phosphorylation is a necessary condition to permit GR-mediated chromatin remodeling and activation of the MMTV promoter in vivo.

A specificity and targeting subunit of a human SWI/SNF family-related chromatin-remodeling complex.

The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. This family includes BAF (also called hSWI/SNF-A) and PBAF (hSWI/SNF-B) from humans and SWI/SNF and Rsc from Saccharomyces cerevisiae. However, the relationship between the human and yeast complexes is unclear because all human subunits published to date are similar to those of both yeast SWI/SNF and Rsc. Also, the two human complexes have many identical subunits, making it difficult to distinguish their structures or functions. Here we describe the cloning and characterization of BAF250, a subunit present in human BAF but not PBAF. BAF250 contains structural motifs conserved in yeast SWI1 but not in any Rsc components, suggesting that BAF is related to SWI/SNF. BAF250 is also a homolog of the Drosophila melanogaster Osa protein, which has been shown to interact with a SWI/SNF-like complex in flies. BAF250 possesses at least two conserved domains that could be important for its function. First, it has an AT-rich DNA interaction-type DNA-binding domain, which can specifically bind a DNA sequence known to be recognized by a SWI/SNF family-related complex at the beta-globin locus. Second, BAF250 stimulates glucocorticoid receptor-dependent transcriptional activation, and the stimulation is sharply reduced when the C-terminal region of BAF250 is deleted. This region of BAF250 is capable of interacting directly with the glucocorticoid receptor in vitro. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.

Behavioural supersensitivity following neonatal 6-hydroxydopamine: attenuation by MK-801.

Male rat pups were administered 6-hydroxydopamine (6-OHDA, 75 microg, intracisternally, 30 min after desipramine, 25 mg/kg, s.c.) on Days 1 or 2 after birth, or were sham-operated (receiving vehicle). In four experiments, the acute effects of apomorphine, with or without pretreatment with MK-801 (0.03 mg/kg), upon motor activity in test chambers was measured. Acute treatment with apomorphine (0.1 mg/kg) increased locomotor, rearing and total activity markedly compared to both the acute saline administered 6-OHDA rats and the sham-operated rats administered saline. Acute MK-801 (0.03 mg/kg) co-administered shortly before (5 min) apomorphine (0.3 or 1.0 mg/kg) reduced markedly locomotion and total activity in 6-OHDA-treated and sham-operated rats. Rearing behaviour was increased in both the 6-OHDA groups of rats. Acute MK-801 increased activity in the 6-OHDA-treated rats, which was not observed in sham-operated rats. At the 0.3 and 1.0 mg/kg doses of apomorphine, neonatal 6-OHDA treatment increased all three parameters of motor activity. Acute treatment with apomorphine (0.1 mg/kg) induced different effects on the motor activity of 6-OHDA-treated and sham-operated mice. In sham-operated rats apomorphine reduced motor activity during the 1st 30-min period but increased locomotion and total activity, but not rearing, during the 2nd and 3rd periods, whereas in 6-OHDA-treated rats, apomorphine increased locomotor, rearing and total activity markedly. Dopamine loss and serotonin elevation in the striatum and olfactory tubercle were confirmed. The present findings confirm the influence of non-competitive glutamate antagonists in attenuating the behavioural supersensitivity to dopamine antagonists.