PubMed Health⌕ Search

Biomedical subjects

Michael H Baumann

Publications and source records attributed to Michael H Baumann.

At least 19 recordsLinked to original sources
PubMed2006

Interaction of amphetamines and related compounds at the vesicular monoamine transporter.

Amphetamine-type agents interact with the vesicular monoamine transporter type 2 (VMAT(2)), promoting the release of intravesicular neurotransmitter and an increase in cytoplasmic neurotransmitter. Some compounds, such as reserpine, "release" neurotransmitter by inhibiting the ability of VMAT(2) to accumulate neurotransmitter in the vesicle, whereas other types of compounds can release neurotransmitter via a carrier-mediated exchange mechanism. The purpose of this study was to determine, for 42 mostly amphetamine-related compounds, their mode of interaction with the VMAT(2). We used a crude vesicular fraction prepared from rat caudate to assay VMAT(2) activity. Test compounds were assessed in several assays, including 1) inhibition of [(3)H]dihydrotetrabenazine binding, 2) inhibition of vesicular [(3)H]dopamine uptake, and 3) release of preloaded [(3)H]dopamine and [(3)H]tyramine. Several important findings derive from this comprehensive study. First, our work indicates that most agents are VMAT(2) substrates. Second, our data strongly suggest that amphetamine-type agents deplete vesicular neurotransmitter via a carrier-mediated exchange mechanism rather than via a weak base effect, although this conclusion needs to be confirmed via direct measurement of vesicular pH. Third, our data fail to reveal differential VMAT(2) interactions among agents that do and do not produce long-term 5-hydroxytryptamine depletion. Fourth, the data reported revealed the presence of two pools of [(3)H]amine within the vesicle, one pool that is free and one pool that is tightly associated with the ATP/protein complex that helps store amine. Finally, the VMAT(2) assays we have developed should prove useful for guiding the synthesis and evaluation of novel VMAT(2) agents as possible treatment agents for addictive disorders.

Amphetamines↗
PubMed2006

Amphetamine analogs increase plasma serotonin: implications for cardiac and pulmonary disease.

Elevations in plasma serotonin (5-HT) have been implicated in the pathogenesis of cardiac and pulmonary disease. Normally, plasma 5-HT concentrations are kept low by transporter-mediated uptake of 5-HT into platelets and by metabolism to 5-hydroxyindoleacetic acid (5-HIAA). Many abused drugs (e.g., substituted amphetamines) and prescribed medications (e.g., fluoxetine) target 5-HT transporters and could thereby influence circulating 5-HT. We evaluated the effects of amphetamines analogs [(+/-)-fenfluramine, (+/-)-3,4-methylenedioxymethamphetamine, (+)-methamphetamine, (+)-amphetamine, phentermine] on extracellular levels (i.e., plasma levels) of 5-HT and 5-HIAA in blood from catheterized rats. Effects of the 5-HT uptake blocker fluoxetine were examined for comparison. Drugs were tested in vivo and in vitro; plasma indoles were measured using a novel microdialysis method in whole blood. We found that baseline dialysate levels of 5-HT are approximately 0.22 nM, and amphetamine analogs evoke large dose-dependent increases in plasma 5-HT ranging from 4 to 20 nM. The ability of drugs to elevate plasma 5-HT is positively correlated with their potency as 5-HT transporter substrates. Fluoxetine produced small, but significant, increases in plasma 5-HT. Although the drug-evoked 5-HT concentrations are below the micromolar levels required for contraction of pulmonary arteries, they approach concentrations reported to stimulate mitogenesis in pulmonary artery smooth muscle cells. Additional studies are needed to determine the effects of chronic administration of amphetamines on circulating 5-HT.

Amphetamines↗
PubMed2006

3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug. In animals, high-dose administration of MDMA produces deficits in serotonin (5-HT) neurons (e.g., depletion of forebrain 5-HT) that have been interpreted as neurotoxicity. Whether such 5-HT deficits reflect neuronal damage is a matter of ongoing debate. OBJECTIVE: The present paper reviews four specific issues related to the hypothesis of MDMA neurotoxicity in rats: (1) the effects of MDMA on monoamine neurons, (2) the use of "interspecies scaling" to adjust MDMA doses across species, (3) the effects of MDMA on established markers of neuronal damage, and (4) functional impairments associated with MDMA-induced 5-HT depletions. RESULTS: MDMA is a substrate for monoamine transporters, and stimulated release of 5-HT, NE, and DA mediates effects of the drug. MDMA produces neurochemical, endocrine, and behavioral actions in rats and humans at equivalent doses (e.g., 1-2 mg/kg), suggesting that there is no reason to adjust doses between these species. Typical doses of MDMA causing long-term 5-HT depletions in rats (e.g., 10-20 mg/kg) do not reliably increase markers of neurotoxic damage such as cell death, silver staining, or reactive gliosis. MDMA-induced 5-HT depletions are accompanied by a number of functional consequences including reductions in evoked 5-HT release and changes in hormone secretion. Perhaps more importantly, administration of MDMA to rats induces persistent anxiety-like behaviors in the absence of measurable 5-HT deficits. CONCLUSIONS: MDMA-induced 5-HT depletions are not necessarily synonymous with neurotoxic damage. However, doses of MDMA which do not cause long-term 5-HT depletions can have protracted effects on behavior, suggesting even moderate doses of the drug may pose risks.

Animals↗
PubMed2006

Management of spontaneous pneumothorax.

Management of patients with a spontaneous pneumothorax continues to challenge clinicians. Recent guidelines help provide care pathways for these patients and highlight the many areas in need of additional study. Management options for spontaneous pneumothoraces should be selected based primarily upon a patient's clinical status. Observation or pleural air drainage, in selected patients, plays a significant role in patients with primary spontaneous pneumothorax. By contrast, pleural air drainage plays the central role in patients with a secondary spontaneous pneumothorax. Surgically directed recurrence prevention and air leak management are preferred for both primary and secondary spontaneous pneumothorax patients.

Drainage↗
PubMed2006

Grading strength of recommendations and quality of evidence in clinical guidelines: report from an american college of chest physicians task force.

While grading the strength of recommendations and the quality of underlying evidence enhances the usefulness of clinical guidelines, the profusion of guideline grading systems undermines the value of the grading exercise. An American College of Chest Physicians (ACCP) task force formulated the criteria for a grading system to be utilized in all ACCP guidelines that included simplicity and transparency, explicitness of methodology, and consistency with current methodological approaches to the grading process. The working group examined currently available systems, and ultimately modified an approach formulated by the international GRADE group. The grading scheme classifies recommendations as strong (grade 1) or weak (grade 2), according to the balance among benefits, risks, burdens, and possibly cost, and the degree of confidence in estimates of benefits, risks, and burdens. The system classifies quality of evidence as high (grade A), moderate (grade B), or low (grade C) according to factors that include the study design, the consistency of the results, and the directness of the evidence. For all future ACCP guidelines, The College has adopted a simple, transparent approach to grading recommendations that is consistent with current developments in the field. The trend toward uniformity of approaches to grading will enhance the usefulness of practice guidelines for clinicians.

Advisory Committees↗
PubMed2006

Performance measures and pay for performance.

Performance measures and pay for performance are terms creating considerable angst among physicians today. Understanding the driving forces behind these concepts will help practitioners to strategically plan for their impact on individual physician practices and on health care in general. Medical societies can play a vital role in assisting physicians in the identification of appropriate performance measures used to gauge physician practices and by supporting efforts to develop equitable principles driving reimbursement based on adherence to those measures. Performance measures and pay for performance are terms evoking considerable angst across all sectors of the health services industry.

Cost-Benefit Analysis↗
PubMed2005

Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats.

Endogenous opioids seem to play a critical role in the regulation of mood states. For example, there is accumulating evidence that stimulation of kappa-opioid receptors, upon which the endogenous opioid dynorphin acts, can produce depressive-like behaviors in laboratory animals. Here we examined whether systemic administration of salvinorin A (SalvA), a potent and highly selective kappa-opioid agonist, would produce depressive-like effects in the forced swim test (FST) and intracranial self-stimulation (ICSS) test, which are behavioral models often used to study depression in rats. We extracted, isolated, and purified SalvA from Salvia divinorum plant leaves and examined its effects on behavior in the FST and ICSS test across a range of doses (0.125-2.0 mg/kg) after systemic (intraperitoneal) administration. SalvA dose dependently increased immobility in the FST, an effect opposite to that of standard antidepressant drugs. Doses of SalvA that produced these effects in the FST did not affect locomotor activity in an open field. Furthermore, SalvA dose dependently elevated ICSS thresholds, an effect similar to that produced by treatments that cause depressive symptoms in humans. At a dose that caused the depressive-like effects in both the FST and ICSS assays, SalvA decreased extracellular concentrations of dopamine (DA) within the nucleus accumbens (NAc), a critical component of brain reward circuitry, without affecting extracellular concentrations of serotonin (5-HT). These data provide additional support for the hypothesis that stimulation of brain kappa-opioid receptors triggers depressive-like signs in rats and raise the possibility that decreases in extracellular concentrations of DA within the NAc contribute to these effects.

Animals↗
PubMed2005

Targeted screening for biogenic amine transporters: potential applications for natural products.

The biogenic amine transporters (BATs) are integral membrane proteins that terminate the actions of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) by pumping these substrates from the extracellular space back into the nerve terminal. Numerous drugs and medications target BATs, acting as inhibitors or substrates. This paper will review some of the methods used to measure the activity of test drugs at the BATs. These methods include traditional uptake inhibition assays and transporter binding assays, as well as methods developed in our lab to determine if a test agent is a BAT substrate or inhibitor. Newer methods, developed in our lab, are used to determine the potency of test drugs as BAT substrates in a relatively high throughput manner. The potential application of these methods to characterizing natural products will be discussed in reference to results obtained with "purified" natural products, such as ephedrine stereoisomers.

Animals↗
PubMed2005

(+/-)-3,4-Methylenedioxymethamphetamine administration to rats does not decrease levels of the serotonin transporter protein or alter its distribution between endosomes and the plasma membrane.

We showed that the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) reduces brain tissue 5-HT, decreases expression of 5-HT transporter (SERT) protein, and increases expression of glial fibrillary acidic protein (GFAP). In contrast, doses of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) that decrease brain tissue 5-HT fail to alter expression of SERT or GFAP. Using a new and highly sensitive anti-SERT antibody, we determined whether MDMA alters the subcellular distribution of SERT protein by measuring SERT expression in endosomes and plasma membranes 2 weeks after MDMA administration. Rat brain tissues (caudate, cortex, and hippocampus) were collected 3 days and 2 weeks after MDMA (7.5 mg/kg i.p., every 2 h x 3 doses) or 5,7-DHT (150 microg/rat i.c.v.) administration. Representative results from cortex are as follows. At both 3 days and 2 weeks postinjection, MDMA decreased tissue 5-HT (65%) and had no effect on GFAP expression. MDMA increased heat shock protein 32 (HSP32; a marker for microglial activation) expression (30%) at 3 days, but not 2 weeks. MDMA did not alter SERT expression at either time point and did not alter SERT levels in either endosomes or plasma membranes (2 weeks). 5,7-DHT decreased tissue 5-HT (80%), increased HSP32 expression at both time points (about 50%), and increased GFAP expression at 2 weeks (40%). 5,7-DHT decreased SERT expression (33%) at 2 weeks, but not at 3 days. These findings indicate that a dosing regimen of MDMA that depletes brain 5-HT does not alter SERT protein expression or the distribution of SERT between endosomes and the plasma membrane and does not produce detectable evidence for neurotoxicity.

5,7-Dihydroxytryptamine↗
PubMed2005

Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration.

Convergent lines of evidence support a dual deficit model of stimulant withdrawal, where reductions in synaptic dopamine (DA) and 5-hydroxytryptamine (serotonin) (5-HT) contribute to dysphoria, drug craving, and relapse. Thus, we predicted that a nonamphetamine compound with substrate activity at DA and 5-HT transporters (i.e., a dual DA/5-HT releaser) would be an effective medication for treating stimulant addictions. Ideally, this type of medication would alleviate withdrawal symptoms, suppress cocaine self-administration, and lack side effects commonly associated with central nervous system stimulants. In the present work, more than 350 compounds were screened in vitro for activity as substrate-type releasing agents at DA, 5-HT, and norepinephrine transporters. These efforts identified PAL-287 (1-napthyl-2-aminopropane) as a nonamphetamine compound with potent substrate activity at biogenic amine transporters. In vivo microdialysis in rats demonstrated that PAL-287 (1-3 mg/kg i.v.) increased extracellular DA and 5-HT in frontal cortex, but effects on 5-HT were somewhat greater. PAL-287 induced substantially less locomotor stimulation than (+)-amphetamine, a drug that increases only extracellular DA. Administration of high-dose (+)-methamphetamine or (+/-)-3,4-methylenedioxymethamphetamine to rats produced long-lasting depletion of cortical 5-HT, whereas PAL-287 (18 mg/kg i.p. x 3) did not. PAL-287 displayed little or no reinforcing properties in rhesus monkeys trained to self-administer cocaine, yet PAL-287 produced a dose-dependent decrease in responding for cocaine when infused at a dose of 1.0 mg/kg/h. Collectively, the findings reported here demonstrate that nonamphetamine monoamine releasing agents such as PAL-287 might be promising candidate medications for the treatment of stimulant dependence.

Animals↗
PubMed2005

Effects of chronic social stress on neuroendocrine responsiveness to challenge with ethanol, dexamethasone and corticotropin-releasing hormone.

Neuroendocrine and behavioral profiles of group-housed rodents differ from those of singly-housed ones. Subordinate rats have elevated plasma corticosterone (CORT) concentration and impaired activity of the hypothalamic-pituitary-adrenal (HPA) axis compared to dominant cagemates. However, little is known about the effects of social hierarchy on other stress-related hormones. We examined plasma prolactin (PRL) and CORT responses to saline and ethanol (EtOH) injections, and 1 month later to dexamethasone (DEX) and corticotropin-releasing hormone (CRH) challenges of group- (triad) and single-housed male rats over a period of 225 days. Social status was determined from behaviors displayed upon initial triad housing. Subordinate rats had lower basal PRL and higher CORT compared to dominant rats. The injection of EtOH (1.25 g/kg) depressed PRL and elevated CORT levels significantly more than the saline injection only in dominant and singly-housed rats. DEX increased PRL levels, most strikingly in dominant rats, and suppressed CORT only in dominant rats. After CRH challenge, plasma CORT increased in all groups, subdominant and subordinate rats displaying blunted responses. Our data demonstrate that social rank and housing conditions affect plasma PRL and CORT concentrations, and modify responses to EtOH, possibly reflecting impairments of HPA axis regulation in socially-housed rats.

Animals↗
PubMed2005

Noradrenergic and dopaminergic effects of (+)-amphetamine-like stimulants in the baboon Papio anubis.

(+)-Amphetamine, (+/-)-ephedrine, and phentermine are commonly used appetite suppressants that release monoamines from nerve cells by acting as substrates for biogenic amine transporters. One key difference among the three drugs is their selectivity for norepinephrine (NE) release vs. dopamine (DA) release. The NE/DA selectivity ratios for these drugs as determined in vitro [(EC50 NE(-1))/(EC50 DA(-1))] are (+/-)-ephedrine (18.6) > phentermine (6.7) > (+)-amphetamine (3.5). The in vitro data suggest that when administered in vivo, these stimulants might differ in their ability to release DA from nerve terminals in the brain. To test this hypothesis, noradrenergic effects (i.e., plasma NE) and dopaminergic effects (i.e., central DA release) were assessed when each drug was administered intravenously (1.5 mg/kg) to anesthetized baboons. Central DA release was determined via positron emission tomography using the method of [11C]raclopride displacement. In the present investigation, high doses of these stimulants increased plasma NE and DA in parallel, but only (+)-amphetamine released central DA from neurons and decreased plasma prolactin. None of the drugs altered plasma amine metabolite levels, indicating no inhibition of monoamine oxidase activity at the administered doses. Plasma drug levels measured in baboons were higher than those measured in human patients taking prescribed doses of the drugs. Viewed collectively, the present data indicate that typical clinical doses of phentermine and (+/-)-ephedrine may not release central DA in humans, a hypothesis that should ultimately be tested in controlled clinical studies.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy').

3,4-Methylenedioxymethamphetamine (MDMA, or 'Ecstasy') is an illicit drug that stimulates the release of serotonin (5-HT) and dopamine (DA) from neurons. Recent evidence reveals that drug users are ingesting piperazine analogs, like 1-benzylpiperazine (BZP, or 'A2') and 1-(m-trifluoromethylphenyl)piperazine (TFMPP, or 'Molly'), to mimic psychoactive effects of MDMA. In the present study, we compared the neurochemistry of MDMA, BZP, and TFMPP in rats. The effects of MDMA, BZP, and TFMPP on transporter-mediated efflux of [3H]5-HT and [3H]MPP+ (DA transporter substrate) were determined in synaptosomes. The effects of drugs on extracellular levels of 5-HT and DA were examined using in vivo microdialysis in conscious rats. MDMA evoked transporter-mediated release of [3H]5-HT and [3H]MPP+. BZP released [3H]MPP+, whereas TFMPP was a selective releaser of [3H]5-HT. MDMA (1-3 mg/kg, i.v.) increased dialysate 5-HT and DA in a dose-related fashion, with actions on 5-HT being predominant. BZP (3-10 mg/kg, i.v.) elevated dialysate DA and 5-HT, while TFMPP (3-10 mg/kg, i.v.) elevated 5-HT. Administration of BZP plus TFMPP at a 1:1 ratio (BZP/TFMPP) produced parallel increases in dialysate 5-HT and DA; a 3 mg/kg dose of BZP/TFMPP mirrored the effects of MDMA. At a 10 mg/kg dose, BZP/TFMPP increased dialysate DA more than the summed effects of each drug alone, and some rats developed seizures. Our results show that BZP/TFMPP and MDMA share the ability to evoke monoamine release, but dangerous drug-drug synergism may occur when piperazines are coadministered at high doses.

Animals↗
PubMed2004

3,4-methylenedioxymethamphetamine (MDMA) administration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein.

UNLABELLED: Previous experiments conducted in this laboratory showed that administration of high-dose D-fenfluramine (D-FEN) and p-chloroamphetamine (PCA) decreased 5-HT transporter (SERT) binding and tissue 5-HT by 30-60% in caudate and whole brain tissue 2 days and 2 weeks after drug administration. However, protein expression as determined by Western blot analysis did not change in either tissue or time point, except for a 30% decrease in the caudate 2 days after PCA administration. In the present study, we studied the effect of MDMA and 5,7-dihydroxytryptamine (5,7-DHT) on tissue 5-HT levels and the protein expression level of SERT and glial fibrillary acidic protein (GFAP), a validated neurotoxicity marker. HYPOTHESIS: MDMA administration decreases SERT expression. METHODS: Two weeks after MDMA administration (7.5 mg/kg i.p., q 2 h x 3 doses) or 2 weeks after i.c.v. administration of 5,7,-DHT (150 microg/rat), male Sprague-Dawley rats were sacrificed and the caudate, cortex, and hippocampal tissue collected. Western blots for SERT and GFAP were generated using published methods. Tissue 5-HT levels were determined by HPLC coupled to electrochemical detection. RESULTS: MDMA treatment decreased tissue 5-HT in cortex, hippocampus, and caudate by about 50%. However, MDMA treatment had no significant effect on expression level of SERT and GFAP in any brain region. In contrast, 5,7-DHT reduced tissue 5-HT by more than 90%, decreased SERT protein expression by 20-35%, and increased GFAP by 30-39%. CONCLUSION: These data suggest the MDMA treatment regimen used here does not cause degeneration of 5-HT nerve terminals. Viewed collectively with our previous results and other published data, these data indicate that MDMA-induced persistent 5-HT depletion may occur in the absence of axotomy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Synthesis and pharmacological evaluation of 3-(3,4-dichlorophenyl)-1-indanamine derivatives as nonselective ligands for biogenic amine transporters.

In our efforts toward developing a nonselective ligand that would block the effects of stimulants such as methamphetamine at dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporters, we synthesized a series of 3-(3,4-dichlorophenyl)-1-indanamine derivatives. Two of the examined higher affinity compounds had a phenolic hydroxyl group enabling preparation of a medium to long chain carboxylic acid ester that might eventually be useful for a long-acting depot formulation. The in vitro data indicated that (-)-(1R,3S)-trans-3-(3,4-dichlorophenyl)-6-hydroxy-N-methyl-1-indanamine ((-)-(1R,3S)-11) displays high-affinity binding and potent inhibition of uptake at all three biogenic amine transporters. In vivo microdialysis experiments demonstrated that intravenous administration of (-)-(1R,3S)-11 to rats elevated extracellular DA and 5-HT in the nucleus accumbens in a dose-dependent manner. Pretreating rats with 0.5 mg/kg (-)-(1R,3S)-11 elevated extracellular DA and 5-HT by approximately 150% and reduced methamphetamine-induced neurotransmitter release by about 50%. Ex vivo autoradiography, however, demonstrated that iv administration of (-)-(1R,3S)-11 produced a dose-dependent, persistent occupation of 5-HT transporter binding sites but not DA transporter sites.

Animals↗