Meeting the need. A primary health care model for a community-based/nurse-managed health center.

Long before the World Health Conference at Alma-Ata, when 113 nations agreed to incorporate the concepts and principles of primary health care in their health care systems (World Health Organization [WHO], 1978), nurses were practicing primary health care. Indeed, such care has been practiced since the time of Florence Nightingale. Here, in the United States, the records show that public health nurses were involved in numerous primary health care activities in the early and mid-1900s (Fitzpatrick, 1975).

A double-blind, randomized study to provide safety information on switching fluoxetine-treated patients to paroxetine without an intervening washout period.

BACKGROUND: The long elimination half-lives of fluoxetine and norfluoxetine, the active metabolite of fluoxetine, are of potential consequence when alternative antidepressant agents are introduced after the termination of fluoxetine therapy. It is not known whether paroxetine, an antidepressant agent in the same pharmacologic class as fluoxetine, can be substituted for fluoxetine without the need for an intervening washout period. The objective of this trial was to assess the tolerability of an immediate switch from fluoxetine to paroxetine therapy. METHOD: Patients who were treated for moderate to moderately severe major depressive disorder (DSM-III-R 296.2 or 296.3) with a stable dose of fluoxetine for a minimum of 6 weeks' duration were randomized in a double-blind fashion to one of two treatment groups. One group (N = 123) was started on 20 mg of paroxetine daily the morning after their last dose of fluoxetine, and the other group (N = 119) was started on 20 mg of paroxetine daily following a 2-week placebo-washout period. Patient visits were scheduled at weekly intervals for a total of 4 weeks. Adverse experience monitoring was conducted at each visit. RESULTS: There was no difference in the proportion of patients who discontinued prematurely from the trial due to an adverse experience. Eight patients in the immediate-switch group and 6 patients in the placebo-washout group withdrew from the trial in response to an adverse experience (p = .63, chi-square). The overall profile of adverse experiences was similar in the two treatment groups over the 4-week period. The incidence of adverse experiences in the first 2 weeks following the initiation of paroxetine was generally lower in the group with the intervening 2-week placebo-washout period. CONCLUSION: The immediate switch from fluoxetine to paroxetine was as well tolerated as the switch to paroxetine after a 2-week placebo-washout period.

Thyrotropin-releasing hormone: an inhibitory regulatory peptide of feline lower esophageal sphincter.

The functional role of thyrotropin-releasing hormone (TRH) at the lower esophageal sphincter (LES) was examined in the cat. The specific aims of this study were to determine: 1) the relative distribution of TRH throughout the feline gastrointestinal tract and 2) the effect of TRH on LES basal pressures and its response to exogenously induced contractions. TRH concentrations were determined by radioimmunoassay in tissue extracts from 12 sites. The mean concentration of TRH at the manometrically determined LES was 240 +/- 85 pg/g wet wt tissue, and the maximal concentration was just distal to the LES (659 +/- 189 pg/g wet wt). TRH concentration was higher in the mucosa than the underlying muscle layer of the fundus, antrum, duodenum, and ileum. In physiological studies, TRH given selectively via the left gastric artery had no effect on basal LES or esophageal pressures. TRH (2.8 x 10(-8) mol/kg) decreased the LES response to the D50 of substance P by 47.2% (34.8 +/- 3.1 to 18.4 +/- 2.9 mmHg, P < 0.01). In the presence of tetrodotoxin, TRH gave a similar inhibition of substance P-induced contractions (53.5%). TRH also decreased bombesin-induced contractions by 47.5% (29.6 +/- 6.0 to 15.8 +/- 3.9 mmHg, P < 0.025). TRH, however, had no effect on bethanechol-induced contractions. We conclude that 1) TRH is present throughout the gastrointestinal tract, with highest concentrations in the region distal to the LES; 2) TRH has no effect on basal LES tone; and 3) TRH inhibits the LES response to endogenously released and exogenous substance P but not the LES response to bethanechol.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyrotropin-releasing hormone-immunoreactive projections to the dorsal motor nucleus and the nucleus of the solitary tract of the rat.

Thyrotropin-releasing hormone-immunoreactive nerve terminals heavily innervate the dorsal motor nucleus and nucleus of the solitary tract, whereas cell bodies containing thyrotropin-releasing hormone residue most densely in the hypothalamus and raphe nuclei. By using double-labeling techniques accomplished by retrograde transport of Fluoro-Gold following microinjection into the dorsal motor nucleus/nucleus of the solitary tract combined with immunohistochemistry for thyrotropin-releasing hormone, it was demonstrated that thyrotropin-releasing hormone-immunoreactive neurons projecting to the dorsal motor nucleus/nucleus of the solitary tract reside in the nucleus raphe pallidus, nucleus raphe obscurus, and the parapyramidal region of the ventral medulla, but not in the paraventricular nucleus of the hypothalamus. The parapyramidal region includes an area along the ventral surface of the caudal medulla, lateral to the pyramidal tract and inferior olivary nucleus and ventromedial to the lateral reticular nucleus. Varying the position of the Fluoro-Gold injection site revealed a rostral to caudal topographic organization of these raphe and parapyramidal projections.

Destruction of the nucleus raphe obscurus and potentiation of serotonin-mediated behaviors following administration of the neurotoxin 3-acetylpyridine.

Systemic administration of the neurotoxin 3-acetylpyridine (3-AP) to rats produced spontaneous episodes of spasmodic movement involving the trunk and limbs including torticollis, contortions of the trunk and rigid extension of the limbs. Because the neurotransmitter serotonin (5-HT) has been implicated in various human involuntary movement disorders, the functional and anatomical integrity of the 5-HT system in rats treated with 3-AP were examined. 5-HT-containing neurons in the brain stem were studied using immunohistochemical labeling with antiserum to 5-HT. Cells in the nucleus raphe obscurus were found to be altered following 3-AP treatment as shown by a decrease in 5-HT immunoreactivity as compared to control rats. No changes in 5-HT immunoreactivity were observed in any other region containing 5-HT cell bodies. Behaviorally, rats treated with 3-AP were 2.5-fold more sensitive to the ability of the 5-HT1A agonist 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.33-3.3 mg/kg) to produce the 5-HT syndrome. Similarly, 3-AP-treated rats were 2-fold more sensitive to the selective 5-HT2 agonist 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB; 0-1.0 mg/kg) at producing the head shake response. Although these behaviors associated with brain stem 5-HT receptors were potentiated by 3-AP, the hypothermic effect of 8-OH-DPAT which involves ascending mesencephalic 5-HT neurons was unchanged following 3-AP treatment. Treatment with 3-AP did not produce significant alterations of 5-HT or 5-hydroxyindoleacetic acid (5-HIAA) content in any brain region studied. Quantitative autoradiographic analysis of the density of 5-HT1A receptors labeled with [3H]8-OH-DPAT revealed that these sites were unchanged in regions of the brain (frontal cortex, hippocampus and brain stem) and in the spinal cord. Similarly, few changes in the density of 5-HT2 receptors measured with [3H]ketanserin were observed in various brain regions. These results suggest that neurons from the nucleus raphe obscurus are involved in the elicitation of 5-HT-mediated behavioral responses by 5-HT1A and 5-HT2 receptor agonists that are though to be mediated through brain stem and spinal cord mechanisms. In addition, because of the close neuroanatomical relationship of the nucleus raphe obscurus with various brain regions known to be involved in motor control, the destruction of this region by 3-AP may contribute to the spasmodic motor behaviors observed following 3-AP treatment.

Reduction of thyrotropin-releasing hormone concentrations in central nervous system of African lungfish during estivation.

Thyrotropin-releasing hormone (TRH) has been implicated as an important modulator of arousal state in mammals. Changes in the content of TRH in several brain regions accompany hibernation in the ground squirrel. In the present study, the involvement of TRH in the regulation of arousal was further investigated in the African lungfish, Protopterus annectens, which contain high concentrations of TRH throughout its central nervous system and enter a hibernation-like state, estivation. Lungfish were divided into three groups. Group 1 was fed normally, group 2 was starved while aquatic, and group 3 was allowed to enter into a state of estivation. After 3 months, the lungfish were sacrificed and the concentrations of TRH, norepinephrine, dopamine, and serotonin were determined in the telencephalon, diencephalon, medulla, and spinal cord. In estivation, there was a significant decline in the concentration of TRH in the diencephalon, with no alteration in other regions. Starvation had no effect on regional TRH concentrations. The concentration of norepinephrine, dopamine, and serotonin did not change in estivation; however, a significant elevation of norepinephrine in the diencephalon and dopamine in the telencephalon was observed in starvation. Starvation and estivation were associated with significant declines in the protein content of the diencephalon and medulla. The estivation-linked decline in TRH in the diencephalon of the lungfish is similar to the decrease in TRH content in the hypothalamus in hibernating ground squirrels. These findings lend further support to the importance of TRH in the regulation of arousal state.

Systemic administration of kainic acid produces elevations in TRH in rat central nervous system.

Several studies have suggested that the concentration of thyrotropin releasing hormone (TRH) in the central nervous system (CNS) is influenced by the level of CNS activation. Hibernation in the ground squirrel and estivation in the lungfish result in region-specific decreases in TRH concentrations. Repeated electroconvulsive shock (ECS) and amygdaloid kindling have been shown to result in elevations of TRH in limbic brain regions. In the present study, limbic seizures induced by systemic administration of kainic acid resulted in substantial increases in the TRH content of posterior cortex and of dorsal and ventral hippocampus, and in moderate elevations in anterior cortex, amygdala/piriform cortex and corpus striatum. Maximal elevations in TRH were observed 2-4 days after kainic acid administration, and by 14 days TRH levels were similar to control values, with the exception of the dorsal hippocampus, which exhibited more prolonged elevations in TRH levels. Prior exposure to limbic seizure activity attenuated the magnitude of TRH elevation in response to a second administration of kainic acid in the posterior cortex but in no other region. These results indicate that seizure-related processes or events influence TRH systems in the CNS. Neuronal populations involved in limbic seizure induced damage may be involved in the modulation of posterior cortical TRH levels.

Ultrastructural localization of thyrotropin-releasing hormone immunoreactivity in the dorsal vagal complex in rat.

Thyrotropin-releasing hormone-like immunoreactivity (TRH-LI) was localized at the ultrastructural level in the dorsal vagal complex (DVC: dorsal motor nucleus of the vagus (DMV) and the nucleus of the solitary tract (NST] in rat. TRH-LI was concentrated in large granular vesicles in axons, presynaptic terminals, and non-synaptic axon varicosities. TRH-LI presynaptic terminals established both asymmetric and symmetric synaptic contacts with dendrites. These observations are consistent with recently described direct inhibitory and facilitatory effects of TRH on the electrical activity of neurons in the DVC.

TRH and TRH receptors in the spinal cord.

Over the past 12 years, substantial progress has been made in delineating the localization of TRH and TRH receptors in spinal cord. High concentrations of both the peptide and its receptor have been observed in the ventral horn in the region of the motoneurons and in the dorsal horn in the substantia gelatinosa. As noted, pharmacological effects of TRH administration on various parameters of spinal cord function have been reported in a number of studies. To date, however, substantial questions remain regarding the physiological role of TRH in the spinal cord. Nevertheless, it is hoped that the extensive information that has been obtained on localization of TRH and TRH receptors in spinal cord will provide a basis for answering these complex questions.

Characterization of thyrotropin-releasing hormone in the central nervous system of African lungfish.

Central administration of thyrotropin-releasing hormone (TRH) produces potent effects on various physiological parameters, such as arousal, respiration, and cardiovascular function, in several species. As part of an investigation into the evolution of this tripeptide as a central modulator of these parameters, we examined its distribution in the central nervous system of the African lungfish (Protopterus). Lungfish brains were dissected into three regions: telencephalon, diencephalon, and medulla. Each region was assayed for TRH by radioimmunoassay and for norepinephrine, dopamine, and serotonin by HPLC/electrochemical methods. TRH immunoreactivity (IR-TRH) was present in all regions of lungfish brain examined. The telencephalon contained the highest concentrations of TRH, the diencephalon also contained a high concentration of TRH, and the medulla contained a markedly lower concentration. Similar concentration gradients (telencephalon greater than diencephalon greater than medulla) were observed for norepinephrine, dopamine, and serotonin. The identity of IR-TRH as authentic TRH was confirmed by elution profiles on HPLC. The results of this investigation demonstrated that TRH and the monoamine neurotransmitters are present in high concentrations in various regions of lungfish brain. The lungfish may represent a promising model for further studies of the interactions of TRH with these neurotransmitter systems.

Reduction of feeding behavior by the serotonin uptake inhibitor sertraline.

Administration of the selective serotonin (5-HT) uptake inhibitor sertraline produced a dose-dependent reduction of food intake in rats. Doses of sertraline of 10 mg/kg or greater reduced the intake of solid pellets significantly (P less than 0.01) during the 1st hour of a 4-h feeding test in rats deprived of food and water for 24 h. Food intake during the remaining 3 h and water intake during the feeding test was unaffected by sertraline. Sertraline (2-18 mg/kg IP) also reduced milk consumption in food-deprived rats. Pretreatment with the nonselective 5-HT antagonists metergoline (2 mg/kg IP) or methysergide (3.3 mg/kg IP) blocked sertraline's inhibition of dry food intake, whereas pretreatment with the selective 5-HT2 receptor antagonist ketanserin (3.3 mg/kg IP) or the peripheral 5-HT2 antagonist xylamidine (2.5 mg/kg IP) failed to block sertraline's anorexic effect. The feeding-suppressant effect of 10 mg/kg sertraline was prevented following the destruction of central 5-HT neurons by the 5-HT neurotoxic agent, 5,7-dihydroxytryptamine (200 micrograms ICV). This result is consistent with sertraline's anorexic effect depending on intact 5-HT neurotransmission. Therefore, sertraline appears to reduce feeding by enhancing the action of endogenous serotonin at central synapses mediated by 5-HT1 rather than 5-HT2 receptors.

Labeling in vivo of serotonin uptake sites in rat brain after administration of [3H]cyanoimipramine.

The properties of sites in rat brain labeled in vivo after administration of [3H]cyanoimipramine ([3H]CN-IMI) have been studied. The radioactivity in hypothalamus and cortex 20 min to 2 hr after [3H]CN-IMI administration was reduced in rats pretreated with chlorimipramine (10 mg/kg) 5 min before [3H]CN-IMI. No effect of chlorimipramine pretreatment was seen in the cerebellum; levels of radioactivity in this tissue were subtracted from total levels in hypothalamus and cortex to define specific binding. This represented approximately 50 and 30% of total binding in hypothalamus and cortex, respectively. Specific binding in hypothalamus and cortex was reduced by a number of drugs which are potent blockers of serotonin uptake and the binding was inhibited in a stereoselective manner by the stereoisomers of norzimelidine. In contrast, pretreatment with drugs which are weak inhibitors of serotonin uptake had no effect on specific binding. Experiments using increasing doses of [3H]CN-IMI showed that the binding in vivo was saturable. Lesioning rats with the serotonin neurotoxin 5,7-dihydroxytryptamine resulted in an 80% decrease in the specific binding in hypothalamus and a 35% decrease in cortex. The potencies of drugs to inhibit the specific binding of [3H]CN-IMI in vivo were highly correlated with their previously published potencies for inhibiting serotonin uptake in human blood platelets in vitro and for preventing the serotonin depletion induced by 4-methyl-alpha-ethyl-metatyramine in vivo. These results indicate that [3H]CN-IMI can be given to rats to provide a measure of serotonin uptake sites in the central nervous system in vivo.

The effect of age on release of norepinephrine by tyramine from rat heart.

The effect of age on the capacity of tyramine to promote the release of norepinephrine (NE) at the cardiac adrenergic neuroeffector junction was investigated in isolated hearts of rats, 6, 12 and 24 months of age. Hearts were perfused by the method of Langendorff and tyramine was administered in increasing doses as a bolus injection. There was no age-related difference in the effect of tyramine on NE release nor on the relationship between the amount of NE released and chronotropic response induced by the released NE. These findings indicate that there is no difference in the effectiveness of tyramine in promoting the release of NE from the tyramine-sensitive pool as a function of age.

Effects of aging at the adrenergic cardiac neuroeffector junction.

Adrenergic neural degeneration was seen to increase with age. This is thought to contribute to the decreased cardiac content of the transmitter. Pharmacologically, it was found with the use of tyramine that virtually all of the norepinephrine (NE) pool is available for release, and that there is no difference in the amount of NE released in relation to age. Cardiac responsiveness to adrenergic agonists decreases with age. Our results suggest that this is caused in great measure by increased activity of the prejunctional, neuronal uptake mechanism in the older animal.

The effect of age on the tyramine-sensitive intraneuronal pool of norepinephrine in rat heart.

The effect of age on the amount of norepinephrine (NE) released by tyramine (TYR) was investigated in hearts from Fischer 344 rats, 6, 12, and 24 months of age. Isolated hearts were perfused through an aortic cannula with Krebs-Ringer solution containing 1.6 X 10(-4) M TYR. alpha-Methyl-p-tyrosine (7.5 X 10(-5) M) and fusaric acid (10(-5) M) were added to inhibit de novo synthesis of NE. The effluent from the heart was collected continuously throughout 4 h of perfusion with TYR. The content of NE in the perfusion effluent was measured by electrochemical (EC) detection methods after alumina extraction and high-performance liquid chromatography (HPLC) separation. In addition, the amount of NE remaining in the heart after TYR perfusion was measured with HPLC/EC methodology. The amount of NE released from hearts was not significantly different among the ages [6 months, 612.5 +/- 68.2 ng; 12 months, 640.2 +/- 53.0 ng; 24 months, 593.8 +/- 38.2 ng; p greater than 0.05, analysis of variance (ANOVA)]. These amounts represent more than 93% of total cardiac NE at all ages (6 months, 97.6 +/- 0.5%; 12 months, 94.8 +/- 1.3%; 24 months, 93.7 +/- 1.7%). The t1/2 for the decline in NE in hearts was also similar at the three ages (6 months, 45.0 +/- 4.9 min; 12 months, 53.6 +/- 5.2 min; 24 months, 60.4 +/- 7.8 min; p greater than 0.05, ANOVA). These results indicate that the amount of NE released by TYR does not change with increasing age.

Intraventricular 6-hydroxydopamine increases thyrotropin-releasing hormone (TRH) content in regions of rat brain.

Rats were given intraventricular (ivt) injections of various doses (50-400 micrograms, hydrobromide salt) of 6-hydroxydopamine (6-OHDA) and killed 1, 3 or 6 days later. Brains were removed, dissected into 11 regions, and the thyrotropin-releasing hormone (TRH) content of each region was measured by radioimmunoassay. 6-OHDA (400 micrograms) caused significant elevations in the TRH content of 6 regions: olfactory bulb, anterior cortex, brainstem, posterior cortex, hippocampus, and amygdala-piriform cortex. The magnitude of these increases ranged from 59% in olfactory bulb to 497% in hippocampus and was, in all cases, greatest at 3 days. These results suggest that the TRH content of certain brain regions may be regulated by catecholamine neurotransmitters.

Immunohistochemical localization of TRH in rat CNS: comparison with RIA studies.

The localization of thyrotropin releasing hormone (TRH) in rat brain determined by use of avidin-biotin immunoperoxidase histochemistry was compared with the distribution and quantitation by radioimmunoassay (RIA). Male Sprague-Dawley rats received intracisternal injections of 100 micrograms of colchicine or saline and were sacrificed 24 hours later. Brains were either perfused with lysine-periodate fixative and processed for TRH immunohistochemistry or were dissected into 9 brain regions for TRH RIA. In colchicine pretreated rats. TRH immunoreactive perikarya were observed only in nuclei of the hypothalamus and brain stem. No cell body staining was observable in non-colchicine treated rats. With the exception of the olfactory bulb, brain regions exhibiting dense TRH staining contained high concentrations of TRH as measured by RIA. Colchicine pretreatment did not alter the concentration of TRH in most brain regions, however, there was a significant increase in brain stem TRH content 24 hours following colchicine administration. These findings indicate that immunohistochemical localization of TRH corresponds well with endogenous concentrations of TRH determined by RIA.

Effects of age on the adrenergic cardiac neuroeffector junction.

Although it is clear that adrenergic nervous system control of cardiac function decreases with age and that the effector organ fails to adjust to this decreased control, it is not completely evident which of the many mechanisms operant at the adrenergic-cardiac neuroeffector junction contribute to this state. Prejunctionally, it appears that norepinephrine content decreases with age and that adrenergic axonal degeneration occurs. Also, evidence is available to suggest that modulation by prejunctional alpha adrenergic receptors of norepinephrine release is altered with increasing age, as is neuronal uptake of norepinephrine. Postjunctionally, it appears that beta-adrenergic receptor sensitivity to agonists undergoes age-related alterations, and possibly post receptor mechanisms involved in receptor-response coupling. Other mechanisms, such as those involved in transmitter uptake into extraneuronal sites, adrenergic neuronal responsiveness to stimulation, transmitter release and turnover, calcium and prejunctional receptor modulation of transmitter release, postjunctional receptor development of supersensitivity or subsensitivity, need further elucidation in order to have an understanding of the factors that contribute to the breakdown of homeostatic mechanisms that regulate the heart.

Effect of age on adrenergic neuronal uptake in rat heart.

Cardiovascular responsiveness to sympathetic influences is reduced with increasing age. This reduced responsiveness may reflect alterations in effector mechanisms or in neurohumoral transmission processes. We investigated the effect of age on the cardiac adrenergic neuronal uptake mechanism in the Fischer 344 rat by measuring the cocaine-induced potentiation of norepinephrine (NE) positive chronotropic responses. Hearts from male rats (6, 12 and 24 months old) were perfused according to a modified method of Langendorff. For each heart, chronotropic responses to increasing doses of NE were obtained. After this, hearts were perfused with 1 microM cocaine to block the neuronal uptake of NE. A second series of NE doses were administered and heart rate (HR) responses measured. Under control perfusion conditions, HR responses to NE decreased with increasing age. In the presence of cocaine, HR responses to NE were significantly augmented in the 12 and 24 months rat hearts, but not in the 6 months rat hearts. However, the cocaine-potentiated responses to NE at 12 and 24 months did not exceed responses to NE alone at 6 months. In a separate series of experiments, HR responses to isoproterenol were not modified by cocaine at any age. These results indicate that activity of neuronal uptake pump is greater in the 12 and 24 months rats than in the 6 months rats. This increased uptake activity may account at least in part for the reduced responsiveness of older hearts to NE.

TRH concentration in rat olfactory bulb is undiminished by deafferentation.

The effect of deafferentation of the rat olfactory bulb on bulbar TRH concentration was studied. TRH concentrations in the lesioned bulbs did not decline when compared to concentrations in sham-lesioned bulbs for the post-lesion intervals of 1 h through 14 days. Since TRH concentrations did not decline following deafferentation, TRH in the olfactory bulb does not derive from centrifugal neurons.