RESUMEN
OBJECTIVE: 5- (5 times oral levodopa tablet taken/day) 2- (2 hours of OFF time/day) 1- (1 hour/day of troublesome dyskinesia) criteria have been proposed by a Delphi expert consensus panel for diagnosing advanced Parkinson's disease (PD). The aim of the present study is to compare quality of life (QoL) in PD patients with "5-2-1 positive criteria" vs QoL in PD patients without "5-2-1 positive criteria" (defined as meeting ≥1 of the criteria). METHODS: This is a cross-sectional, observational, monocenter study. Three different instruments were used to assess QoL: the 39-Item Parkinson's Disease Quality of Life Questionnaire Summary Index Score (PDQ-39SI); a subjective rating of perceived QoL (PQ-10); and the EUROHIS-QOL 8-Item Index (EUROHIS-QOL8). RESULTS: From a cohort of 102 PD patients (65.4 ± 8.2 years old, 53.9% males; disease duration 4.7 ± 4.5 years), 20 (19.6%) presented positive 5-2-1 criteria: 6.9% for 5, 17.6% for 2, and 4.9% for 1. 37.5% (12/32) and 25% (5/20) of patients with motor complications and dyskinesia, respectively, presented 5-2-1 negative criteria. Both health-related (PDQ-39SI, 25.6 ± 14 vs 12.1 ± 9.2; p < 0.0001) and global QoL (PQ-10, 6.1 ± 2 vs 7.1 ± 1.3; p=0.007; EUROHIS-QOL8, 3.5 ± 0.5 vs 3.7 ± 0.4; p=0.034) were worse in patients with 5-2-1 positive criteria. Moreover, nonmotor symptoms burden (Non-Motor Symptoms Scale total score, 64.8 ± 44.8 vs 39.4 ± 35.1; p < 0.0001) and autonomy for activities of daily living (ADLS scale, 73.5 ± 13.1 vs 89.2 ± 9.3; p < 0.0001) were worse in patients with 5-2-1 positive criteria. Patient's principal caregiver's strain (Caregiver Stain Index, 4.3 ± 3 vs 1.5 ± 1.6; p < 0.0001), burden (Zarit Caregiver Burden Inventory, 28.4 ± 12.5 vs 10.9 ± 9.8; p < 0.0001), and mood (Beck Depression Inventory II, 12.2 ± 7.2 vs 6.2 ± 6.1; p < 0.0001) were worse in patients with 5-2-1 positive criteria as well. CONCLUSIONS: QoL is worse in patients meeting ≥1 of the 5-2-1 criteria. This group of patients and their caregivers are more affected as a whole. These criteria could be useful for identifying patients in which it is necessary to optimize Parkinson's treatment.
RESUMEN
BACKGROUND AND PURPOSE: The objective of this study was to analyze the relationship between motor complications and non-motor symptom (NMS) burden in a population of patients with Parkinson's disease (PD) and also in a subgroup of patients with early PD. METHODS: Patients with PD from the COPPADIS cohort were included in this cross-sectional study. NMS burden was defined according to the Non-Motor Symptoms Scale (NMSS) total score. Unified Parkinson's Disease Rating Scale (UPDRS) part IV was used to establish motor complication types and their severity. Patients with ≤5 years of symptoms from onset were included as patients with early PD. RESULTS: Of 690 patients with PD (62.6 ± 8.9 years old, 60.1% males), 33.9% and 18.1% presented motor fluctuations and dyskinesia, respectively. The NMS total score was higher in patients with motor fluctuations (59.2 ± 43.1 vs. 38.3 ± 33.1; P < 0.0001) and dyskinesia (63.5 ± 40.7 vs. 41.4 ± 36.3; P < 0.0001). In a multiple linear regression model and after adjustment for age, sex, disease duration, Hoehn & Yahr stage, UPDRS-III score and levodopa equivalent daily dose, UPDRS-IV score was significantly related to a higher NMSS total score (ß = 0.27; 95% confidence intervals, 2.81-5.61; P < 0.0001), as it was in a logistic regression model on dichotomous NMSS total score (≤40, mild or moderate vs. >40, severe or very severe) (odds ratio, 1.31; 95% confidence intervals, 1.17-1.47; P < 0.0001). In the subgroup of patients with early PD (n = 396; mean disease duration 2.7 ± 1.5 years), motor fluctuations were frequent (18.1%) and similar results were obtained. CONCLUSIONS: Motor complications were frequent and were associated with a greater NMS burden in patients with PD even during the first 5 years of disease duration.
Asunto(s)
Enfermedad de Parkinson , Anciano , Estudios Transversales , Femenino , Humanos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiología , Índice de Severidad de la EnfermedadRESUMEN
In November 1999, CARE Madagascar, Population Services International (PSI), and the Centers for Disease Control and Prevention (CDC) selected 30 poor communities in urban Antananarivo as the target population for launch of the Safe Water System. The system consists of behavior change techniques along with point-of-use treatment and safe storage of water. The project was launched in March 2000, ahead of schedule, because a cholera epidemic struck Madagascar in January. Because of the enormous demand created by the cholera epidemic and by 3 cyclones that followed in the next 3 months, the project grew to national scale in less than a year. The combination of community mobilization and social marketing resulted in increased demand for and use of the Safe Water System.
Asunto(s)
Cólera/prevención & control , Desastres , Desinfección/métodos , Hipoclorito de Sodio , Purificación del Agua/métodos , Cólera/epidemiología , Conducta Cooperativa , Promoción de la Salud/organización & administración , Humanos , Madagascar/epidemiología , Evaluación de Programas y Proyectos de Salud , Hipoclorito de Sodio/economía , Microbiología del Agua , Purificación del Agua/instrumentación , Abastecimiento de Agua/normasRESUMEN
Certain aminotetralins are known to be potent dopamine D2 receptor agonists. N-0923, [-]2-(N-propyl-N-2-thienylethylamino)-5- hydroxytetralin HCl, recognizes the high and low affinity states of the D2 receptor in membranes from bovine caudate with a Klow of 79 nM. The selectivity ratio is D2/D1 = 15 and D2/alpha 2 = 1.4. N-0923 also inhibits dopamine uptake and prolactin secretion, and it is an antagonist at the alpha 2 receptor. N-0923 (3-300 nmol/kg, s.c.) induced dose-dependent contralateral turning behavior in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. The ED50 of 30 nmol/kg was effective for 1 h. The positive enantiomer (N-0924; 300 nmol/kg, s.c.) was without effect. A hemiparkinsonian syndrome was induced in four Macaca nemestrina monkeys by unilateral infusion of the neurotoxin MPTP into the right carotid artery. Video recordings of free-moving behavior revealed bradykinesia, disuse of the contralateral upper limb and turning in a direction ipsilateral to the lesion. N-0923 (3-300 nmol/kg, i.m.) induced contralateral turning behavior, exploratory activity, and contralateral limb usage. The ED50 for turning (30 nmol/kg) was effective for 0.5 h. The potency order for induction of contralateral rotations was (+)-PHNO > N-0923 > bromocriptine. N-0924 (300 nmol/kg, i.m.) was ineffective. We conclude that N-0923 may be useful as a therapeutic agent in the treatment of Parkinson's disease.
Asunto(s)
Dopaminérgicos/farmacología , Enfermedad de Parkinson Secundaria/fisiopatología , Receptores de Dopamina D2/efectos de los fármacos , Tetrahidronaftalenos/farmacología , Tiofenos/farmacología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Bromocriptina/farmacología , Modelos Animales de Enfermedad , Dominancia Cerebral/efectos de los fármacos , Dominancia Cerebral/fisiología , Femenino , Inyecciones Intramusculares , Macaca nemestrina , Masculino , Oxazinas/farmacología , Oxidopamina/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Prolactina/sangre , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/fisiología , Conducta Estereotipada/efectos de los fármacos , Conducta Estereotipada/fisiología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiopatologíaRESUMEN
A few seconds of tetanic preganglionic stimulation of rat sympathetic ganglia results in potentiation of cholinergic synaptic transmission lasting several hours. However, ganglia from aged (28-32 months) rats did not develop as much potentiation as did ganglia from young (3-6 months) rats. This potentiation appears to decay exponentially but in two phases. The early component decays in 15 minutes, a time course consistent with the phenomenon of post-tetanic potentiation (PTP). The later component decays over several hours and is a form of long-term potentiation (LTP). A double exponential decay model was employed to quantitatively resolve the decay of potentiation and allow quantitative comparison of the decay parameters in both aged and young rats. It is clear that the magnitude and duration of PTP was the same in both age groups. However both the magnitude and decay time-constant for LTP were 30-50% smaller in the aged group of rats. Several agents which mimic cyclic AMP or stimulate cyclic AMP production in the ganglion enhance nicotinic transmission for several hours. However, these agents, 8-bromo cAMP, forskolin, isoproterenol, and secretin were equally effective in potentiating transmission in ganglia from both young and aged rats. Previous studies demonstrated that stimulus induced LTP and cyclic AMP induced potentiation was the result of enhanced release of acetylcholine (ACh) and not from increased postsynaptic responsiveness. Presumably these agents act through the same pathway and by the same mechanism that generates LTP following preganglionic tetany. These observations demonstrate that there is a selective age-dependent decline in the capacity for sympathetic ganglia to generate long-term changes in synaptic efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Envejecimiento/fisiología , Ganglios Simpáticos/fisiología , Plasticidad Neuronal , Sinapsis/fisiología , Animales , AMP Cíclico/farmacología , AMP Cíclico/fisiología , Estimulación Eléctrica , Electrofisiología , Femenino , Ratas , Ratas Endogámicas F344RESUMEN
1. Nicotinic fast excitatory postsynaptic potentials (fast EPSPs) were recorded intracellularly from postganglionic neurones in the isolated rat superior cervical ganglion. 2. An hours-long potentiation of the fast EPSP could be induced by brief tetanic stimulation of the preganglionic nerve (5 Hz for 5 s to 20 Hz for 20 s). While long-term potentiation (LTP) can be detected in every ganglion by extracellular techniques, LTP was induced in only two-thirds of the nicotinic synaptic responses. 3. Muscarinic blockade with atropine did not prevent LTP of the fast EPSP. 4. LTP of the fast EPSP did not correlate with changes in input resistance nor cell potential, as recorded in the soma. 5. The formation of nicotinic LTP appeared to depend upon stimulation of the nerve terminals. Non-synaptic tetanic depolarization of the postganglionic neurone, effected by injecting depolarizing current pulses through the intracellular microelectrode, was not sufficient. LTP could be induced by synaptic tetani in two-thirds of the same neurones. 6. The response to exogenous 1,1-dimethyl-4-phenylpiperazinium (DMPP), a selective nicotinic agonist, was not increased during nicotinic synaptic LTP. This was true whether DMPP was applied by pressure-ejection from an extracellular micropipette during intracellular recording, or by brief superfusion during sucrose-gap recording of postganglionic responses. 7. Responses to exogenous acetylcholine and carbachol were increased during nicotinic LTP when these non-selective cholinergic agonists were applied by pressure-ejection during intracellular recording. However, the potentiation of the fast EPSP was always at least twofold greater than the potentiation of the response to these exogenous agonists. 8. Potentiation of the responses to acetylcholine and carbachol may have been due to long-term enhancement of muscarinic responses. Thus, no postsynaptic basis for nicotinic LTP was uncovered in these studies.
Asunto(s)
Ganglios Simpáticos/fisiología , Receptores Nicotínicos/fisiología , Acetilcolina/farmacología , Potenciales de Acción , Animales , Atropina/farmacología , Carbacol/farmacología , Estimulación Eléctrica , Femenino , Técnicas In Vitro , Masculino , Potenciales de la Membrana , Terminaciones Nerviosas/fisiología , Ratas , Ratas Endogámicas , Receptores Muscarínicos/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Factores de TiempoRESUMEN
1. Using the rat superior cervical ganglion in vitro, the relative efficacy of nicotinic synaptic transmission was estimated by recording the postganglionic compound action potential and the amount of endogenous acetylcholine (ACh) released. These two parameters were correlated in individual ganglia by sampling the bathing medium for the assay of ACh while simultaneously recording the postganglionic response. 2. The beta-adrenoceptor agonist isoprenaline potentiated both the evoked release of ACh and the postganglionic response by about 20% during preganglionic stimulation at 0.2 Hz. 3. The adenosine receptor agonist 2-chloroadenosine inhibited ACh release and the postganglionic response by about 35%. 4. Tetanic preganglionic stimulation for a few seconds induced a long-term potentiation of nicotinic responses and of ACh release. Both of these potentiations were dependent upon extracellular Ca2+ during the tetani. 5. Forskolin and analogues of cyclic AMP also caused a long-lasting potentiation of both the evoked release of ACh and the postganglionic response, indicating that cyclic AMP may regulate transmission by a presynaptic mechanism. The specificity of the cyclic AMP analogues was tested using various butyryl- and bromo-purine nucleotides. 6. The effects of forskolin and 8-bromo-cyclic AMP did not appear to be dependent upon extracellular Ca2+. 7. The potentiation caused by forskolin was consistently augmented by three phosphodiesterase inhibitors--AH 21-132, papaverine and SQ 20-006. However, the effect of forskolin was not consistently enhanced by theophylline, nor was it reduced by the adenylate cyclase inhibitor SQ 22-536. 8. The neurogenic long-term potentiation was augmented by two of the phosphodiesterase inhibitors that also augmented the forskolin-induced potentiation--papaverine and SQ 20-006. 9. It was concluded that cyclic AMP can enhance nicotinic transmission, and can do so by increasing the evoked release of ACh. However, it was not possible to prove that cyclic AMP mediates the long-term potentiation induced by tetanic preganglionic stimulation.
Asunto(s)
Acetilcolina/metabolismo , AMP Cíclico/fisiología , Receptores Nicotínicos/fisiología , Sinapsis/metabolismo , Transmisión Sináptica/efectos de los fármacos , Inhibidores de Adenilato Ciclasa , Animales , Bucladesina/farmacología , Calcio/fisiología , Colina/metabolismo , Colforsina/farmacología , Femenino , Técnicas In Vitro , Masculino , Nucleótidos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Ratas , Ratas Endogámicas , Receptores Nicotínicos/efectos de los fármacos , Factores de TiempoRESUMEN
The release of radioactive metabolites from isolated rat superior cervical ganglia was measured under various conditions following preloading with 3H-adenosine. The 3H label was recovered primarily in the adenosine metabolites, ATP, ADP, AMP, IMP, and inosine, rather than in adenosine itself. Increased release was evoked by preganglionic stimulation or by exposure to a high-K+ medium, whereas in a low-Ca2+-high-Mg2+ medium, both spontaneous release and evoked release of most metabolites were inhibited. Exposure of the ganglion to an atmosphere of N2 also increased the release of most labeled metabolites, but this release was not substantially affected by a low-Ca2+ medium. The fluorescent derivatives of the endogenous adenine-containing compounds present in the ganglion were prepared from homogenates and separated by high-performance liquid chromatography (HPLC). By the end of the testing period (6 hr), levels of ATP in the isolated ganglia had dropped to 10-20% of the initial values, while levels of ADP, AMP, and adenosine increased. There was little difference in these values between nonstimulated ganglia and those exposed to N2 or to a high-K+ medium.
Asunto(s)
Ganglios Simpáticos/metabolismo , Purinas/metabolismo , Sinapsis/fisiología , Adenosina/metabolismo , Animales , Medios de Cultivo , Estimulación Eléctrica , Ganglios Simpáticos/fisiología , Técnicas In Vitro , Nitrógeno/farmacología , Potasio/farmacología , Ratas , Ratas Endogámicas , TritioRESUMEN
The release of endogenous acetylcholine (ACh) from the in vitro rat superior cervical ganglion was measured by assaying the bathing medium. Simultaneously, synaptic transmission in the ganglion was assessed by recording post-ganglionic compound action potentials. A brief period of tetanic preganglionic stimulation (20 Hz for 20 s) induced a long-term potentiation of the post-ganglionic compound action potential. The same tetanic stimulation also consistently induced a long-term potentiation of stimulated ACh release. Spontaneous (non-stimulated) ACh release was not enhanced after tetanic stimulation. The content of ACh in the ganglion was not measurably increased after tetanic stimulation. These results suggest that the long-term increase in synaptic efficacy is due, at least in part, to an increase in the amount of ACh released by the afferent impulse.
Asunto(s)
Acetilcolina/metabolismo , Ganglios Simpáticos/fisiología , Sinapsis/fisiología , Potenciales de Acción , Animales , Femenino , Técnicas In Vitro , Masculino , Ratas , Ratas Endogámicas , Transmisión Sináptica , Factores de TiempoRESUMEN
The effect of nerve stimulation on inositol phospholipid hydrolysis in autonomic tissue was assessed by direct measurement of [3H]inositol phosphate production in ganglia that had been preincubated with [3H]inositol. Within minutes, stimulation of the preganglionic nerve increased the [3H]inositol phosphate content of the superior cervical sympathetic ganglion indicating increased hydrolysis of inositol phospholipids. This effect was blocked in a low Ca2+, high Mg2+ medium. It was also greatly reduced when nicotinic and muscarinic antagonists were present together in normal medium. However, neither the nicotinic antagonist nor the muscarinic antagonist alone appeared to be as effective as both in combination. In other experiments, stimulation of the vagus nerve caused dramatic increases in [3H]inositol phosphate in the nodose ganglion but did not increase [3H]inositol phosphate in the nerve itself. This effect was insensitive to the cholinergic antagonists. Thus, neuronal activity increased inositol phospholipid hydrolysis in a sympathetic ganglion rich in synapses, as well as in a sensory ganglion that contains few synapses. In the sympathetic ganglion, synaptic stimulation activated inositol phospholipid hydrolysis and this was primarily due to cholinergic transmission; both nicotinic and muscarinic pathways appeared to be involved.
Asunto(s)
Ganglios Simpáticos/fisiología , Fosfatos de Inositol/metabolismo , Neuronas/metabolismo , Fosfatidilinositoles/metabolismo , Fosfatos de Azúcar/metabolismo , Animales , Calcio/metabolismo , Estimulación Eléctrica , Ganglios Parasimpáticos/fisiología , Magnesio/metabolismo , Masculino , Ratas , Ratas Endogámicas , Factores de Tiempo , Nervio Vago/fisiologíaRESUMEN
Brief tetanic stimulation of the preganglionic nerve induced a persistent potentiation of nicotinic synaptic transmission in the rat superior cervical sympathetic ganglion. Quantitative measurements of the post-tetanic increase in synaptic efficacy revealed two distinct time courses. The early, rapidly decaying component, termed post-tetanic potentiation (p.t.p.), had a decay time constant of 2-3 min, as reported elsewhere. The duration of the more persistent component, called long-term potentiation (l.t.p.), was extremely temperature dependent, lasting much longer at 32 degrees C than at 22 degrees C. In half of the experiments performed at 32 degrees C, l.t.p. showed no detectable decay over the course of 1 h or more after a brief tetanic stimulation. Other experiments were conducted at 22 degrees C. The induction of l.t.p. was dependent on the extracellular [Ca2+]. Transient elevation of the extracellular [K+] also produced a long-term enhancement of synaptic efficacy, and this effect was also Ca2+ dependent. The tetani that were effective in inducing l.t.p. (5-20 Hz for 5-20 s) were well within the physiological range of preganglionic activity. The magnitude and time course were related to frequency and duration of stimulation. The occurrence of l.t.p. was restricted to those preganglionic fibres that were tetanically stimulated. This lack of heterosynaptic or generalized effects was demonstrated by splitting the preganglionic nerve into two branches that could be independently tested and conditioned. Physiological activation of muscarinic or nicotinic receptors apparently does not play an essential role in causing ganglionic l.t.p., which is expressed as an enhancement of nicotinic transmission. A muscarinic antagonist (2 microM-atropine) did not block l.t.p. Preganglionic stimulation induced l.t.p. even when a high concentration of a nicotinic antagonist (3 mM-hexamethonium) was present during the tetanic stimulation. Furthermore, bath application of a cholinergic agonist (100-1000 microM-carbachol) could not substitute for tetanic stimulation in provoking l.t.p. Activation of adrenergic receptors also appeared not to play an essential role. Neither a beta-adrenergic antagonist (10 microM-sotolol or 1 microM-propranolol) nor an alpha-adrenergic antagonist (1 microM-phentolamine) had any significant effect on the magnitude or duration of l.t.p. The results indicate that ganglionic l.t.p. is a Ca2+- and temperature-dependent process that can be created independently of the activation of nicotinic, muscarinic or adrenergic receptors.
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Ganglios Simpáticos/fisiología , Potenciales de Acción , Animales , Atropina/farmacología , Calcio/farmacología , Estimulación Eléctrica , Femenino , Hexametonio , Compuestos de Hexametonio/farmacología , Técnicas In Vitro , Masculino , Potasio/farmacología , Ratas , Ratas Endogámicas , Receptores Adrenérgicos/fisiología , Receptores Muscarínicos/fisiología , Receptores Nicotínicos/fisiología , Transmisión Sináptica , Temperatura , Factores de TiempoRESUMEN
Adenosine inhibited three Ca2+-dependent potentials recorded intracellularly from post-ganglionic neurones of the rat superior cervical ganglion. A shoulder on the falling phase of the action potential elicited in normal Locke solution, a hyperpolarizing after-potential (h.a.p.) that follows the spike, and a regenerative Ca2+ spike elicited in Locke solution containing TTX and TEA were all reversibly inhibited by adenosine analogues in a dose-dependent fashion. The maximum rate of rise of the Ca2+ spike (dV/dt) was markedly reduced suggesting that the underlying mechanism of adenosine action is inhibition of the Ca2+ conductance mechanism and thus, the voltage-sensitive Ca2+ current. I/V curves in low Ca2+, high Mg2+, TTX, TEA, and Co2+ to block the Ca2+ current show no change in resistance in the presence of 2-chloroadenosine. The actions of adenosine were nearly eliminated in the presence of 1 mM-theophylline, an adenosine receptor antagonist. The order of agonist potency on the inhibition of the h.a.p. was: N-6-[L-phenylisopropyl] adenosine (L-PIA) greater than 2-chloroadenosine greater than adenosine greater than cyclic AMP = 5' AMP. The concentration of L-PIA which produced a half-maximal effect (EC50) was 0.5 microM and that for cyclic AMP was 100 microM. Dipyridamole, an adenosine uptake blocker, potentiated the effects of low concentrations of adenosine and shifted the dose-response curve for adenosine towards that of 2-chloroadenosine (EC50 = 1 microM). These results are consistent with the concept of an external adenosine receptor, but we are unable to assign a receptor subtype. Cyclic AMP mimicked the effects of adenosine, but these effects were eliminated by adenosine deaminase. Our results suggest that the electrogenic effects of bath-applied cyclic AMP may result from the metabolism of cyclic AMP to adenosine by ganglionic tissue. We conclude that adenosine activates a receptor on the neuronal cell surface to inhibit the voltage-dependent Ca2+ current.
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Adenosina/farmacología , Fibras Autónomas Posganglionares/fisiología , 2-Cloroadenosina , Potenciales de Acción/efectos de los fármacos , Adenosina/análogos & derivados , Animales , Calcio/farmacología , AMP Cíclico/farmacología , Dipiridamol/farmacología , Relación Dosis-Respuesta a Droga , Ganglios Simpáticos/fisiología , Ratas , Receptores de Superficie Celular/efectos de los fármacos , Receptores Purinérgicos , Teofilina/farmacologíaRESUMEN
Brief tetanic stimulation of the preganglionic nerves to the superior cervical ganglion enhances the postganglionic response to single preganglionic stimuli for 1 to 3 hours. This long-term potentiation of transmission through the ganglion is apparently not attributable to a persistent muscarinic action of the preganglionic neurotransmitter, acetylcholine, since neither the magnitude nor the time course of the phenomenon is reduced by atropine. The decay of long-term potentiation can be described by a first-order kinetic process with a mean time constant of 80 minutes. We conclude that long-term potentiation, once considered a unique property of the hippocampus, is in fact a more general feature of synaptic function. This form of synaptic memory may significantly influence information processing and control in other regions of the nervous system, including autonomic ganglia.
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Ganglios Simpáticos/fisiología , Aprendizaje/fisiología , Sinapsis/fisiología , Transmisión Sináptica , Animales , Cinética , Plasticidad Neuronal , Ratas , Factores de TiempoRESUMEN
The superior cervical sympathetic ganglion is currently being used as a model neuronal system for the study of Ca2+-dependent processes in the mammalian nervous system. We have characterized a regenerative calcium conductance in postganglionic neurons. This Ca2+ current contributes to the shoulder of the action potential. In addition, Ca2+ influx during the spike activates a K+ conductance, which generates a hyperpolarizing afterpotential. These Ca2+-dependent potentials are antagonized by catecholamines. Pharmacologic studies suggest that alpha 2-adrenergic receptors inhibit the regenerative voltage-dependent Ca2+ influx that occurs during the action potential. Alpha-adrenergic agonists were also found to reduce the depression of the compound action potential following a train of preganglionic stimuli. We hypothesize that alpha 2-receptors function primarily to antagonize Ca2+ influx and thereby exert significant control over neuronal excitability and release of neurotransmitters.
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Calcio/farmacología , Ganglios Simpáticos/fisiología , Neuronas/fisiología , Receptores Adrenérgicos alfa/fisiología , Receptores Adrenérgicos/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Catecolaminas/farmacología , Neuronas/efectos de los fármacos , Norepinefrina/farmacología , Fentolamina/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Tetrodotoxina/farmacologíaRESUMEN
Electrophysiological approaches using intracellular microelectrode techniques have failed to critically test the hypothesis that cyclic AMP (cAMP) mediates the slow inhibitory postsynpatic potential (IPSP). The slow IPSP is not readily elicited, and the resting membrane potential is relatively insensitive to application of catecholamines and adenine nucleotides. However, comprehensive studies of voltage-dependent events in postganglionic neurons reveal three Ca2+-dependent potentials that are quite sensitive to catecholamines and adenine nucleotides. The hyperpolarizing afterpotential, the action potential shoulder, and the Ca2+ spike are all inhibited by alpha-adrenergic agonists, adenosine, and cAMP. We have proposed that simulation of alpha-adrenergic and adenosine receptors on the post-synaptic membrane results in antagonism of an inward Ca2+ current. Further experimentation is necessary to determine if cAMO acts as a second messenger or only by activating an adenosine receptor. Preliminary studies suggest that catecholamines and adenine nucleotides have similar and potent actions on the terminals of preganglionic axons. Here, inhibition of Ca2+ influx results in reduced acetylcholine release but facilitates high-frequency cholinergic transmission. More quantitative biophysical and pharmacological studies are required to better characterize the synaptic mechanisms in sympathetic ganglia.
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Catecolaminas/fisiología , AMP Cíclico/fisiología , Ganglios Autónomos/fisiología , Adenosina/farmacología , Adenosina/fisiología , Animales , Calcio/fisiología , Catecolaminas/farmacología , Epinefrina/farmacología , Ganglios Autónomos/efectos de los fármacos , Potenciales de la Membrana , Modelos Biológicos , Norepinefrina/farmacología , Norepinefrina/fisiología , Conejos , Ratas , Receptores de Neurotransmisores/fisiología , Transmisión SinápticaRESUMEN
The effect of repetitive stimulation on synaptic transmission was studied in the isolated superior cervical ganglion of the rabbit under conditions of reduced quantal content. Excitatory postsynaptic potentials (EPSP) were recorded with the sucrose gap technique to obtain estimates of transmitter release. Four components of increased transmitter release, with time constants of decay similar to those observed at the frog neuromuscular junction at 20 degrees C, were found in the ganglion at 34 degrees C: a first component of facilitation, which decayed with a time constant of 59 +/- 14 ms (mean +/- SD); a second component of facilitation, which decayed with a time constant of 388 +/- 97 ms; augmentation, which decayed with a time constant of 7.2 +/- 1 s; and potentiation, which decayed with a time constant of 88 +/- 25 s. The addition of 0.1-0.2 mM Ba2+ to the Locke solution increased the magnitude but not the time constant of decay of augmentation. Ba2+ had little effect on potentiation. The addition of 0.2-0.8 mM Sr2+ to the Locke solution appeared to increase the magnitude of the second component of facilitation. Sr2+ had little effect on augmentation or potentiation. These selective effects of Ba2+ and Sr2+ on the components of increased transmitter release in the rabbit ganglion are similar to the effects of these ions at the frog neuromuscular junction. Although the effects of Ba2+ and Sr2+ are similar in the two preparations, the magnitudes of augmentation and the second component of facilitation after a single impulse were about 6-10 times greater in the rabbit ganglion than at the frog neuromuscular junction. These results suggest that the underlying mechanisms in the nerve terminal that give rise to the components of increased transmitter release in the rabbit ganglion and frog neuromuscular junction are similar but not identical.
Asunto(s)
Bario/farmacología , Calcio/farmacología , Ganglios Simpáticos/fisiología , Estroncio/farmacología , Sinapsis/fisiología , Transmisión Sináptica/efectos de los fármacos , Animales , Computadores , Técnicas In Vitro , Matemática , ConejosRESUMEN
1. Post-ganglionic neurones of the rat superior cervical ganglion were studied in vitro (21-26 degrees C) using single intracellular micro-electrode methods. 2. Three Ca2+-dependent potentials were studied: the shoulder on the normal action potential, the hyperpolarizing afterpotential (h.a.p.), and th Ca2+ spike. 3. Bath-applied noradrenaline reversibly inhibited these Ca2+-dependent potentials. The EC50 for inhibition of peak h.a.p. amplitude was about 1 microM. The order of catetholamine potency was: L-adrenaline > L-noradrenaline > D-noradrenaline congruent to dopamine > DL-isoprenaline. Phentolamine (10 microM), an alpha-blocker, but not MJ-1999 (10 microM), a beta-blocker, antagonized the action of noradrenaline. 4. Noradrenaline (10 microM) hyperpolarized most neurones (1-6 mV) studied, with no detectable change in resting membrane conductance. 5. Superfusion with low external Ca2+ and high Mg2+ mimicked the effect of noradrenaline. Either procedure alone antagonized the h.a.p. conductance increase but did not alter the h.a.p. reversal potential. However, in the presence of low Ca2+, high Mg2+, the remaining action potential and h.a.p. were not further reduced by noradrenaline. 6. The Ca2+-dependent shoulder of the action potential did not appear dependent upon GK. Noradrenaline and low Ca2+ antagonized the shoulder when enhanced by TEA+ or Ba2+. 7. Both the rate of rise and amplitude of the Ca2+ spike were antagonized by noradrenaline. 8. We propose that activation of an alpha-adrenoceptor inhibits a voltage-sensitive Ca2+ conductance (GCa(V)), thereby reducing the inward Ca2+ current which may generate the noraml action potential shoulder and the rising phase of the Ca2+ spike. Reduction of Ca2+ current would also reduce the Ca2+-dependent portion of outward K+ current underlying the h.a.p.