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Biomedical subjects

J Bergman

Publications and source records attributed to J Bergman.

At least 19 recordsLinked to original sources

Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects.

BACKGROUND: There are sex differences in the clinical features of several neuropsychiatric illnesses associated with dopamine dysfunction. The effects of sex on brain dopaminergic function have been sparsely studied in human subjects using modern imaging techniques. We have previously reported that the apparent affinity of [(11)C]raclopride for striatal D(2) dopamine receptors in vivo is lower in women than in men, whereas D(2) receptor density is not different. This finding indirectly suggests that women have a higher synaptic concentration of dopamine in the striatum. We explored further the basis of this phenomenon in an independent study and hypothesized that striatal presynaptic dopamine synthesis capacity would also be elevated in women. METHODS: A total of 23 healthy men and 12 healthy women (age range 20-60 years) were studied using positron emission tomography and [(18)F]fluorodopa. RESULTS: Women had significantly higher striatal [(18)F]fluorodopa uptake (Ki values) than men. The difference was more marked in the caudate (+26%) than in the putamen (+12%). In addition, there was a negative correlation between striatal [(18)F]fluorodopa Ki values and age in men but not in women. CONCLUSIONS: The results further substantiate sex differences in striatal dopaminergic function in humans. This finding may be associated with sex differences in vulnerability and clinical course of neuropsychiatric disorders with dopaminergic dysregulation, e.g., schizophrenia, alcohol dependence, and Parkinson's disease.

Adult↗

Comparison of acute toxicities of indolo[3,2-b]carbazole (ICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons are environmental toxicants that act via the AH receptor (AHR). In vitro studies have demonstrated that some indole derivatives present in cruciferous vegetables also bind to the AHR. One of the highest AHR binding affinities is exhibited by indolo[3,2-b]carbazole (ICZ). Since exposure to these dietary indoles is quantitatively far larger than that to halogenated aromatic compounds, their potential toxic risks have raised concern. In the present study, we compared the effects of ICZ with those of a single dose of 20 microg/kg TCDD in the most TCDD-sensitive rat strain (Long-Evans [Turku AB]) (L-E). Whereas TCDD elicited the expected toxicity syndrome, ICZ, either as a single subcutaneous dose (63.5, 127 or 508 microg/kg) or with repeated sc dosing (508 microg/kg for 5 days) failed to reproduce any toxic impacts of TCDD. Furthermore, a simultaneous ICZ treatment (63.5 or 127 microg/kg for 10 days) did not interfere with TCDD (20 microg/kg; single exposure) action. A moderate hepatic induction of CYP1A1 could be triggered by repeated intragastric administration of ICZ (127 microg/kg for 4 days, the last treatment 2.5 h prior to termination). In control experiments in a reconstituted yeast system, ICZ potently and dose-dependently activated L-E rat AHR function demonstrating that it represents a bona fide high-affinity ligand for the rat receptor in vivo. Thus, the present study does not support the view that dietary exposure to ICZ would present a hazard of AHR-mediated adverse health effects to humans.

Animals↗

Caffeine: behavioral effects of withdrawal and related issues.

Acquired tolerance to some behavioral effects of caffeine in humans is widely assumed to occur but is poorly documented and appears, at most, to be of low magnitude. Withdrawal from regular consumption of caffeine has been reported to result in a variety of symptoms, including: irritability, sleepiness, dysphoria, delerium, nausea, vomiting, rhinorrhea, nervousness, restlessness, anxiety, muscle tension, muscle pains and flushed face. Some of these same symptoms have been reported following excess intake of caffeine. The prevalence of symptoms reported on withdrawal in different studies also covers a wide range from 11% or less to 100%. It is suggested that the evidence leads to the conclusion that non pharmacological factors related to knowledge and expectation are the prime determinants of symptoms and their reported prevalence on withdrawal of caffeine after regular consumption.

Behavior↗

Severe somatization in women is associated with altered cerebral glucose metabolism.

BACKGROUND: Somatization is a clinical phenomenon characterized by multiple, medically unexplained somatic symptoms. The pathophysiology remains unknown. We aimed to test the hypothesis of a central nervous system dysfunction in the pathophysiology of this disorder. METHOD: We studied 10 female patients diagnosed as having somatization disorder or undifferentiated somatoform disorder with no current Axis I disorders according to DSM-IV. They were compared with 17 healthy female volunteers using brain [18F]-fluorodeoxyglucose-PET with MRI reference. RESULTS: The patients had lower cerebral metabolism rates of glucose (P<0.05) in both caudate nuclei, left putamen and right precentral gyrus compared with healthy volunteers. CONCLUSIONS: This is the first study to demonstrate changes in brain metabolism in somatizing women. The regional cerebral hypometabolism is probably associated with the pathophysiology of somatization.

Adult↗

2-[(18)F]fluoro-2-deoxy-D-glucose combined with microdialysis can be used for the comparison of tissue glucose metabolism in obese and lean rats.

AIMS: Direct assessment of tissue metabolism in vivo is important to understand the pathogenesis of obesity. Labelled glucose analogues are potential candidates to be used for this purpose. The aim of this study was to compare the kinetics and metabolism of 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) in obese (fa/fa) and lean (Fa/?) Zucker rat tissues with microdialysis, and the measurement of uptake and phosphorylation with or without insulin bolus injection. METHODS: Obese (n = 10) and lean (n = 11) anaesthetized rats underwent a microdialysis study after FDG-injection either with or without insulin stimulation. Microdialysis probes were inserted in the jugular vein, quadriceps muscle and liver. After 110 min, tissue [(18)F]-uptake and intracellular phosphorylation of FDG were studied in blood, liver, skeletal muscle, subcutaneous adipose tissue, intra-abdominal adipose tissue and hypothalamus. RESULTS: When measured with microdialysis, insulin-enhanced FDG disappeared from the blood pool and interstitial space of skeletal muscle and liver more effectively in lean rather than in obese animals. Insulin-stimulated skeletal muscle and adipose tissue[(18)F]-uptake was impaired in obese Zucker rats compared with lean animals. Hypothalamic FDG uptake was six to sevenfold higher than in other measured tissues, but was attenuated in obese rats. In liver and in mesenteric fat, insulin-enhanced FDG phosphorylation in lean rats compared with obese animals. CONCLUSIONS: Positron-emitting glucose analogue FDG, combined with microdialysis and tissue analysis, is a feasible method in studying glucose metabolism at the cellular level in animal studies.

Animals↗

Comparison of vedaprofen and meloxicam in dogs with musculoskeletal pain and inflammation.

In this randomised, multicentre clinical study, dogs with musculoskeletal pain and inflammation were treated with either vedaprofen or meloxicam administered orally at the recommended dose rates. Clinical examinations were carried out regularly and clinical severity scores assigned. In total, 214 cases (73 acute, 141 chronic) were evaluated. Treatment with vedaprofen and meloxicam was continued for 14 and 17 days, respectively, in the acute cases, and 38 and 39 days in the chronic cases. NSAID treatment resulted in a significant improvement in clinical scores. The overall response to treatment ('responders') at the final clinical examination was 89 per cent and 87 per cent in the acute cases and 72 per cent and 65 per cent in the chronic cases in the vedaprofen and meloxicam groups, respectively. Mild transient gastrointestinal signs were observed in both groups (11 per cent vedaprofen, 12 per cent meloxicam). Adverse effects related to NSAIDs resulted in treatment cessation in 5 per cent of the dogs in each group. Vedaprofen and meloxicam were efficacious in, and well tolerated by, most of the dogs in the study.

Acute Disease↗

Interactions between cocaine and dopamine agonists on cardiovascular function in squirrel monkeys.

Conscious squirrel monkeys were treated i.v. with cocaine and various dopamine agonist drugs. Cocaine produced a dose-dependent increase in blood pressure, heart rate, and the rate-pressure product (RPP). The dopamine D1 receptor agonist (+/-)-6-chloro-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 82958) produced effects comparable to cocaine. The D1 agonist (+/-)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) also produced increases in blood pressure and heart rate but was much less potent than either cocaine or SKF 82958. The partial D1 agonist (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF 77434) did not significantly affect any cardiovascular parameters. The D2 agonist quinpirole slightly decreased blood pressure and increased heart rate. As such, the RPP only slightly increased. The selective dopamine uptake inhibitor 1-[2-[bis-(4-fluorphenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) produced increases in blood pressure, heart rate, and RPP, but again these effects were smaller and only seen at doses higher than cocaine. Effects similar to those with GBR 12909 were seen with the dopamine autoreceptor antagonist cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232). The combination of GBR 12909, SKF 82958, or SKF 77434 with cocaine produced effects that were clearly subadditive. The effects of quinpirole in combination with cocaine were comparable to, or lower than, those of cocaine alone on blood pressure and RPP. The effects on heart rate were additive. Only UH 232 produced additive effects with cocaine for all three measures. As dopamine agonists have been proposed as potential treatments for cocaine abuse, these results suggest that dopamine D1 agonists and uptake inhibitors can be used safely in combination with cocaine. Caution may be warranted, however, with the use of dopamine autoreceptor antagonists in the treatment of cocaine abuse.

Animals↗

Personality traits and brain dopaminergic function in Parkinson's disease.

A distinctive personality type, characterized by introversion, inflexibility, and low novelty seeking, has been suggested to be associated with Parkinson's disease. To test the hypothesis that Parkinson's disease is associated with a specific dopamine-related personality type, the personality structures of 61 unmedicated Parkinson's disease patients and 45 healthy controls were examined. Additionally, in 47 Parkinson's disease patients, the dopaminergic function in the brain was directly measured with 6-[(18)F]fluoro-l-dopa ((18)F-dopa) positron emission tomography (PET) with MRI coregistration. The novelty-seeking personality score, supposedly associated with the parkinsonian personality, was slightly lower in the Parkinson's disease group compared with controls, but it did not have a significant relationship with (18)F-dopa uptake in any of the brain regions studied (r = -0.12 to 0.11, P > 0.15). The harm-avoidance personality score, associated with anxiety and depression, was clearly increased in patients with Parkinson's disease and it had a paradoxical, highly significant positive correlation with the (18)F-dopa uptake in the right caudate nucleus (r = 0.53, P = 0.04, Bonferroni corrected for 220 comparisons). Although the results of this study are not in disagreement with the concept of low-novelty-seeking personality type in Parkinson's disease, the personality type does not seem to be dopamine dependent. The correlation between the personality trait of harm avoidance and (18)F-dopa may reflect a specific feedback circuitry of neurotransmitters that is associated with negative emotionality in Parkinson's disease.

Aged↗

Decreased striatal dopamine transporter binding in vivo in chronic schizophrenia.

We have previously reported that average striatal dopamine transporter (DAT) binding in vivo is unaltered in neuroleptic-naive first-episode schizophrenic patients [Laakso et al., Am. J. Psychiatry 157 (2000) 269]. However, as it has been suggested that some of the brain changes in schizophrenia may vary depending on the illness phase, we studied DAT density in eight stable, medicated chronic schizophrenic patients and eight matched controls using positron emission tomography and [18F]CFT, a marker of dopamine nerve terminals. [18F]CFT binding potentials were significantly lower in chronic schizophrenic patients than in controls, both in the caudate and the putamen (-9 to -16%). Together with the finding of unchanged average striatal DAT levels in first-episode patients and relative insensitivity of striatal [18F]CFT binding to endogenous dopamine and neuroleptic drugs, the result is in line with a relative loss of striatal dopaminergic nerve terminals and/or decreased expression of DAT in a subset of chronic schizophrenic patients.

Adult↗

Positron emission tomography shows that impaired frontal lobe functioning in Parkinson's disease is related to dopaminergic hypofunction in the caudate nucleus.

We examined the relation between the dopaminergic function and the cognitive performance of patients with Parkinson's disease (PD). The subject sample consisted of ten patients in the early course of PD and with no previous antiparkinsonian medication. The dopaminergic function of the caudate nucleus and the putamen was studied with [(18)F]fluorodopa positron emission tomography, and the cognitive performance with a comprehensive battery of neuropsychological tests including tests sensitive to frontal lobe function. The decreased [(18)F]fluorodopa uptake in the right caudate nucleus was found to be related to slow processing time, measured as the difference between the incongruent and the congruent subtests of the Stroop Test (r=-0.85, P=0.002), a similar trend was seen in the left caudate (r=-0.60, P=0.07). Similar correlation was not detected in the putamen. The present findings provide evidence that the decreased dopaminergic function in the right caudate nucleus is related to the impaired performance in tests sensitive to frontal lobe function in patients at an early stage of PD and with no antiparkinsonian medication.

Adult↗

Psychomotor stimulant effects of beta-phenylethylamine in monkeys treated with MAO-B inhibitors.

RATIONALE AND OBJECTIVE: Sufficiently high doses of beta-phenylethylamine (beta-PEA), a trace amine that is rapidly metabolized by monoamine oxidase-type B (MAO-B), can produce effects comparable to those of cocaine or methamphetamine (MA). The present experiments were conducted to study how the discriminative-stimulus (S(D)) and reinforcing-stimulus (S(R)) effects of beta-PEA in monkeys are modified by treatment with inhibitors of MAO-B [R-(-)-deprenyl and MDL 72974]. METHODS AND RESULTS: In studies of its S(D) effects, doses of beta-PEA up to 30 mg/kg engendered only sporadic responding on the drug-associated lever in squirrel monkeys that discriminated intramuscular injections of 0.3 mg/kg MA from vehicle whereas lower doses of 0.3-1.0 mg/kg beta-PEA produced full substitution when administered after either R-(-)-deprenyl or MDL 72974 (0.3 mg/kg). The MA-like S(D) effects of beta-PEA were attenuated by either dopamine D(1) or D(2) receptor blockers. In studies of its S(R) effects, high doses of beta-PEA maintained responding in two of three monkeys under a second-order fixed-interval schedule (3.0 or 10 mg/kg per injection) and two of three monkeys under a simple fixed ratio (FR) schedule (0.3-1.0 mg/kg per injection) of intravenous (i.v.) self-administration. MAO-B inhibition by R-(-)-deprenyl or MDL 72974 enhanced the S(R) effects of beta-PEA in all monkeys and, under the FR schedule, induced a 30-fold or greater leftward shift in the dose-response function for its i.v. self-administration. Based on time-course determinations, the enhanced S(R) effects of beta-PEA under the FR schedule were long-lasting and dissipated gradually over 3-7 days. CONCLUSIONS: These results show that inhibition of MAO-B enhances S(D) and S(R) effects of beta-PEA in monkeys, presumably by delaying its inactivation. MAO-B inhibition leading to increased levels of beta-PEA may be useful, alone or in combination with other therapeutic agents, in the pharmacological management of selected aspects of drug dependence.

Animals↗

[(18)F]FDOPA and [(18)F]CFT are both sensitive PET markers to detect presynaptic dopaminergic hypofunction in early Parkinson's disease.

The aim of this study was to compare two PET ligands, 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) and (18)F-labeled CFT, 2beta-carbomethoxy-3beta-(4-[(18)F]-fluorophenyl)tropane ([(18)F]CFT), in detecting presynaptic dopaminergic hypofunction in early Parkinson's disease (PD). These ligands reflect different aspects of presynaptic dopaminergic function, since [(18)F]FDOPA mainly reflects 6-[(18)F]fluorodopamine (fluorodopamine) synthesis and storage whereas [(18)F]CFT uptake is related to dopamine transporter function. Eight de novo patients with PD who had never been on antiparkinsonian medication were investigated with [(18)F]FDOPA and [(18)F]CFT PET. Five healthy volunteers were studied as controls. In PD patients, both [(18)F]FDOPA and [(18)F]CFT uptakes were significantly reduced both in the contralateral and ipsilateral anterior and posterior putamen. The reduction was greatest in the contralateral posterior putamen (to 28% of control mean for [(18)F]FDOPA, P < 0.0001 and to 16% for [(18)F]CFT, P < 0.0001). Individually, all patients' [(18)F]FDOPA and [(18)F]CFT uptake values in the contralateral anterior and posterior putamen were below 3 SD of the control mean. In the caudate nucleus, the mean uptake of both tracers was significantly reduced both ipsilaterally and contralaterally, but less severely than in the putamen (to 69% of the control mean for [(18)F]FDOPA, P = 0.003 and to 60% for [(18)F]CFT, P = 0.001 contralaterally). Our results show that both [(18)F]FDOPA as well as [(18)F]CFT sensitively detect presynaptic dopaminergic hypofunction in early PD. They demonstrate a considerable reduction of tracer uptake that is greatest in the posterior putamen, followed by the anterior putamen and the caudate nucleus.

Aged↗

Total syntheses of the benzodiazepine alkaloids circumdatin F and circumdatin C.

Total syntheses of circumdatin F and circumdatin C, which both possess a 3H-quinazolin-4-one as well as a 1,4-benzodiazepin-5-one moiety, are described. A tripeptide derivative was synthesized as a key intermediate and dehydrated to a benzoxazine by reaction with triphenylphosphine, iodine, and a tertiary amine. The natural products were attained via rearrangements to an amidine intermediate, deprotection with 45% HBr in acetic acid, and cyclization on silica gel.

Alkaloids↗

Detection of response to COMT inhibition in FDOPA PET in advanced Parkinson's disease requires prolonged imaging.

The aim was to investigate whether the improved 6-[(18)F]fluoro-L-dopa (FDOPA) availability induced by catechol-O-methyltransferase (COMT) inhibition can be more clearly seen during late than during standard (early) imaging in FDOPA uptake in Parkinson's disease (PD) patients with severe dopaminergic hypofunction. Six PD patients and six healthy controls were investigated up to 3.5 h after FDOPA injection with and without a single 400-mg dose of a peripheral COMT inhibitor, entacapone. Prolonged (late) imaging showed a significantly higher increase in FDOPA uptake than standard 1.5 h (early) imaging after entacapone both in controls and in PD patients. The increase in the (putamen-occipital):occipital ratios was 37.4% during early and 70.4% during late imaging in controls. In PD patients, there was no significant change in the ratios during early imaging, but the late imaging showed a significant increase in the putamen-to-occipital ratio of 54.2% after COMT inhibition. Late imaging reveals more clearly the prolonged FDOPA availability induced by COMT inhibition leading to higher cumulated striatal activity compared with early imaging. This might be worth considering in FDOPA studies, especially if investigations are planned to do without blood sampling. Late imaging shows the storing potential of FDA better than is seen during early FDOPA PET imaging after entacapone administration. In patients with severe presynaptic dopaminergic hypofunction, its detection requires prolonged imaging.

Aged↗

Rate of progression in Parkinson's disease: a 6-[18F]fluoro-L-dopa PET study.

The aim of this study was to investigate the rate of progression in Parkinson's disease (PD) with 6-[(18)F]fluoro-L-dopa (FDOPA) positron emission tomography (PET). We investigated 21 patients with PD and eight healthy controls. Ten of the patients were de novo at the time of the first PET scan and antiparkinsonian medication was started thereafter, with a favourable response. A FDOPA PET scan was carried out twice at an approximately 5-year interval. The regions of interest were drawn on individual magnetic resonance imaging (MRI) images, matched with the PET images. At the first PET scan, in PD patients the mean k(i)(occ) (x 10(-3) min(-1)) in the anterior putamen was 5.6 +/- 2.7 (mean +/- S.D.; 55% of the control mean) and in the posterior putamen 4.5 +/- 2.4 (45% of the control mean). The k(i)(occ) value for the caudate nucleus was 7.5 +/- 2.1 (x 10(-3) min(-1); 76% of the control mean). The FDOPA uptake declined by the time of the second PET scan and the annual rate of decline was 8.3 +/- 6.3% (P < 0.001) of the baseline mean in the anterior putamen and 10.3 +/- 4.8% (P < 0.001) in the posterior putamen. In the caudate nucleus, FDOPA uptake decreased by 5.9 +/- 5.1% (P < 0.001) of the baseline mean per year. The estimated preclinical period was longest for the posterior putamen being 6.5 years. For the anterior putamen the preclinical period was 4.6 years. In the caudate nucleus, the estimated FDOPA uptake was at normal level at disease onset. In healthy controls, there was no significant decline in FDOPA uptake in any striatal subregion. Our results suggest that the disease process in PD first affects posterior putamen, followed by the anterior putamen and the caudate nucleus, but once started, the absolute rate of decline is the same. In healthy controls, no significant decline in FDOPA was detected.

Adult↗

Different types of GABA(A) receptors may mediate the anticonflict and response rate-decreasing effects of zaleplon, zolpidem, and midazolam in squirrel monkeys.

RATIONALE: The role of different types of GABA(A) receptors in mediating anticonflict and response rate-decreasing effects of benzodiazepines in primate species is not known. OBJECTIVE: To examine the behavioral effects of the benzodiazepine-site, GABA(A) agonists zolpidem, zaleplon, and midazolam in the presence of two antagonists, flumazenil and beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) in squirrel monkeys. METHODS: Two schedules of operant responding were used: (1) a multiple fixed-ratio (FR) schedule of food presentation involving punished and nonpunished behavior, and (2) an FR schedule of stimulus shock-termination. RESULTS: Midazolam (0.03-1.0 mg/kg), zolpidem (0.1-3.0 mg/kg), and zaleplon (0.1-3.0 mg/kg) increased rates of punished responding and decreased rates of nonpunished responding under the multiple schedule. Pretreatment with flumazenil (0.3-1.0 mg/kg) antagonized the anticonflict and response rate-decreasing effects of all three agonists. Pretreatment with beta-CCt (3-10 mg/kg) antagonized the anticonflict and rate-decreasing effects of midazolam, as well as the rate-decreasing effects of zolpidem and zaleplon. However, beta-CCt did not antagonize the anticonflict effects of zolpidem and zaleplon; instead, these effects of zolpidem and zaleplon were apparently enhanced in the presence of beta-CCt. Under the schedule of stimulus shock-termination, both flumazenil and beta-CCt antagonized zolpidem and zaleplon; however, the effects of beta-CCt were less consistent than the effects of flumazenil. CONCLUSION: In nonhuman primates, different types of GABAA receptors may mediate the anticonflict and the response rate-decreasing effects of the nonselective GABAA agonist midazolam and the selective GABAA1 agonists zolpidem and zaleplon.

Acetamides↗

Automated synthesis and purification of [18F]bromofluoromethane at high specific radioactivity.

[18F]Bromofluoromethane was synthesised from dibromomethane by substitution of bromine with [18F]fluoride. The synthesis and separation of the [18F]bromofluoromethane were automated. [18F]Bromofluoromethane was used to convert a phenolic and a thiophenolic precursor into a labelled ether and thioether, respectively. The specific radioactivity of these labelled products was determined with both high-performance liquid chromatography (with UV-absorbance detection) and liquid chromatography (with mass spectrometric detection). The median for the specific radioactivity, corrected at the end of radionuclide production, was 934GBq/micromol (range 40-9900 GBq/micromol; n = 83).

Automation↗

Synthesis of S-([18F]fluoromethyl)-(+)-McN5652 as a potential PET radioligand for the serotonin transporter.

The present study describes the synthesis of the [18F]fluoromethyl analogue of (+)-McN5652 ([18F]FMe-McN) as a new potential tracer for the serotonin transporter. In vitro binding studies have shown that FMe-McN displays only slightly lower affinity for the serotonin transporter (K(i) = 2.3 +/- 0.1 nM) than (+)-McN5652 (K(i) = 0.72 +/- 0.2 nM). The radiofluorinated tracer [18F]FMe-McN was prepared by reaction of normethyl (+)-McN5652 with the fluoromethylation agent [18F]bromofluoromethane in an overall radiochemical yield of 5 +/- 1% (decay-corrected, related to [18F]fluoride) and with high specific radioactivity (200-2,000 GBq/micromol at the end of synthesis).

Animals↗