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Modulation of dopamine release by striatal 5-HT2C receptors.

Previous work has demonstrated that dopamine (DA) transmission is regulated by serotonin-2C (5-HT2C) receptors but the site(s) in the brain where these receptors are localized is not known. The present work utilized in vivo microdialysis to investigate the modulation of DA release by 5-HT2C receptors localized in the nerve terminal regions of the mesocortical and nigrostriatal DA pathways. Microdialysis probes implanted in the striatum or the prefrontal cortex (PFC) measured dialysate DA concentrations, while the selective 5-HT2B/2C inverse agonist SB 206553 was given locally by reverse dialysis into these terminal regions. Additionally, the effects of the 5-HT2C agonist mCPP on striatal DA were measured. Local administration of SB 206553 (0.1-100 microM) into the striatum increased DA efflux in a concentration-dependent manner. Systemic administration of mCPP (1.0 mg/kg i.p.) decreased striatal DA and attenuated the SB 206553-induced increase. In contrast, infusion of SB 206553 (0.1-500 microM) by reverse dialysis into the PFC had no significant effect on basal DA efflux in this region. Additionally, high concentrations of SB 206553 had no effect on high potassium (K(+))-stimulated DA release in the PFC. These data contribute to a body of evidence indicating that 5-HT2C receptors inhibit nigrostriatal dopaminergic transmission. In addition, the results suggest that the nigrostriatal system is regulated by 5-HT2C receptors localized in the dorsal striatum. Elucidating the mechanisms by which serotonin (5-HT) modulates striatal and prefrontocortical DA concentrations may lead to improvements in the treatment of diverse syndromes such as schizophrenia, Parkinson's disease, anxiety, drug abuse, and/or depression.

Animals↗

Further evidence for a correlation between EEG synchronization and plasma DBH activity in normal subjects.

In a former investigation we had got evidence for a relationship between synchronization of the resting EEG and plasma dopamine-beta-hydroxylase (DBH) activity in healthy males. In order to substantiate this finding we now examined a new sample of males and a sample of females, both with either low-voltage or monotonous alpha-EEGs, and relatives of probands with either EEG type. In the new sample of males, the carriers of a low-voltage EEG (n = 15) again had significantly lower plasma DBH activity than the subjects with a monotonous alpha-EEG (n = 16). In females there was no difference. In the families of probands with a monotonous alpha-EEG the relatives carrying the trait significantly exceeded non-trait-carriers in DBH activity. This effect is mainly due to the male subjects, confirming the results in the proband groups. Presumably there are common genetic factors that contribute to the variability of both the EEG and DBH.--Taking into account experimental findings on central catecholaminergic activity and EEG synchronization, a hypothesis on the mechanisms that are responsible for the relationship is proposed.

Brain↗

[Physiologic variability of plasma catecholamines].

In an earlier publication, we described a modified procedure for the determination of plasma catecholamine levels using high-performance liquid chromatography (HPLC), followed by amperometry. In this paper, we present our results on the variability of normal catecholamine values in plasma for noradrenaline (NA), adrenaline (A) and dopamine (DA). In 122 women and men at rest, the range for NA was 0.15-3.5 nmol/l, for A 0.01-0.8 nmol/l and for DA 0.04-4.5 nmol/l. We also describe the effects of orthostasis, intravenous catheters, food intake, cigarette smoking, age and sex on venous catecholamine levels. The efficiency of the HPLC method allowed us to check, using a large subject group, the results obtained by other authors from studies involving smaller subject groups with more expensive and time-consuming methods.

Adult↗

Electrochemical detection of catecholamines in urine and plasma after separation with HPLC.

The catecholamines in plasma and urine were determined by electrochemical detection after separation on a HPLC column RCM 100 C 18. Linear calibration plots of epinephrine, norepinephrine and dopamine have been obtained in the range expected to appear in urine or plasma. Coefficients of variation (0.5 to 10%), recovery rates (60 to 80%) and the standard deviation were satisfactory, whereas plasma dopamine showed a greater variation (10-15%). The values ascertained by this technique were compared with those determined by the radioenzymatic assay of Da Prada et al. They showed a good correlation for norepinephrine r = 0.92, p less than 0.001 and epinephrine r = 0.80, p less than 0.01, but less for dopamine r = 0.1. Experimental details of isolation from plasma with Al2O3 adsorption and desorption with HClO4, and from urine with ion exchange chromatography on Bio-Rex 70 and elution with boric acid are described. Technical modifications which improve the method are reported. The optimized assay could reliably be employed in investigations of more than 3000 urine and plasma samples obtained from patients and athletes before and after exercise.

Chromatography, High Pressure Liquid↗

M100,907, a selective 5-HT(2A) antagonist, attenuates dopamine release in the rat medial prefrontal cortex.

Previous research has suggested that serotonin 5-HT(2A) receptors modulate the functioning of the mesocortical dopamine (DA) pathway. However, the specific role of 5-HT(2A) receptors localized within the medial prefrontal cortex (mPFC) is not known. The present study employed in vivo microdialysis to examine the role of this receptor in the modulation of basal and K(+)-stimulated (Ca(2+)-dependent) DA release. The selective 5-HT(2A) antagonist M100,907 was infused directly into the mPFC of conscious rats. This resulted in a concentration-dependent blockade of K(+)-stimulated DA release. Intracortical application of M100,907 also blocked increases in DA release produced by the systemic administration of the 5-HT(2A/2C) agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). These findings demonstrate that local 5-HT(2A) antagonism has an inhibitory effect on stimulated, Ca(2+)-dependent DA release. They suggest that cortical 5-HT(2A) receptors potentiate the phasic release of mesocortical DA.

Amphetamines↗

Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat.

Altered dopamine regulation in the medial prefrontal cortex has been linked to drug abuse and disorders such as schizophrenia. Heterogeneous expression of the dopamine transporter, as well as the ability of the norepinephrine transporter to clear dopamine in the prefrontal cortex, delineates two potential sites for the regulation of synaptic dopamine within the cortex. The present study used in vivo microdialysis to compare the effects of local infusions of dopamine and norepinephrine uptake blockers in the caudate putamen and two subregions of the prefrontal cortex, the anterior cingulate and prelimbic/infralimbic cortices. Results revealed that all dopamine uptake blockers produced greater increases in dopamine efflux in the caudate-putamen relative to the prefrontal cortex. In addition, amphetamine administration increased dopamine efflux to a greater degree in the prelimbic, relative to the anterior cingulate, cortex. In contrast, the increase in dopamine efflux was similar in both subregions in the presence of nomifensine and desmethylimipramine. Infusions of the selective dopamine uptake blocker GBR 12909 failed to alter dopamine efflux in any prefrontocortical subregion. These data indicate a more prominent role for the dopamine transporter in the clearance of extracellular dopamine in the caudate-putamen relative to the prefrontal cortex and an important role for NET in the clearance of dopamine in both the prelimbic and anterior cingulate subregions of the rat medial prefrontal cortex.

Adrenergic Uptake Inhibitors↗

Russian program of planetary missions.

In the area of Solar System Exploration most of recently proposed mission oriented to the studies of Mars. Except MARS-96 and possibly MARS SAMPLE RETURN missions other Mars missions use Molnija class launchers. All Russian missions heavily involve international partners.

Equipment Design↗

Ion irradiation: its relevance to the evolution of complex organics in the outer solar system.

Ion irradiation of carbon containing ices produces several effects among which the formation of complex molecules and even refractory organic materials whose spectral color and molecular complexity both depend on the amount of deposited energy. Here results from laboratory experiments are summarized. Their relevance for the formation and evolution of simple molecules and complex organic materials on planetary bodies in the external Solar System is outlined.

Carbon↗

Normal values of catecholamines in blood plasma determined by high-performance liquid chromatography with amperometric detection.

Norepinephrine (NE), epinephrine (EPI), and dopamine (DA) were determined in the blood plasma of 122 subjects by high-performance liquid chromatography with amperometric detection (HPLCA). The range of normal values in the supine position was 0.15-3.50 nmol/l for NE, 0.01-0.80 nmol/l for EPI, and 0.04-4.50 nmol/l for DA. The effect induced by inserting intravenous catheters, food intake, cigarette smoking, varying body positions, and sex differences are also presented in this paper. As a modified HPLCA method was used, we were able to examine a large collective group. Thus, it was possible to compare the results of other authors which have been found in smaller collective groups.

Adult↗

Cardiocirculatory, hormonal, and metabolic reactions to various forms of ergometric tests.

The sympathoadrenergic reaction is not only dependent on the duration and intensity of work but also on the body position and the involvement of small or large muscle masses. This observation made in field tests comparing different sports disciplines such as swimming, running, or diving encouraged us to investigate this topic under the following laboratory conditions. Twelve healthy sport students participated in ergometric tests on a bicycle ergometer in a horizontal and vertical body position as well as on a treadmill and a swim bench ergometer. The changes of plasma catecholamines (CA) obtained in the different ergometric tests were compared with those cardiocirculatory, metabolic, and hormonal parameters which can be influenced by the sympathoadrenergic stimulation. In the horizontal body position we found a smaller increase of norepinephrine at submaximal and maximal work loads combined with a similar reaction of renin, whereas the diastolic blood pressure and the mean arterial blood pressure increased more. The substrates of lipolysis and aerobic and anaerobic glycolysis did not show obvious differences depending on the body position. In the swim bench test, however, the lactate increase started earlier and was comparatively higher than in the other ergometric tests in which the maximal work load and VO2max were higher. Although a smaller muscle mass was used and a lower maximal oxygen uptake was reached, we did not find statistically different CA values during the swim bench ergometric test compared with the bicycle ergometric test in a horizontal body position. In our ergometric tests, the venous CA levels (especially norepinephrine) were predominantly influenced by the body position.

Adult↗

Role of development in reorganization of the SI forelimb-stump representation in fetally, neonatally, and adult amputated rats.

Rats that sustain forelimb removal on postnatal day (P) 0 exhibit numerous multi-unit recording sites in the forelimb-stump representation of primary somatosensory cortex (SI) that also respond to hindlimb stimulation when cortical GABAA+B receptors are blocked. Most of these hindlimb inputs originate in the medial SI hindlimb representation. Although many forelimb-stump sites in these animals respond to hindlimb stimulation, very few respond to stimulation of the face (vibrissae or lower jaw), which is represented in SI just lateral to the forelimb. The lateral to medial development of SI may influence the capacity of hindlimb (but not face) inputs to "invade" the forelimb-stump region in neonatal amputees. The SI forelimb-stump was mapped in adult (>60 days) rats that had sustained amputation on embryonic day (E) 16, on P0, or during adulthood. GABA receptors were blocked and subsequent mapping revealed increases in nonstump inputs in E16 and P0 amputees: fetal amputees exhibited forelimb-stump sites responsive to face (34%), hindlimb (10%), and both (22%); neonatal amputees exhibited 10% face, 39% hindlimb, and 5% both; adult amputees exhibited 10% face, 5% hindlimb, and 0% both, with approximately 80% stump-only sites. These results indicate age-dependent differences in receptive-field reorganization of the forelimb-stump representation, which may reflect the spatiotemporal development of SI. Results from cobalt chloride inactivation of the SI vibrissae region and electrolesioning of the dysgranular cortex suggest that normally suppressed vibrissae inputs to the SI forelimb-stump area originate in the SI vibrissae region and synapse in the dysgranular cortex.

Action Potentials↗

Reducing contralateral SI activity reveals hindlimb receptive fields in the SI forelimb-stump representation of neonatally amputated rats.

In adult rats that sustained forelimb amputation on the day of birth, >30% of multiunit recording sites in the forelimb-stump representation of primary somatosensory cortex (SI) also respond to cutaneous hindlimb stimulation when cortical GABA(A+B) receptors are blocked (GRB). This study examined whether hindlimb receptive fields could also be revealed in forelimb-stump sites by reducing one known source of excitatory input to SI GABAergic neurons, the contralateral SI cortex. Corpus callosum projection neurons connect homotopic SI regions, making excitatory contacts onto pyramidal cells and interneurons. Thus in addition to providing monosynaptic excitation in SI, callosal fibers can produce disynaptic inhibition through excitatory synapses with inhibitory interneurons. Based on the latter of these connections, we hypothesized that inactivating the contralateral (intact) SI forelimb region would "unmask" normally suppressed hindlimb responses by reducing the activity of SI GABAergic neurons. The SI forelimb-stump representation was first mapped under normal conditions and then during GRB to identify stump/hindlimb responsive sites. After GRB had dissipated, the contralateral (intact) SI forelimb region was mapped and reversibly inactivated with injections of 4% lidocaine, and selected forelimb-stump sites were retested. Contralateral SI inactivation revealed hindlimb responses in approximately 60% of sites that were stump/hindlimb responsive during GRB. These findings indicate that activity in the contralateral SI contributes to the suppression of reorganized hindlimb receptive fields in neonatally amputated rats.

Action Potentials↗

Local GABA receptor blockade reveals hindlimb responses in the SI forelimb-stump representation of neonatally amputated rats.

In adult rats that sustained forelimb amputation on the day of birth, there are numerous multi-unit recording sites in the forelimb-stump representation of primary somatosensory cortex (SI) that also respond to cutaneous stimulation of the hindlimb when cortical receptors for GABA are blocked. These normally suppressed hindlimb inputs originate in the SI hindlimb representation and synapse in the dysgranular cortex before exciting SI forelimb-stump neurons. In our previous studies, GABA (A + B) receptor blockade was achieved by topically applying a bicuculline methiodide/saclofen solution (BMI/SAC) to the cortical surface. This treatment blocks receptors throughout SI and does not allow determination of where along the above circuit the GABA-mediated suppression of hindlimb information occurs. In this study, focal injections of BMI/SAC were delivered to three distinct cortical regions that are involved in the hindlimb-to-forelimb-stump pathway. Blocking GABA receptors in the SI hindlimb representation and in the dysgranular cortex was largely ineffective in revealing hindlimb inputs ( approximately 10% of hindlimb inputs were revealed in both cases). In contrast, when the blockade was targeted at forelimb-stump recording sites, >80% of hindlimb inputs were revealed. Thus GABAergic interneurons within the forelimb-stump representation suppress the expression of reorganized hindlimb inputs to the region. A circuit model incorporating these and previous observations is presented and discussed.

Amputation Stumps↗

Factors affecting reproductive decisions of African American women living with HIV.

PURPOSE: This exploratory study used focus groups to examine attitudes and beliefs of HIV-infected African American women of child-bearing age about pregnancy and antiretroviral therapy. METHODS: A convenience sample of thirty-three African American women of child-bearing age participated in five focus groups. Attitudes and beliefs about pregnancy decisions and the use of antiretroviral therapy during pregnancy were examined. RESULTS: Many of the women in this study living with HIV remained committed to having children and expressed confusion about their chances of transmitting the virus to their children. CONCLUSIONS: Health care providers must be aware of these concerns and convey clear and accurate information through the most readily accepted channels. Participants suggested that messages about these issues be conveyed by other women living with HIV who have faced these same decisions.

Adolescent↗

Process mapping as a tool for home health network analysis.

Process mapping is a qualitative tool that allows service providers, policy makers, researchers, and other concerned stakeholders to get a "bird's eye view" of a home health care organizational network or a very focused, in-depth view of a component of such a network. It can be used to share knowledge about community resources directed at the older population, identify gaps in resource availability and access, and promote on-going collaborative interactions that encourage systemic policy reassessment and programmatic refinement. This article is a methodological description of process mapping, which explores its utility as a practice and research tool, illustrates its use in describing service-providing networks, and discusses some of the issues that are key to successfully using this methodology.

Community Health Planning↗

Utility of pedometers for assessing physical activity: convergent validity.

Valid assessment of physical activity is important to researchers and practitioners interested in surveillance, screening, programme evaluation and intervention. The validity of an assessment instrument is commonly considered its most important attribute. Convergent validity is the extent to which an instrument's output is associated with that of other instruments intended to measure the same exposure of interest. A systematic review of the literature produced 25 articles directly relevant to the question of convergent validity of pedometers against accelerometers, observation, and self-reported measures of physical activity. Reported correlations were pooled and a median r-value was computed. Pedometers correlate strongly (median r = 0.86) with different accelerometers (specifically uniaxial accelerometers) depending on the specific instruments used, monitoring frame and conditions implemented, and the manner in which the outputs are expressed. Pedometers also correlate strongly (median r = 0.82) with time in observed activity. Time in observed inactivity correlated negatively with pedometer outputs (median r = -0.44). The relationship with observed steps taken depended upon monitoring conditions and speed of walking. The highest agreement was apparent during ambulatory activity (running, walking) or during sitting (when both observation and pedometers would register few steps taken). There was consistent evidence of reduced accuracy during slow walking. Pedometers correlate moderately with different measures of energy expenditure (median r = 0.68). The relationship between pedometer outputs and energy expenditure is complicated by the use of many different direct and indirect measures of energy expenditure and population samples. Concordance with self-reported physical activity (median r = 0.33) varied depending upon the self-report instrument used, individuals assessed, and how pedometer outputs are expressed (e.g. steps, distance travelled, energy expenditure). Pedometer output has an inverse relationship with reported time spent sitting (r = -0.38). The accumulated evidence herein provides ample support that the simple and inexpensive pedometer is a valid option for assessing physical activity in research and practice.

Activities of Daily Living↗