Contributions of Influenza Virus Hemagglutinin and Host Immune Responses Toward the Severity of Influenza Virus: Streptococcus pyogenes Superinfections.

Influenza virus infections can be complicated by bacterial superinfections, which are medically relevant because of a complex interaction between the host, the virus, and the bacteria. Studies to date have implicated several influenza virus genes, varied host immune responses, and bacterial virulence factors, however, the host-pathogen interactions that predict survival versus lethal outcomes remain undefined. Previous work by our group showed that certain influenza viruses could yield a survival phenotype (A/swine/Texas/4199-2/98-H3N2, TX98), whereas others were associated with a lethal phenotype (A/Puerto Rico/8/34-H1N1, PR8). Based on this observation, we developed the hypothesis that individual influenza virus genes could contribute to a superinfection, and that the host response after influenza virus infection could influence superinfection severity. The present study analyzes individual influenza virus gene contributions to superinfection severity using reassortant viruses created using TX98 and PR8 viral genes. Host and pathogen interactions, relevant to survival and lethal phenotypes, were studied with a focus on pathogen clearance, host cellular infiltrates, and cytokine levels after infection. Specifically, we found that the hemagglutinin gene expressed by an influenza virus can contribute to the severity of a secondary bacterial infection, likely through modulation of host proinflammatory responses. Altogether, these results advance our understanding of molecular mechanisms underlying influenza virus-bacteria superinfections and identify viral and corresponding host factors that may contribute to morbidity and mortality.

FOXOs modulate proteasome activity in human-induced pluripotent stem cells of Huntington's disease and their derived neural cells.

Although it has been speculated that proteasome dysfunction may contribute to the pathogenesis of Huntington's disease (HD), a devastating neurodegenerative disorder, how proteasome activity is regulated in HD affected stem cells and somatic cells remains largely unclear. To better understand the pathogenesis of HD, we analyzed proteasome activity and the expression of FOXO transcription factors in three wild-type (WT) and three HD induced-pluripotent stem cell (iPSC) lines. HD iPSCs exhibited elevated proteasome activity and higher levels of FOXO1 and FOXO4 proteins. Knockdown of FOXO4 but not FOXO1 expression decreased proteasome activity. Following neural differentiation, the HD-iPSC-derived neural progenitor cells (NPCs) demonstrated lower levels of proteasome activity and FOXO expressions than their WT counterparts. More importantly, overexpression of FOXO4 but not FOXO1 in HD NPCs dramatically enhanced proteasome activity. When HD NPCs were further differentiated into DARPP32-positive neurons, these HD neurons were more susceptible to death than WT neurons and formed Htt aggregates under the condition of oxidative stress. Similar to HD NPCs, HD-iPSC-derived neurons showed reduced proteasome activity and diminished FOXO4 expression compared to WT-iPSC-derived neurons. Furthermore, HD iPSCs had lower AKT activities than WT iPSCs, whereas the neurons derived from HD iPSC had higher AKT activities than their WT counterparts. Inhibiting AKT activity increased both FOXO4 level and proteasome activity, indicating a potential role of AKT in regulating FOXO levels. These data suggest that FOXOs modulate proteasome activity, and thus represents a potentially valuable therapeutic target for HD.

Reduced body weight gain in ubiquilin-1 transgenic mice is associated with increased expression of energy-sensing proteins.

Ubiquilin-1 (Ubqln1), a ubiquitin-like protein, is implicated in a variety of pathophysiological processes, but its role in mediating body weight gain or metabolism has not been determined. Here, we demonstrate that global overexpression of Ubqln1 in a transgenic (Tg) mouse reduces the animal's body weight gain. The decreased body weight gain in Tg mice is associated with lower visceral fat content and higher metabolic rate. The Ubqln1 Tg mice exhibited reduced leptin and insulin levels as well as increased insulin sensitivity manifested by homeostatic model assessment of insulin resistance. Additionally, the reduced body weight in Tg mice was associated with the upregulation of two energy-sensing proteins, sirtuin1 (SIRT1) in the hypothalamus and AMP-activated protein kinase (AMPK) in the skeletal muscle. Consistent with the in vivo results, overexpression of Ubqln1 significantly increased SIRT1 and AMPK levels in the mouse embryonic fibroblast cell culture. Thus, our results not only establish the link between Ubqln1 and body weight regulation but also indicate that the metabolic function of Ubqln1 on body weight may be through regulating energy-sensing proteins.

Sexual dimorphism of cardiopulmonary regulation in the arcuate nucleus of the hypothalamus.

The arcuate nucleus of the hypothalamus (ANH) interacts with other hypothalamic nuclei, forebrain regions, and downstream brain sites to affect autonomic nervous system outflow, energy balance, temperature regulation, sleep, arousal, neuroendocrine function, reproduction, and cardiopulmonary regulation. Compared to studies of other ANH functions, how the ANH regulates cardiopulmonary function is less understood. Importantly, the ANH exhibits structural and functional sexually dimorphic characteristics and contains numerous neuroactive substances and receptors including leptin, neuropeptide Y, glutamate, acetylcholine, endorphins, orexin, kisspeptin, insulin, Agouti-related protein, cocaine and amphetamine-regulated transcript, dopamine, somatostatin, components of renin-angiotensin system and gamma amino butyric acid that modulate physiological functions. Moreover, several clinically relevant disorders are associated with ANH ventilatory control dysfunction. This review highlights how ANH neurotransmitter systems and receptors modulate breathing differently in male and female rodents. Results highlight the significance of the ANH in cardiopulmonary regulation. The paucity of studies in this area that will hopefully spark investigations of sexually dimorphic ANH-modulation of breathing.

Muscimol microinjected in the arcuate nucleus affects metabolism, body temperature & ventilation.

Effects of microinjection of 2 doses of γ-aminobutyric acid (GABA)A receptor agonist, muscimol (M), into the hypothalamic arcuate nucleus on oxygen consumption and control of ventilation over time and body temperature (BT) at the end of the experiment were compared in adult male and female rats. Relative to cerebrospinal fluid (CSF, 0 nmol), BT was decreased only in male rats with both doses of M, while in female rats, the 5 nmol dose depressed oxygen consumption. Ventilation was depressed by 5 nmol M in male and 10 nmol M in female rats by decreasing tidal volume. M did not affect the ventilatory response of male or female rats to hypoxia, whereas in females 5 and 10 nmol M and in males 10 nmol M depressed the ventilatory response to hypercapnia. Thus, in rats GABAA receptors in the arcuate nucleus modulate BT, oxygen consumption, and ventilation in air and in response to hypercapnia in a sexually dimorphic manner.

In adult female hamsters hypothyroidism stimulates D1 receptor-mediated breathing without altering D1 receptor expression.

Hypothyroidism affects cardiopulmonary regulation and function of dopaminergic receptors. Here we evaluated effects of 5 months of hypothyroidism on dopamine D1 receptor modulation of breathing in female hamsters using a D1 receptor antagonist SCH 23390. Euthyroid hamsters (EH) served as controls. Results indicated that hypothyroid female hamsters (HH) exhibited decreased body weights and minute ventilation (VE) following hypoxia due to decreased frequency of breathing (F). Moreover, SCH 23390 administration in HH increased VE by increasing tidal volume during exposure to air, hypoxia and following hypoxia. Relative to vehicle, SCH 23390 treatment decreased body temperature and hypoxic VE responsiveness in both groups. In EH, SCH 23390 decreased F in air, hypoxia and post hypoxia, and VE during hypoxia trended to decrease (P=0.053). Finally, expression of D1 receptor protein was not different between the two groups in any region evaluated. Thus, hypothyroidism in older female hamsters affected D1 receptor modulation of ventilation differently relative to euthyroid animals, but not expression of D1 receptors.

T3 supplementation affects ventilatory timing & glucose levels in type 2 diabetes mellitus model.

Type II diabetes mellitus (T2DM) can affect ventilation, metabolism, and fasting blood glucose levels. Hypothyroidism may be a comorbidity of T2DM. In this study T2DM was induced in 20 female Sprague Dawley rats using Streptozotocin (STZ) and Nicotinamide (N). One of experimental STZ/N groups (N=10 per group) was treated with a low dose of triiodothyronine (T3). Blood glucose levels, metabolism and ventilation (in air and in response to hypoxia) were measured in the 3 groups. STZ/N-treated rats increased fasting blood glucose compared to control rats eight days and 2 months post-STZ/N injections indicating stable induction of T2DM state. Treatments had no effects on ventilation, metabolism or body weight. After one month of T3 supplementation, there were no physiological indications of hyperthyroidism, but T3 supplementation altered ventilatory timing and decreased blood glucose levels compared to STZ/N rats. These results suggest that low levels of T3 supplementation could offer modest effects on blood glucose and ventilatory timing in this T2M model.

Low-dose T3 replacement restores depressed cardiac T3 levels, preserves coronary microvasculature and attenuates cardiac dysfunction in experimental diabetes mellitus.

Thyroid dysfunction is common in individuals with diabetes mellitus (DM) and may contribute to the associated cardiac dysfunction. However, little is known about the extent and pathophysiological consequences of low thyroid conditions on the heart in DM. DM was induced in adult female Sprague Dawley (SD) rats by injection of nicotinamide (N; 200 mg/kg) followed by streptozotocin (STZ; 65 mg/kg). One month after STZ/N, rats were randomized to the following groups (N = 10/group): STZ/N or STZ/N + 0.03 µg/mL T3; age-matched vehicle-treated rats served as nondiabetic controls (C). After 2 months of T3 treatment (3 months post-DM induction), left ventricular (LV) function was assessed by echocardiography and LV pressure measurements. Despite normal serum thyroid hormone (TH) levels, STZ/N treatment resulted in reductions in myocardial tissue content of THs (T3 and T4: 39% and 17% reduction versus C, respectively). Tissue hypothyroidism in the DM hearts was associated with increased DIO3 deiodinase (which converts THs to inactive metabolites) altered TH transporter expression, reexpression of the fetal gene phenotype, reduced arteriolar resistance vessel density, and diminished cardiac function. Low-dose T3 replacement largely restored cardiac tissue TH levels (T3 and T4: 43% and 10% increase versus STZ/N, respectively), improved cardiac function, reversed fetal gene expression and preserved the arteriolar resistance vessel network without causing overt symptoms of hyperthyroidism. We conclude that cardiac dysfunction in chronic DM may be associated with tissue hypothyroidism despite normal serum TH levels. Low-dose T3 replacement appears to be a safe and effective adjunct therapy to attenuate and/or reverse cardiac remodeling and dysfunction induced by experimental DM.

Hypothyroidism affects D2 receptor-mediated breathing without altering D2 receptor expression.

Bromocriptine depressed ventilation in air and D2 receptor expression in the nucleus tractus solitaries (NTS) in male hypothyroid hamsters. Here we postulated that in age-matched hypothyroid female hamsters, the pattern of D2 receptor modulation of breathing and D2 receptor expression would differ from those reported in hypothyroid males. In females hypothyroidism did not affect D2 receptor protein levels in the NTS, carotid bodies or striatum. Bromocriptine, but not carmoxirole (a peripheral D2 receptor agonist), increased oxygen consumption and body temperature in awake air-exposed hypothyroid female hamsters and stimulated their ventilation before and following exposure to hypoxia. Carmoxirole depressed frequency of breathing in euthyroid hamsters prior to, during and following hypoxia exposures and stimulated it in the hypothyroid hamsters following hypoxia. Although hypothyroidism did not affect expression of D2 receptors, it influenced central D2 modulation of breathing in a disparate manner relative to euthyroid hamsters.

Restoration of cardiac tissue thyroid hormone status in experimental hypothyroidism: a dose-response study in female rats.

Thyroid hormones (THs) play a pivotal role in regulating cardiovascular homeostasis. To provide a better understanding of the coordinated processes that govern cardiac TH bioavailability, this study investigated the influence of serum and cardiac TH status on the expression of TH transporters and cytosolic binding proteins in the myocardium. In addition, we sought to determine whether the administration of T(3) (instead of T(4)) improves the relationship between THs in serum and cardiac tissue and cardiac function over a short-term treatment period. Adult female Sprague Dawley rats were made hypothyroid by 7 weeks treatment with the antithyroid drug 6-n-propyl-2-thiouracil (PTU). After establishing hypothyroidism, rats were assigned to 1 of 5 graded T(3) dosages plus PTU for a 2-week dose-response experiment. Untreated, age-matched rats served as euthyroid controls. PTU was associated with depressed serum and cardiac tissue T(3) and T(4) levels, arteriolar atrophy, altered TH transporter and cytosolic TH binding protein expression, fetal gene reexpression, and cardiac dysfunction. Short-term administration of T(3) led to a mismatch between serum and cardiac tissue TH levels. Normalization of serum T(3) levels was not associated with restoration of cardiac tissue T(3) levels or cardiac function. In fact, a 3-fold higher T(3) dosage was necessary to normalize cardiac tissue T(3) levels and cardiac function. Importantly, this study provides the first comprehensive data on the relationship between altered TH status (serum and cardiac tissue), cardiac function, and the coordinated in vivo changes in cardiac TH membrane transporters and cytosolic TH binding proteins in altered TH states.

Influence of the H1N1 pandemic on university students' knowledge of influenza.

BACKGROUND: Avoidance of influenza among college students requires understanding the risks for falling ill, outcomes of this disease, and utilizing methods to prevent developing influenza. We hypothesized that the behavior and knowledge of college students in the midst of a pandemic situation would be different than that during a regular influenza season. METHODS: We evaluated influenza knowledge of 311 university students in 2008 prior to and 318 students during the 2009-2010 H1N1 pandemic using voluntary online surveys that contained 25 questions regarding vaccination behaviors and influenza knowledge. Data were analyzed according to year and vaccination uptake. RESULTS: Very similar overall knowledge levels were found in the two cohorts independent of vaccination status. Both cohorts overestimated the prevalence of influenza and the number of people hospitalized due to influenza, but underestimated the number of deaths. Vaccination rates for seasonal influenza were in the two cohorts about 36 percent. By contrast, 4.8 percent participants had received the H1N1 vaccine, 40.1 percent intended to and 54.8 percent had no intentions of being vaccinated. CONCLUSIONS: The overall knowledge levels and vaccination behaviors of college students were not affected by the presence of an influenza pandemic. However, students' responses displayed a shift in belief toward greater rates of hospitalization and deaths in the 2009 sample, suggesting a change in perception due to the ongoing pandemic.

Student understanding of type 2 diabetes mellitus.

BACKGROUND: An estimated 25.8 million people in the United States have type 2 diabetes, including seven million people who have the disease but are undiagnosed. These numbers indicate that education about diabetes is needed. METHODS: To evaluate university students' knowledge about diabetes (risk factors, signs and symptoms and complications) we utilized a survey. Specifically, we determined: (1) knowledge of type 2 diabetes; (2) if participants' academic field of study affected their knowledge of type 2 diabetes; (3) if participants who had a family member with type 2 diabetes had a greater knowledge of the disease; and (4) if age affected students' knowledge of the disease. RESULTS: A questionnaire was completed by 469 students from The University of South Dakota. Students' knowledge of type 2 diabetes was poor: 30.1 percent of the students scored higher than 70 percent (with only 6.8 percent of the students scoring higher than 80 percent). No significant differences in knowledge scores were found between students who pursued health-related fields of study versus students who did not. Participants who had a family member with type 2 diabetes had a greater knowledge of the disease and felt that they had a higher risk for getting the disease. Significant differences in knowledge were only found between the youngest and oldest age groups. CONCLUSIONS: USD students' knowledge of type 2 diabetes is limited. Solutions need to communicate the risk factors and severity of the disease. Possible ways for improving diabetes education is to include health fairs as well as to integrate diabetes modules into K-12 education courses.

Effects of hypothyroidism on the respiratory system and control of breathing: Human studies and animal models.

Hypothyroidism, subclinical hypothyroidism and euthyroid sick syndrome, are prevalent disorders that affect all body systems including the respiratory system and control of breathing. The purpose of this review article is to discuss the regulation of thyroid hormone production and their function at the cellular level; the many causes of hypothyroidism; the effects of hypothyroidism on the respiratory system and on control of ventilation in hypothyroid patients; the variety of ways animal models of hypothyroidism are induced; and how in animal models hypothyroidism affects the respiratory system and control of breathing including neurotransmitters that influence breathing. Finally, this review will present controversies that exist in the field and thus encourage new research directions. Because of the high prevalence of hypothyroidism and subclinical forms of hypothyroidism and their influence on ventilation and the respiratory system, understanding underlying molecular mechanisms is necessary to ascertain how and sometimes why not thyroid replacement may normalize function.

Hypothyroidism stimulates D2 receptor-mediated breathing in response to acute hypoxia and alters D2 receptors levels in carotid bodies and brain.

Hypothyroidism can depress breathing and alter dopamine D2 receptor expression and function. We hypothesized that relative to euthyroid hamsters (EH), hypothyroid hamsters (HH) contain increased D2 receptors in brain regions associated with breathing and carotid bodies (CB), and that stimulation of D2 receptors would decease ventilation more in the HH compared to the EH. Hamsters were treated with vehicle, carmoxirile (peripherally acting D2 receptor agonist), or bromocriptine (central and peripherally acting D2 receptor agonist) and breathing was evaluated during exposure to air, hypoxia, and then air. HH exhibited increased D2 receptor protein levels in the striatum and CB, but decreased levels in the paraventricular hypothalamic nucleus. Relative to vehicle, carmoxirole and bromocriptine stimulated ventilation in the HH during and following exposure to hypoxia. Only bromocriptine depressed ventilation in the EH during and after exposure to hypoxia. Thus, hypothyroidism impacts the expression of D2 receptors in the carotid body, PVN and striatum, and D2 stimulation affects ventilation remarkably differently than in EH.

Hypothyroidism attenuates SCH 23390-mediated depression of breathing and decreases D1 receptor expression in carotid bodies, PVN and striatum of hamsters.

Hypothyroidism can lead to depressed breathing. We determined if propylthiouracil (PTU)-induced hypothyroidismin hamsters (HH) altered dopamine D1 receptor expression, D1 receptor-modulated ventilation, and ventilatory chemoreflex activation by hypoxia or hypercapnia. Hypothyroidism was induced by administering 0.04% PTU in drinking water for 3 months. Ventilation was evaluated following saline or 0.25mg/kg SCH 23390,a D1 receptor antagonist, while awake hamsters breathed normoxic (21% O(2) in N(2)), hypoxic (10% O(2)in N(2)) and hypercapnic (5% CO(2) in O(2))air. Relative to euthyroid hamsters (EH), HH exhibited decreased D1 receptor protein levels in carotid bodies, striatum, and hypothalamic paraventricular nucleus, but not in the nucleus tractus solitarius. Relative to EH, HH exhibited lower ventilation during exposure to normoxia, hypoxia, or hypercapnia, but comparable ventilatory responsiveness to chemoreflex activation. SCH23390 decreased ventilation of EH hamsters exposed to normoxia, hypoxia, and hypercapnia. In HH SCH23390 increased ventilation during baseline normoxia and did not affect ventilation during exposure to hypoxia and hypercapnia, resulting in reduced ventilatory responsivess to chemoreflex activation by hypoxia and hypercapnia. Furthermore, in HH D1 receptor protein levels are decreased in several brain regions and within the carotid bodies. Moreover, D1 receptor-modulation of breathing at rest and during gas exposures were depressed in EH but not HH.

Inactivated and live, attenuated influenza vaccines protect mice against influenza: Streptococcus pyogenes super-infections.

Mortality associated with influenza virus super-infections is frequently due to secondary bacterial complications. To date, super-infections with Streptococcus pyogenes have been studied less extensively than those associated with Streptococcus pneumoniae. This is significant because a vaccine for S. pyogenes is not clinically available, leaving vaccination against influenza virus as our only means for preventing these super-infections. In this study, we directly compared immunity induced by two types of influenza vaccine, either inactivated influenza virus (IIV) or live, attenuated influenza virus (LAIV), for the ability to prevent super-infections. Our data demonstrate that both IIV and LAIV vaccines induce similar levels of serum antibodies, and that LAIV alone induces IgA expression at mucosal surfaces. Upon super-infection, both vaccines have the ability to limit the induction of pro-inflammatory cytokines within the lung, including IFN-γ which has been shown to contribute to mortality in previous models of super-infection. Limiting expression of these pro-inflammatory cytokines within the lungs subsequently limits recruitment of macrophages and neutrophils to pulmonary surfaces, and ultimately protects both IIV- and LAIV-vaccinated mice from mortality. Despite their overall survival, both IIV- and LAIV-vaccinated mice demonstrated levels of bacteria within the lung tissue that are similar to those seen in unvaccinated mice. Thus, influenza virus:bacteria super-infections can be limited by vaccine-induced immunity against influenza virus, but the ability to prevent morbidity is not complete.

In dystrophic hamsters losartan affects control of ventilation and dopamine D1 receptor density.

The BIO 14.6 hamster (DV), an animal model of limb-girdle muscular dystrophy, has elevated angiotensin AT1 receptors that may affect ventilation. Moreover, AT1 receptors may modulate expression of dopamine D1 receptors. We investigated if chronic treatment of BIO 14.6 hamsters (DL) with losartan, an AT1 receptor blocker, affects D1 receptor density in the striatum and nucleus tractus solitarius (NTS) and normalizes ventilation during exposure to air, hypoxia, following hypoxia, and hypercapnia, Ventilation was evaluated using plethysmography. Compared to the golden Syrian hamsters (GS), DV hamsters exhibited lower hypercapnic and hypoxic responsiveness and ventilation during hypercapnic exposure. Relative to GS, DL hamsters increased breathing frequency in air and maintained ventilation during hypercapnia. Post-hypoxic minute ventilation decline occurred in DV but not in DL or GS hamsters. DL hamsters exhibited higher D1 receptor density in the striatum and NTS relative to DV hamsters. Thus, in dystrophic hamsters chronic losartan treatment stimulated frequency of breathing and increased the density of D1 receptors.

In hamsters the D1 receptor antagonist SCH23390 depresses ventilation during hypoxia.

During exposure of animals to hypoxia, brain and blood dopamine levels increase stimulating dopaminergic receptors which influence the integrated ventilatory response to low oxygen. The purpose of the present study is to test the hypothesis that in conscious hamsters, systemic antagonism of D(1) receptors would depress their breathing in air and in response to hypoxic and hypercapnic challenges. Nine male hamsters were treated with saline or 0.25 mg/kg SCH-23390 (SCH), a D(1) receptor antagonist that crosses the blood-brain barrier. Ventilation was determined using the barometric method, and oxygen consumption and CO(2) production were evaluated utilizing the flow-through method. During exposure to air, SCH decreased frequency of breathing. During exposure to hypoxia (10% oxygen in nitrogen), relative to saline, SCH-treated hamsters decreased minute ventilation by decreasing tidal volume and oxygen consumption but not CO(2) production. During exposure to hypercapnia (5% CO(2) in 95% O(2)), frequency of breathing was decreased with SCH, but there was no significant effect on minute ventilation. Relative to saline treatment body temperature was lower in SCH-treated hamsters by 0.6 degrees C. These results demonstrate that in hamsters D(1) receptors can modulate control of ventilation in air and during hypoxia and hypercapnic exposures. Whether D(1) receptors located centrally or on carotid bodies modulate these effects is not clear from this study.

In hamsters dopamine D2 receptors affect ventilation during and following intermittent hypoxia.

We tested the hypothesis that in golden Syrian hamsters (Mesocricetus auratus) carotid body dopaminergic D2 receptors modulate ventilation in air, during exposure to intermittent hypoxia (IH) and reoxygenation. Ventilation was evaluated using the barometric method and CO2 production was determined using the flow through method. Hamsters (n=8) received either subcutaneous injections of vehicle, haloperidol (0.5 mg/kg) or domperidone (0.5 mg/kg). Ventilatory and metabolic variables were determined 30 min following injections, after each of 5 bouts of 5 min of 10% oxygen interspersed by normoxia (IH), and 15, 30, 45 and 60 min following IH when hamsters were exposed to air. Haloperidol, but not domperidone decreased body temperature in hamsters. Neither treatment affected CO2 production. Vehicle-treated hamsters exhibited ventilatory long-term facilitation (VLTF) following IH. Haloperidol or domperidone decreased ventilation in air, during IH and eliminated VLTF due to changes in tidal volume and not frequency of breathing. Thus, in hamsters D2 receptors are involved in control of body temperature and ventilation during and following IH.

Thyroid status affects 5-HT2A receptor modulation of breathing before, during, and following exposure of hamsters to acute intermittent hypoxia.

The BIO 14.6 hamster (dystrophic), animal model of limb girdle muscular dystrophy, exhibits low plasma triiodothyronine levels, muscle weakness, and decreased breathing. After exposure to acute intermittent bouts of hypoxia, dystrophic hamsters depress ventilation relative to baseline resulting in ventilatory long-term depression (LTD). Control hamsters may increase ventilation relative to baseline resulting in ventilatory long-term facilitation (LTF). Serotonin (5-HT) receptors, especially the 5-HT(2A) subtype, are involved in the development of LTF. The purpose of this study was to evaluate the role of 5-HT(2A) receptors in ventilatory and metabolic responses before, during, and following intermittent hypoxia in eleven euthyroid, nine dystrophic, and eleven propylthiouracil (PTU)-induced hypothyroid male hamsters. Animals received subcutaneous injections of vehicle or 0.5 mg/kg MDL (5-HT(2A) receptor antagonist). Plethysmography was used to evaluate ventilatory responses of the three groups to air, five bouts of 5 min of 10% oxygen, each interspersed with 5 min of air, followed by 60 min of exposure to air. CO(2) production was measured using the flow-through method. Vehicle-treated dystrophic and PTU-treated hamsters exhibited LTD. MDL decreased body temperature in all groups. After MDL treatment, the euthyroid group exhibited LTD. MDL treatment in the dystrophic, but not in the PTU-treated hamsters, maintained tidal volume, but did not reverse LTD. CO(2) production was increased in the euthyroid group with MDL treatment. Thus, 5-HT(2A) receptors affect body temperature, ventilation, and metabolism in hamsters. The differential responses noted in this study may be in part dependent on thyroid hormone status.