Donor to recipient age matching in lung transplantation: A European experience.

BACKGROUND: The age profile of organ donors and patients on lung transplantation (LT) waiting lists have changed over time. In Europe, the donor population has aged much more rapidly than the recipient population, making allocation decisions on lungs from older donors common. In this study we assessed the impact of donor and recipient age discrepancy on LT outcomes in the UK and France. METHODS: A retrospective analysis of all adult single or bilateral LT in France and the UK between 2010 and 2021. Recipients were stratified into 3 age author groups: young (≤30 years), middle-aged (30-60) and older (≥60). Their donors were also stratified into 2 groups <60, ≥60. Primary graft dysfunction (PGD) rates and recipient survival was compared between matched and mismatched donor and recipient age groups. Propensity matching was employed to minimize covariate imbalances and to improve the internal validity of our results. RESULTS: Our study cohort was 4,696 lung transplant recipients (LTRs). In young and older LTRs, there was no significant difference in 1 and 5-year post-transplant survival dependent on the age category of the donor. Young LTRs who received older donor grafts had a higher risk of severe grade 3 PGD. CONCLUSION: Our findings show that clinically usable organs from older donors can be utilized safely in LT, even for younger recipients. Further research is needed to assess if the higher rate of PGD3 associated with use of older donors has an effect on long-term outcomes.

Relationship between sensitive skin and sleep disorders, fatigue, dust, sweating, food, tobacco consumption or female hormonal changes: Results from a worldwide survey of 10 743 individuals.

BACKGROUND: Sensitive skin is related to environmental factors. OBJECTIVES: We aimed to investigate the roles of poorly known associated and triggering factors on sensitive skin in a large global population. METHODS: A survey was administrated to a representative sample of the adult population aged 18-75 years in five different countries (Brazil, China, France Russia, and the United States). All participants answered a web-based questionnaire on sociodemographic characteristics, sensitive skin and environmental factors. RESULTS: Among the 10 743 included individuals (5285 men and 5458 women), 48.2% declared that they had sensitive skin. The group with sensitive skin reported significant increases in fatigue, dust or sweating and to a lesser extent food or tobacco consumption. The members of this group also declared that they experienced more sleep disorders than individuals without sensitive skin. Sensitive skin was very frequent in pregnant women, women with painful menstruations or women using contraceptive pills. CONCLUSIONS: This large cohort study identified new factors, including female hormonal status, fatigue, sleep disorders and food, associated with sensitive skin. These associations suggest that sensitive skin is not restricted to an epidermal disorder but may be included in a larger context. The identified factors are potential upstream drivers of neurogenic inflammation in sensitive skin.

Chronic disseminated candidiasis and acute leukemia: Impact on survival and hematopoietic stem cell transplantation agenda.

OBJECTIVES: To study the management of chronic disseminated candidiasis (CDC) in patients presenting with acute leukemia. PATIENTS AND METHODS: Single-center retrospective study of acute leukemia patients (2006-2015) to investigate three aspects of CDC: its impact on the time interval between diagnosis and hematopoietic stem cell transplantation, when required (non-parametric Wilcoxon-Mann-Whitney test); its impact on overall survival (Cox proportional hazard regression model); antifungal therapeutic strategies implemented. RESULTS: A total of 639 patients presenting with acute leukemia were included; 144 were transplanted and 29 developed CDC. CDC did not significantly increase the time interval between diagnosis and transplantation, nor did it impact the overall survival of recipients. An improved overall survival was observed in non-transplanted acute leukemia patients presenting with CDC. CONCLUSION: CDC should not postpone transplantation if antifungal treatment is optimized.

Suggestive evidence of a role of HLA-DRB4 mismatches in the outcome of allogeneic hematopoietic stem cell transplantation with HLA-10/10-matched unrelated donors: a French-Swiss retrospective study.

We have conducted a retrospective study on 251 patients from three centers in France and Switzerland between 2004 and 2010 with the goal to evaluate the impact of HLA-DRB3/B4/B5 allele mismatching after HLA-10/10-matched unrelated allogeneic hematopoietic stem cell transplantation (HSCT). Fourteen (5.5%) patients receiving HSCT from an HLA-10/10-matched unrelated donor had a mismatched DRB4 donor, 23 (9.5%) patients had a mismatched DRB3 donor and 214 (85%) had a fully matched unrelated donor (HLA-10/10) without DRB3- or DRB4-mismatched donor. We compared the outcomes of 37 patients with a DRB3 or DRB4 mismatch with the rest of the population. The median survival for a patient without DRB3/4 mismatch was 18 months (95% confidence interval (CI), 13-29), for DRB3-mismatched patients 32 months (95% CI, 13-NR) and for DRB4-mismatched patients 7 months (95% CI, 3-NR). The multivariate analysis showed a significant impact of DRB4 mismatching on survival (Hazards ratio (HR)=2.1 (95% CI, 1.01-4.67), P=0.045), acute GvHD (HR=2.66 (95% CI, 0.99-7.09) P=0.05) and on transplant-related mortality (HR=2.8; (95% CI, 1.7-4.4) P=0.024). In the view of an impact of DRB4 locus mismatch on clinical outcome, it would be important to confirm this observation in a prospective study as it may be worth considering DRB4 in the unrelated donor selection.

Pre-transplantation risk factors to develop sclerotic chronic GvHD after allogeneic HSCT: a multicenter retrospective study from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Sclerotic chronic GvHD (cGvHD) is one of the most severe complications after allo-hematopoietic stem cell transplantation (HSCT). Risk factors associated with this complication remain not very well defined. With the aim to define a pre-transplantation risk profile, we have conducted a French retrospective analysis in 705 consecutive patients between 2005 and 2010. Analyses to determine pre-transplantation risk factors included as variables: patient and donor age, kind of donor, HLA matching, ABO matching, sex-matching, diagnosis, stem cell source, gender, GvHD prophylaxis and antithymocyte globulin (ATG) in the conditioning regimen. The cumulative incidence of sclerotic cGvHD was 18% (95% CI, 16.6-19.6) 3 years after onset of cGvHD. In univariate analysis, we found a significantly lower number of sclerotic cGvHD form in patients transplanted from cord blood cells (P=0.0021), in patients with a one mismatched donor (P=0.041) and in patients who had received ATG in the conditioning regimen (P=0.002). In multivariate analysis, factors associated with an increased risk of sclerotic cGvHD were young patient age, multiple myeloma and PBSC as the stem cell source. ATG in conditioning regimen and cord blood unit as the stem cell source were associated with a lower risk.

High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation.

BK virus (BKV) reactivation has been increasingly associated with the occurrence of late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT (allo-HSCT) resulting in morbidity and sometimes mortality. We investigated the incidence, risk factors and outcome of BKV-HC in 323 consecutive adult patients undergoing allo-HSCT over a 5-year period. BK viremia values for HC staging were evaluated, as well as the medico-economic impact of the complication. Forty-three patients developed BKV-HC. In univariate analysis, young age (P=0.028), unrelated donor (P=0.0178), stem cell source (P=0.0001), HLA mismatching (P=0.0022) and BU in conditioning regimen (P=0.01) were associated with a higher risk of developing BKV-HC. In multivariate analysis, patients receiving cord blood units (CBUs) (P=0.0005) and peripheral blood stem cells (P=0.011) represented high-risk subgroups for developing BKV-HC. BK viremia was directly correlated to HC severity (P=0.011) with a 3 to 6-log peak being likely associated with grades 3 or 4 HC. No correlation was found between BKV-HC and acute graft versus host disease or mortality rate. Patients with BKV-HC required a significantly longer duration of hospitalization (P<0.0001), more RBC (P=0.0003) and platelet transfusions (P<0.0001). Over the 5-year study period, the financial cost of the complication was evaluated at \[euro]2 376 076 ($3 088 899). Strategies to prevent the occurrence of late-onset BKV-HC after allo-HSCT are urgently needed, especially in CBU and peripheral blood stem cell recipients. BK viremia correlates with the severity of the disease. Prospective studies are required to test prophylactic approaches.

The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry.

We analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation reported to the EBMT registry between 1995 and 2007. There were 198 human leukocyte antigen (HLA)-identical siblings; among unrelated transplants, 31 were well matched in high resolution ('well matched' unrelated donor, WMUD), and 139 were mismatched (MM), including 30 matched in low resolution; 266 patients (72%) received reduced-intensity conditioning and 102 (28%) received standard. According to the EBMT risk score, 11% were in scores 1-3, 23% in score 4, 40% in score 5, 22% in score 6 and 4% in score 7. There was no difference in overall survival (OS) at 5 years between HLA-identical siblings (55% (48-64)) and WMUD (59% (41-84)), P=0.82. In contrast, OS was significantly worse for MM (37% (29-48) P=0.005) due to a significant excess of transplant-related mortality. Also OS worsened significantly when EBMT risk score increased. HLA matching had no significant impact on relapse (siblings: 24% (21-27); WMUD: 35% (26-44), P=0.11 and MM: 21% (18-24), P=0.81); alemtuzumab T-cell depletion and stem cell source (peripheral blood) were associated with an increased risk. Our findings support the use of WMUD as equivalent alternative to HLA-matched sibling donors for allogeneic HSCT in CLL, and justify the application of EBMT risk score in this disease.

Study of the sticking of a hydrogen atom on a graphite surface using a mixed classical-quantum dynamics method.

The sticking of one hydrogen atom chemisorbed on the (0001) graphite surface is investigated using a mixed classical-quantum method. The phonon modes of the system in the collinear scattering approach are included in the dynamics calculations. The vibrational degrees of freedom of the surface (phonons) are treated classically, while the H-surface motion is treated using a one-dimensional quantum wave packet propagation method. The sticking probabilities are calculated and the individual contributions of the phonon bands to the collision dynamics are analyzed for surface temperatures of 10, 150, and 300 K and hydrogen kinetic energies ranging from 0.13 to 1.08 eV. An analytical form of the sticking probability as a function of the surface temperature is also proposed.

Pharmacological, neurochemical, and behavioral profile of JB-788, a new 5-HT1A agonist.

A novel pyridine derivative, 8-{4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl}-8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT(1A) receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area of anxiolytic and antipsychotic drugs.

Effects of betahistine at histamine H3 receptors: mixed inverse agonism/agonism in vitro and partial inverse agonism in vivo.

We previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H(3) receptors (H(3)Rs). However, H(3)Rs exhibit constitutive activity, and most H(3)R antagonists act as inverse agonists. Here, we have investigated the effects of betahistine at recombinant H(3)R isoforms. On inhibition of cAMP formation and [(3)H]arachidonic acid release, betahistine behaved as a nanomolar inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H(3)Rs. The inverse agonist potency of betahistine and its affinity on [(125)I]iodoproxyfan binding were similar in rat and human. We then investigated the effects of betahistine on histamine neuron activity by measuring tele-methylhistamine (t-MeHA) levels in the brains of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED(50) of 0.4 mg/kg, indicating inverse agonism. At higher doses, t-MeHA levels gradually returned to basal levels, a profile probably resulting from agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED(50) of 2 mg/kg, a rightward shift probably caused by almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial inverse agonism. After an oral 8-day treatment, the only effective dose of betahistine was 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by inverse agonism at H(3) autoreceptors.

Quantum dynamic of sticking of a H atom on a graphite surface.

A quantum study of the sticking of a hydrogen atom chemisorbed onto graphite (0001) surface was carried out also including the phonon modes of the system in the collinear scattering approximation. A new model was developed to extract the substrate vibrational modes from density functional theory (DFT) calculation and include them in the total system dynamics. The resulting coupled-channel equations are numerically developed along time using the wave packet methods. The sticking coefficients are calculated for hydrogen atoms incident energies ranging from 0.17 and 1.3 eV for a surface temperature of 10 K and between 0.17 and 0.2 eV for a surface temperature of 150 K. The results are found to be in good agreement with the experimental work.

Autoregulation of McA-RH7777 hepatoma cell proliferation by histamine H3 receptors.

Previous studies have suggested that histamine (HA) acts as an autocrine growth factor. We have explored the modulation of cell proliferation by HA using McA-RH7777 hepatoma cells. High L-histidine decarboxylase (HDC) expression and HA synthesis were found in McA-RH7777 cells. Whereas extracellular HA reached submicromolar concentrations, intracellular levels were very low, indicating that HA was secreted by the cells. McA-RH7777 cells also express H3-receptor (H3R) transcripts and proteins. Reverse transcriptase-polymerase chain reaction analysis detected only transcripts for the long isoform. Immunocytochemistry performed with a selective H3R antibody showed that most cells were immunoreactive. H3R binding sites (Bmax approximately 30 fmol/mg protein) were identified when [125I] iodoproxyfan binding was displaced by the agonist imetit. High-affinity binding also occurred at cytochrome P450 enzymes. This binding was not inhibited by HA, H3R agonists, or by a nonimidazole H3R antagonist but was displaced by imidazole H3R antagonists or by ketoconazole, a imidazole-containing cytochrome inhibitor. HA inhibited proliferation of McA-RH7777 hepatoma cells. The absence of uptake system, its much higher potency at H3Rs, and its low intracellular levels suggested that HA interacted with H3Rs rather than cytochromes. In agreement, both imidazole H3R antagonists, a nonimidazole H3R antagonist, and the HDC inhibitor alpha-monofluoromethyl histidine increased cell proliferation (up to approximately 60%), revealing a H3R-mediated inhibition by endogenous HA. Moreover, exogenous HA inhibited the increase induced by alpha-FMH or H3R antagonists with a nanomolar potency. In conclusion, our findings show that HA regulates proliferation of McA-RH7777 hepatoma cells by interacting with autoinhibitory H3Rs.

Ultrasound-guided coxofemoral arthrocentesis in horses.

REASON FOR PERFORMING STUDY: Coxofemoral joint pain is probably underestimated due to difficulties in identifying hip pain. The deep location of the joint and proximity of the sciatic nerve make arthrocentesis based on external landmarks a difficult and potentially risky procedure in mature horses. OBJECTIVES: To describe an ultrasound-guided injection technique of the coxofemoral joint in standing horses and to evaluate its accuracy and potential difficulties/complications. METHODS: Nine mature horses had both pelvic areas prepared for sterile ultrasound examination (3.5 MHz curvilinear probe). Coxofemoral joints were located and penetrated at their craniodorsolateral aspect under ultrasonographic guidance and injected with sterile contrast medium. A standing ventrodorsal radiographic view of each hemipelvis centred on the hip was obtained for each horse to assess the injection site. Horses were evaluated for 10 days following injection for possible complications. RESULTS: Intra-articular injection was successful in all 18 joints. The procedure was well tolerated by horses under minimal restraint. Mean +/- s.d. needle repositionings required before accurate placement was 1.5 +/- 1.3 per joint. Once the needle was in the joint, synovial fluid was obtained in 7/18 joints. Minimal periarticular contrast medium was detected in 2/18 joints. Mean +/- s.d. ultrasonographic examination time required for coxofemoral localisation, accurate needle positioning and injection was 4.3 +/- 2.1 min. No complications were observed in the 10 days following injection. CONCLUSION: The ultrasound-guided coxofemoral arthrocentesis is an accurate, reliable and safe technique that offers a real time evaluation of needle introduction into the deep and narrow coxofemoral joint space. POTENTIAL RELEVANCE: Although this technique remains to be tested on clinical cases, it is a promising tool to facilitate diagnosis of coxofemoral pain, septic arthritis or administration of intra-articular medication.

Wave-packet study of H2 formation on a graphite surface through the Langmuir-Hinshelwood mechanism.

We have studied the formation of the H2 molecule on a graphite surface, when both H atoms are initially physisorbed. The graphite surface is assumed to be planar. The interaction potential is modeled to reproduce the experimental properties of H physisorption on graphite. Extending our previous work [S. Morisset, F. Aguillon, M. Sizun, and V. Sidis, J. Chem. Phys. 121, 6493 (2004)], full-dimensionality quantum calculations are presented for collision energies ranging from 4 to 50 meV. It is shown that the reaction occurs with a large cross section and produces the H2 molecule with a considerable amount of vibrational energy. The mechanism is either direct or involves the formation of an intermediate complex.

Gene-mediated restoration of cartilage matrix by combination insulin-like growth factor-I/interleukin-1 receptor antagonist therapy.

Combination of growth factor gene-enhanced cartilage matrix synthesis with interleukin-1 receptor antagonist protein (IL-1Ra) abrogation of cartilage matrix degradation may reduce and possibly reverse cartilage loss in synovitis and osteoarthritis. The feasibility of cotransduction of synovial membrane with two such genes that may act on cartilage homeostasis was investigated in an in vitro coculture system. Cultured synoviocytes in monolayer were cotransduced with E1-deleted adenoviral vectors, one containing IGF-I coding sequence under cytomegalovirus (CMV) promoter control (200 multiplicities of infection (moi)), and the second containing IL-1Ra sequence under CMV promoter control (100 moi). Adenovirus-IGF-I (AdIGF-I) transduction and AdIGF-I/AdIL-1Ra cotransduction of synovial monolayer cultures resulted in increased IGF-I mRNA and ligand expression, and similarly AdIL-1Ra and AdIGF-I/AdIL-1Ra-transduced cultures expressed high levels of IL-1Ra. Northern analysis confirmed a single mRNA transcript of the appropriate size for both IGF-I and IL-1Ra transgene expression. Synovial cell monolayer and cartilage explant coculture experiments were used to examine the effects of IGF-I and IL-1Ra protein expressed by transduced synoviocytes on normal and IL-1-depleted cartilage. Transduced monolayer cultures produced peak medium IGF-I content of 114+/-20.2 ng/ml and IL-1Ra levels of 241.8+/-10.5 ng/ml at 48 h after transduction. These IGF-I concentrations were sufficient to produce significantly increased proteoglycan (PG) content of normal cartilage cultured in medium conditioned by AdIGF-I and AdIGF-I/AdIL-1Ra-transduced synoviocytes. Interleukin-1-exposed cartilage was markedly depleted of PG, and this catabolic state was partially reversed in AdIGF-I-transduced cultures and fully reversed by AdIGF-I/AdIL-1Ra-transduced synovial cocultures. These data indicate that cultured synoviocytes are readily cotransduced by two recombinant adenoviral vectors containing transgenes active in restoring joint health. The AdIL-1Ra and AdIGF-I transgenes were abundantly expressed and the secreted products achieved therapeutic concentrations by day 2. The resulting increase in matrix biosynthesis returned cartilage PG content to normal levels. These data suggest that there may be significant value in cotransduction of synovial membrane to attenuate cartilage malacia associated with synovitis, injury, or early arthritis.

Quantum dynamics of H2 formation on a graphite surface through the Langmuir Hinshelwood mechanism.

We have studied the formation of the H2 molecule on a graphite surface, when both H atoms are initially physisorbed. The graphite surface is assumed to be planar, and a model potential is obtained in a semiempirical way to reproduce the experimental properties of H physisorption on graphite. The reaction probability has been computed in the case when the angular momentum of the relative H-H motion lies parallel to the surface plane. Three-dimensional wave packet calculations have been performed for collision energies ranging from 2 to 50 meV. It is shown that the reaction occurs with a significant probability and produces the H2 molecule with a considerable amount of vibrationnal energy. A simple mechanical model is presented, where desorption of the nascent H2 molecule results from two successive binary elastic collisions.

Facilitated ankylosis of the distal interphalangeal joint in a foal.

A 3-month-old Quarter Horse colt sustained a penetrating injury over the coronary band on the right forelimb resulting in an articular bone sequestrum and septic arthritis of the distal interphalangeal joint. Despite aggressive treatment for septic arthritis, severe osteoarthritis and ongoing sepsis resulted in persistent lameness. Facilitated ankylosis of the distal interphalangeal joint was performed using a combination of open surgical debridement, placement of an autogenous cancellous bone graft and stabilisation within a transfixation cast. Bony ankylosis of the joint was observed radiographically 7 weeks following surgery. Evaluation of the horse 30 months following surgery revealed complete fusion of the middle and distal phalanges, and the distal sesamoid bone. The horse is pasture sound and is used as a breeding stallion. This report describes the surgical approach and case management employed to achieve facilitated ankylosis as a treatment for unresolved septic arthritis of the distal interphalangeal joint. This is the first report of successful facilitated ankylosis of the distal interphalangeal joint in a foal.

Therapeutic implications of constitutive activity of receptors: the example of the histamine H3 receptor.

Some G-protein-coupled receptors display constitutive activity, that is spontaneous activity in the absence of agonist: a proportion of the receptor population adopts a conformation that can bind and activate G proteins. Whereas this was mainly shown to occur with recombinant or pathologically mutated receptors, the physiological relevance of the process has remained debated. We have adressed this question in the case of the histamine H3 receptor, a presynaptic inhibitory receptor regulating histamine release in brain. Having identified a neutral antagonist and inverse agonists with variable intrinsic activity, we show that the native H3 receptor in brain displays high constitutive activity in vitro and, in vivo, controls the release of endogenous histamine. This implies that inverse agonists with high intrinsic activity should be preferred for therapeutic application as "cognitive enhancers" in several psychiatric disorders.

Effects of histamine H3 receptor agonist and antagonist on histamine co-transmitter expression in rat brain.

The histaminergic H3-receptor (H3R) controls histamine synthesis and release in the tuberomamillary nucleus. We evaluated the effects of stimulating or blocking of H(3)R on glutamate-decarboxylase 67 kDa (GAD-67) and galanin mRNA expression, two histamine co-transmitters.After in situ hybridization histochemistry (ISHH), we observed a colocalization of 100% between histidine decarboxylase (HDC) and GAD-67 or H3R and of 80 to 97% with galanin. Adult rats received an H3R agonist ((R)alpha-Methylhistamine) or antagonist (ciproxifan) and were sacrificed 1 or 3 hours later. Treatment effects on HDC, galanin and GAD-67 mRNA were studied by quantitative ISHH on serial sections. Treatment with the H3R agonist known to decrease histamine neuron activity initially reduced HDC and galanin gene expression but an inverse change, presumably reflecting a compensatory mechanism, was observed after 3 h on both markers. In contrast, the H3R antagonist known to activate histamine neurons, had opposite effects on the two markers, suggesting that co-transmitters are submitted to independent control mechanisms. Furthermore, GAD-67 mRNA levels were not significantly modified by these treatments.

Acute and chronic effects of methamphetamine on tele-methylhistamine levels in mouse brain: selective involvement of the D(2) and not D(3) receptor.

We have explored the role of endogenous dopamine in the control of histaminergic neuron activity in mouse brain regions evaluated by changes in tele-methylhistamine (t-MeHA) levels. In vitro, methamphetamine released [(3)H]noradrenaline but failed to release [(3)H]histamine from synaptosomes. In vivo, methamphetamine enhanced t-MeHA levels by about 2-fold with ED(50) values of approximately 1 mg/kg in caudate putamen, nucleus accumbens, cerebral cortex, and hypothalamus. This response selectively involved the D(2) and not the D(3) receptor as indicated by its blockade by haloperidol and by its persistence after administration of nafadotride, a D(3) receptor preferential ligand, or in (-/-) D(3) receptor-deficient mice. The t-MeHA response to methamphetamine was delayed compared with the locomotor-activating effect of this drug, suggesting that it is of compensatory nature. In agreement, ciproxifan, an inverse agonist known to enhance histamine neuron activity, decreased the hyperlocomotion induced by methamphetamine. Repeated methamphetamine administration resulted in the expected sensitization to the hyperlocomotor effect of the drug but did not modify either the ED(50) or the E(max) regarding t-MeHA levels. However, it resulted in an enhanced basal t-MeHA level (+30-40%), which was sustained for at least 11 days after withdrawal in hypothalamus, striatum, and cerebral cortex and suppressed by haloperidol. Hence, both the acute and chronic administration of methamphetamine enhance histamine neuron activity, presumably in a compensatory manner. Repeated methamphetamine administration also resulted in a modified balance in the opposite influences of dopamine and serotonin on histaminergic neurons as revealed by the enhanced response to haloperidol and abolished response to ketanserin, respectively.