RESUMEN

BACKGROUND: The Middle East is one of the most vulnerable regions to the impacts of climate change, yet evidence of the heat-related mortality remains limited in this area. Our present study investigated the heat-mortality association in Jordan and the potential modifying effect of greenness, population density and urbanization level on the association. METHODS: For each of the 42 included districts, daily meteorological and mortality data from 2000 to 2020 were obtained for the warmest months (May to September). First, a distributed lag non-linear model was applied to estimate the district level heat-mortality association, then the district specific estimates were pooled using multivariate meta-regression models to obtain an overall estimate. Last, the modifying effect of district level greenness, population density and urbanization level was examined through subgroup analysis. RESULTS: When compared to the minimum mortality temperature (MMT, percentile 0th, 22.20 °C), the 99th temperature percentile exhibited a relative risk (RR) of 1.34 (95 % CI 1.23, 1.45). Districts with low greenness had a higher heat-mortality risk (RR 1.39, 95 % CI 1.22, 1.58) when compared to the high greenness (RR 1.28, 95 % CI 1.13, 1.45). While heat-mortality risk did not significantly differ between population density subgroups, highly urbanized districts had a greater heat-mortality risk (RR 1.41, 95 % CI 1.23, 1.62) as compared to ones with low levels of urbanization (RR 1.32, 95 % CI 1.13, 1.55). Districts with high urbanization level had the highest heat-mortality risk if they were further categorized as having low greenness (RR 1.63, 95 % CI 1.30, 2.04). CONCLUSION: Exposure to heat was associated with increased mortality risk in Jordan. This risk was higher in districts with low greenness and high urbanization level. As climate change-related heat mortality will be on the rise, early warning systems in highly vulnerable communities in Jordan are required and greening initiatives should be pursued.

Asunto(s)

Cambio Climático , Calor , Densidad de Población , Urbanización , Jordania/epidemiología , Calor/efectos adversos , Humanos , Mortalidad

RESUMEN

Substance P (SP) may act within dorsal root ganglia (DRG) to modulate the transmission of nociceptive information. Because peripheral nerve injury (axotomy) alters the peptide content of sensory neurons, we used whole-cell recording to examine the effects of sciatic nerve section on the sensitivity of rat lumbar DRG neurons to SP (0.3--1 microM). At 1 microM, SP increased the excitability of 'small', putative nociceptive neurons but had little effect on the excitability of 'large' neurons. Two-four weeks after sciatic nerve section, however, the effect of SP on 'large' axotomized neurons was increased and its effect on 'small' neurons was decreased. SP did not affect Ca(2+) channel currents in control or axotomized neurons. The effects of SP on the current-voltage (I--V) relationship of 77% of neurons involved increased inward current at potentials below -30 mV and suppressed outward current at potentials above -20 mV. The effects of SP on the I--V relationship were similar in control and in axotomized neurons and the altered sensitivity of 'small' and 'large' cells could not be attributed to axotomy-induced changes in input resistance or membrane potential. The possible relevance of alterations in sensitivity, of 'large' DRG neurons to SP, to the generation of neuropathic pain is discussed.

Asunto(s)

Ganglios Espinales/citología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Sustancia P/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Axotomía , Bario/farmacocinética , Calcio/metabolismo , Proteínas de Unión al GTP/metabolismo , Masculino , Neuralgia/metabolismo , Neuralgia/fisiopatología , Técnicas de Placa-Clamp , Canales de Potasio/fisiología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Nervio Ciático/fisiopatología

RESUMEN

The spontaneous, ectopic activity in sensory nerves that is induced by peripheral nerve injury is thought to contribute to the generation of "neuropathic" pain in humans. To examine the cellular mechanisms that underlie this activity, neurons in rat L(4)-L(5) dorsal root ganglion (DRG) were first grouped as "large," "medium," or "small" on the basis of their size (input capacitance) and action potential (AP) shape. A fourth group of cells that exhibited a pronounced afterdepolarization (ADP) were defined as AD-cells. Whole cell recording was used to compare the properties of control neurons with those dissociated from rats in which the sciatic nerve had been sectioned ("axotomy" group) and with neurons from rats that exhibited self-mutilatory behavior in response to sciatic nerve section ("autotomy" group). Increases in excitability in all types of DRG neuron were seen within 2-7 wk of axotomy. Resting membrane potential (RMP) and the amplitude and duration of the afterhyperpolarization (AHP) that followed the AP were unaffected. Effects of axotomy were greatest in the small, putative nociceptive cells and least in the large cells. Moderate changes were seen in the medium and AD-cells. Compared to control neurons, axotomized neurons exhibited a higher frequency of evoked AP discharge in response to 500-ms depolarizing current injections; i.e., "gain" was increased and accommodation was decreased. The minimum current required to discharge an AP (rheobase) was reduced. There were significant increases in spike width in small cells and significant increases in spike height in small, medium, and AD-cells. The electrophysiological changes promoted by axotomy were intensified in animals that exhibited autotomy; spike height, and spike width were significantly greater than control for all cell types. Under our experimental conditions, spontaneous activity was never encountered in neurons dissociated from animals that exhibited autotomy. Thus changes in the electrical properties of cell bodies alone may not entirely account for injury-induced spontaneous activity in sensory nerves. The onset of autotomy coincided with alterations in the excitability of large, putative nonnociceptive, neurons. Thus large cells from the autotomy group were much more excitable than those from the axotomy group, whereas small cells from the autotomy group were only slightly more excitable. This is consistent with the hypothesis that the onset of autotomy is associated with changes in the properties of myelinated fibers. Changes in Ca2+ and K+ channel conductances that contribute to axotomy- and autotomy-induced changes in excitability are addressed in the accompanying paper.

Asunto(s)

Axotomía , Ganglios Espinales/fisiología , Neuronas Aferentes/fisiología , Automutilación , Potenciales de Acción/fisiología , Animales , Electrofisiología , Ganglios Espinales/citología , Masculino , Neuronas Aferentes/clasificación , Ratas , Ratas Sprague-Dawley , Factores de Tiempo

RESUMEN

Sciatic nerve section (axotomy) increases the excitability of rat dorsal root ganglion (DRG) neurons. The changes in Ca2+ currents, K+ currents, Ca2+ sensitive K+ current, and hyperpolarization-activated cation current (I(H)) that may be associated with this effect were examined by whole cell recording. Axotomy affected the same conductances in all types of DRG neuron. In general, the largest changes were seen in "small" cells and the smallest changes were seen in "large" cells. High-voltage-activated Ca2+ channel current (HVA-I(Ba)) was reduced by axotomy. Although currents recorded in axotomized neurons exhibited increased inactivation, this did not account for all of the reduction in HVA-I(Ba). Activation kinetics were unchanged, and experiments with nifedipine and/or omega-conotoxin GVIA showed that there was no change in the percentage contribution of L-type, N-type, or "other" HVA-I(Ba) to the total current after axotomy. T-type (low-voltage-activated) I(Ba) was not affected by axotomy. Ca2+ sensitive K+ conductance (g(K,Ca)) appeared to be reduced, but when voltage protocols were adjusted to elicit similar amounts of Ca2+ influx into control and axotomized cells, I(K,Ca)(s) were unchanged. After axotomy, Cd2+ insensitive, steady-state K+ channel current, which primarily comprised delayed rectifier K+ current (I(K)), was reduced by about 60% in small, medium, and large cells. These data suggest that axotomy-induced increases in excitability are associated with decreases in I(K) and/or decreases in g(K,Ca) that are secondary to decreased Ca2+ influx. Because I(H) was reduced by axotomy, changes in this current do not contribute to increased excitability. The amplitude and inactivation of I(Ba) in all cell types was changed more profoundly in animals that exhibited self-mutilatory behavior (autotomy). The onset of this behavior corresponded with significant reduction in I(Ba) of large neurons. This finding supports the hypothesis that autotomy, that may be related to human neuropathic pain, is associated with changes in the properties of large myelinated sensory neurons.

Asunto(s)

Axotomía , Canales de Calcio/fisiología , Ganglios Espinales/metabolismo , Neuronas Aferentes/metabolismo , Canales de Potasio/fisiología , Automutilación , Animales , Cadmio/farmacología , Resistencia a Medicamentos , Conductividad Eléctrica , Ganglios Espinales/citología , Masculino , Canales de Potasio/efectos de los fármacos , Ratas , Ratas Sprague-Dawley

RESUMEN

Cellular actions of nociceptin/orphanin FQ (N/OFQ) resemble those of micro-, delta-, and kappa-opioids, i.e. activation of inwardly rectifying K(+) conductance, inhibition of high-voltage-activated Ca(2+) channel currents, and impediment of neurotransmitter release. Differences in ORL(1) and micro-receptor distribution lead to: 1) more widespread actions of N/OFQ on periaqueductal gray neurons than opioids and 2) differential effects of N/OFQ and opioids in the brainstem. Also, unlike opioids, N/OFQ inhibits T-type Ca(2+) channel current in sensory neurons. Opioids and N/OFQ may modulate glutamate responses in different ways, and certain actions of N/OFQ are potentiated following nerve injury whereas those of micro-opioids are attenuated. Agonists at ORL(1) receptors may therefore be of clinical interest in the management of neuropathic pain.

Asunto(s)

Péptidos Opioides/metabolismo , Péptidos Opioides/fisiología , Animales , Tronco Encefálico/metabolismo , Calcio/metabolismo , Electrofisiología , Hipocampo/metabolismo , Humanos , Hipotálamo/metabolismo , Narcóticos/agonistas , Neuronas/metabolismo , Neurotransmisores/metabolismo , Potasio/metabolismo , Médula Espinal/metabolismo , Vasodilatadores/metabolismo , Xenopus , Nociceptina

RESUMEN

In this paper, methane emissions from municipal wastewater treatment plants and municipal solid waste (MSW) landfills in Jordan for 1994 have been estimated using the methodology developed by the Intergovernmental Panel on Climate Change (IPCC). For this purpose, the 14 domestic wastewater treatment plants in the country were surveyed. Generation rates and characterization of MSW components as well as dumping and landfilling practices were surveyed in order to estimate 1994 CH4 emissions from these sites. Locally available waste statistics were used in cases where those of the IPCC guidelines were not representative of Jordan's statistics. Methane emissions from domestic wastewater in Jordan were estimated at 4.66 gigagrams (Gg). Total 1994 CH4 emissions from MSW management facilities in Jordan are estimated at 371.76 Gg--351.12 Gg (94.45%) from sanitary landfills, 19.83 Gg (5.33%) from MSW open dumps, and 0.81 Gg (0.22%) from raw sewage-water dumping ponds. Uncertainties associated with these estimations are presented.

Asunto(s)

Efecto Invernadero , Metano/análisis , Aguas del Alcantarillado/análisis , Jordania

RESUMEN

Neuropeptide Y (NPY) increases the excitability of 'small', nociceptive, dorsal root ganglion (DRG) neurons. This effect, which may contribute to the etiology of 'neuropathic' pain, has been attributed to attenuation of Ca2+-sensitive K+ conductance(s) (gK,Ca) following suppression of Ca2+ entry via N-type Ca2+ channels. A problem arises with this conclusion because rat DRG neurons normally contain high intracellular Cl- and some of them express a Ca2+-dependent Cl- conductance (gCl,Ca). In this study, we find that in rat DRG neurons increasing intracellular Cl- does not attenuate the effect of 1 microM NPY because gCl,Ca is not found in 'small' DRG cells and the peptide failed to affect the gCl,Ca found in 'large' cells. Thus, the presence of gCl,Ca in a subpopulation of 'large' DRG neurons does not alter the conclusion that excitatory effects of NPY result from attenuation of gK,Ca.

Asunto(s)

Calcio/fisiología , Canales de Cloruro/fisiología , Ganglios Espinales/citología , Neuronas Aferentes/fisiología , Neuropéptido Y/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Axotomía , Tamaño de la Célula/fisiología , Células Cultivadas , Cloruros/metabolismo , Electrofisiología , Activación del Canal Iónico/efectos de los fármacos , Activación del Canal Iónico/fisiología , Síndromes de Compresión Nerviosa/fisiopatología , Neuronas Aferentes/química , Neuronas Aferentes/citología , Ganglio Nudoso/citología , Dolor/fisiopatología , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/citología , Sistema Nervioso Simpático/fisiopatología , Ganglio del Trigémino/citología

RESUMEN

Damage to sensory nerves invokes the expression of neuropeptide Y in the cell bodies of sensory neurons in dorsal root ganglia. We therefore compared the action of this peptide on control dorsal root ganglia neurons with its action on neurons from animals in which the sciatic nerve had been cut. Neuropeptide Y (0.1-1.0 microM) increased the excitability of 24% of control neurons and its effect was stronger and more cells (56%) were affected after axotomy. Increased excitability was mediated via a Y2-receptor and resulted from attenuation of Ca2+-sensitive K+-conductance(s) secondary to suppression of N-type Ca2+ channel current. Y1-agonists potentiated L-type Ca2+ channel current in control neurons without altering excitability. This Y1-effect was attenuated whereas effects mediated via Y2-receptors were enhanced after axotomy. No evidence was found for involvement of Y4- or Y5-receptor subtypes in the actions of neuropeptide Y either on control or on axotomized dorsal root ganglion neurons. It is concluded that neuropeptide Y increases the excitability of sensory neurons by interacting with a Y2-receptor and thereby decreasing N-type Ca2+ channel current and Ca2+-sensitive K+-conductance(s). When peripheral nerves are damaged, dorsal root ganglion neurons start to express neuropeptide Y and its excitatory Y2-excitatory effects are enhanced. The peptide may therefore contribute to the generation of aberrant sensory activity and perhaps to the etiology of injury-induced neuropathic pain.

Asunto(s)

Causalgia/fisiopatología , Ganglios Espinales/citología , Neuronas Aferentes/química , Neuropéptido Y/agonistas , Nervio Ciático/lesiones , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Agonistas alfa-Adrenérgicos/farmacología , Animales , Axotomía , Bario/metabolismo , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/fisiología , Proteínas de Unión al GTP/metabolismo , Masculino , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Neuropéptido Y/análogos & derivados , Neuropéptido Y/farmacología , Nifedipino/farmacología , Norepinefrina/farmacología , Técnicas de Placa-Clamp , Fragmentos de Péptidos , Péptido YY/farmacología , Péptidos/farmacología , Potasio/metabolismo , Canales de Potasio/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Neuropéptido Y/fisiología , Nervio Ciático/citología , omega-Conotoxina GVIA

RESUMEN

There is some doubt as to the effectiveness of opioids in the management of neuropathic pain. We therefore examined the actions of morphine and the opioid-like peptide nociceptin (both 1 mu) on dorsal root ganglion (DRG) neurons that were isolated from control or from nerve-injured rats. Both substances reduced omega-conotoxin (CTX) GVIA-sensitive, N-type Ca2+ channel current and small persistent nifedipine/ CTX-insensitive (non-N, non-L type) current. Nifedipine-sensitive L-type current was unaffected. The effect of nociceptin was antagonized by naloxone benzoylhydrazone (nalbzoh) but not by naloxone. Sciatic nerve section (axotomy) profoundly reduced the effects of morphine and the mu-receptor agonist D-ala2, N-Me-Phe4,Gly-ol5 enkephalin (DAMGO). The effect of the kappa-agonist [(+)-(5alpha,7alpha, 8beta)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4, 5)dec-8-yl)-benzeneacetamide] (U69593) was unchanged, whereas the effect of nociceptin was increased. All agonists produced their strongest effects on the small, putative nociceptive cells and their weakest effects on the largest cells. The delta-receptor agonist, enkephalin D-pen2,5 (DPDPE), was without effect on control or on axotomized cells. These and other data suggest that the functional downregulation of mu-opioid receptors on sensory nerves contributes to the poor efficacy of opioids in neuropathic pain. Also, the increased effectiveness of nociceptin after axotomy supports the hypothesis that its actions are mediated via a "non-opioid" receptor. Pronounced suppression of Ca2+ channel current in axotomized DRG neurons by nociceptin led to a reduction in Ca2+-dependent K+ conductance and a marked increase in excitability. Despite this, the spinal administration of nociceptin or agonists that activate ORL1 (opioid-like orphan receptor) may prove to be of clinical interest in the management of neuropathic pain.

Asunto(s)

Analgésicos Opioides/farmacología , Bencenoacetamidas , Causalgia/tratamiento farmacológico , Ganglios Espinales/citología , Morfina/farmacología , Neuronas Aferentes/fisiología , Péptidos Opioides/farmacología , Analgésicos/farmacología , Animales , Axotomía , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/fisiología , Canales de Calcio Tipo L , Dihidropiridinas/farmacología , Encefalina Ala(2)-MeFe(4)-Gli(5) , Encefalina D-Penicilamina (2,5) , Encefalinas/farmacología , Masculino , Síndromes de Compresión Nerviosa/tratamiento farmacológico , Síndromes de Compresión Nerviosa/fisiopatología , Neuronas Aferentes/química , Péptidos/farmacología , Potasio/metabolismo , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Nervio Ciático/química , Nervio Ciático/citología , Sodio/metabolismo , Médula Espinal/citología , omega-Conotoxina GVIA , Nociceptina

RESUMEN

Nociceptin (orphanin FQ) is a novel, opioid-like, heptadecapeptide that is an endogenous ligand for the opioid receptor-like (ORL1) receptor. Unlike classical opioids, nociceptin can produce hyperalgesia when injected intracerebroventricularly into mice. Despite this, nociceptin has been reported to decrease transmitter release, activate an inwardly rectifying K+ conductance, and suppress high-voltage-activated Ca2+ channel conductances (HVA gCa) in much the same way as micro-, delta-, and kappa-opioids. We report an action of nociceptin that is not shared by morphine: the suppression of low-voltage-activated, transient calcium (barium) current (IBa,T) in acutely dissociated rat dorsal root ganglion (DRG) neurons (EC50 = 100 nM). This effect was reflected as inhibition of bursts of action potentials that can be evoked in "medium-sized" DRG neurons. Experiments with GTP-gamma-S (100 microM), GDP-beta-S (2 mM), or aluminum fluoride (AlF3) (100 microM) in the patch pipette failed to provide evidence for G-protein involvement in nociceptin-induced IBa,T suppression. By contrast, both morphine and nociceptin suppressed HVA gCa, and the latter response was affected by intracellular GTP-gamma-S, GDP-beta-S, and AlF3 in ways that confirmed G-protein involvement. The selective effect of nociceptin on IBa,T may therefore be relevant to understanding why its behavioral actions differ from those of other opioids. This G-protein-independent effect of the action of nociceptin may reflect a new general mechanism of action for opioid peptides within the nervous system.

Asunto(s)

Bloqueadores de los Canales de Calcio/farmacología , Proteínas de Unión al GTP/metabolismo , Neuronas Aferentes/química , Péptidos Opioides/farmacología , Potenciales de Acción/efectos de los fármacos , Analgésicos Opioides/farmacología , Animales , Calcio/metabolismo , Canales de Calcio/efectos de los fármacos , Canales de Calcio/fisiología , Electrofisiología , Ganglios Espinales/química , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/fisiología , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Masculino , Morfina/farmacología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Opioides/agonistas , Nociceptina

RESUMEN

Dorsal root ganglion (DRG) neurons from control rats or from rats in which the sciatic nerve had been sectioned were studied by whole-cell recording techniques. Noradrenaline (10-100 micro;M) activated beta-adrenoceptors and increased L-type Ca2+ channel current in control DRG cells, but this had little effect on excitability (the number of action potentials generated by a pulse of current at rheobasic strength). By contrast, in cells from nerve-damaged animals, noradrenaline activated alpha2-adrenoceptors, suppressed N-type Ca2+ channel current, and increased excitability. In axotomized cells, it also reduced total outward current recorded at +70 mV. Because noradrenaline did not affect total outward current recorded in the presence of the Ca2+ channel blocker Cd2+ (0. 5-1 mM), its effects on excitability may result from reduction of Ca2+-sensitive K+-conductance(s) following suppression of N-type Ca2+ channel current. The strongest effects of noradrenaline were seen in small cells and in cells from animals that exhibited autotomy, a self-mutilatory behavior that can accompany peripheral nerve damage. Because many of these small DRG cells may be involved in the transmission of nociceptive information, changes in coupling between Ca2+ channels and adrenoceptors may contribute to the generation of the ectopic sensory nerve activity that has been implicated in the etiology of neuropathic pain.

Asunto(s)

Canales de Calcio/metabolismo , Calcio/metabolismo , Neuronas Aferentes/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Cadmio/farmacología , Desnervación , Ganglios Espinales/patología , Masculino , Norepinefrina/farmacología , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta/efectos de los fármacos , Nervio Ciático/lesiones , Automutilación

RESUMEN

The previous articles in this series [4,9] have shown that unilateral AMPA lesions of the nucleus basalis magnocellularis (nbm) produced widespread morphological and functional changes to the forebrain cholinergic projection system that could be reversed by transplants of fetal cholinergic tissue. At earlier postgraft time points, the effects of cholinergic grafts were specific to the neocortical region (frontal or parietal cortex) into which the grafts were targeted. Here we report that nbm lesion-induced spatial learning and memory deficits in the Morris water maze were reversed at 6-8 weeks postsurgery only by cholinergic grafts placed in the frontal cortex or frontal and parietal cortices combined. Similar grafts to parietal cortex only and noncholinergic fetal transplants to any cortical site were ineffective. In contrast, using separate groups of animals, deficits in sensorimotor function could be reversed in only one measure (open field turning) by cholinergic transplants targeted to the parietal (somatosensory) cortex or frontal and parietal cortex combined. These behavioural dissociations demonstrate that the frontal cortical cholinergic innervation from the nbm is necessary for effective spatial cognitive performance.

Asunto(s)

Corteza Cerebral/trasplante , Aprendizaje por Laberinto/efectos de los fármacos , Prosencéfalo/trasplante , Sustancia Innominada/efectos de los fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología , Animales , Conducta Animal/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley

RESUMEN

Unilateral AMPA lesions of the nucleus basalis magnocellularis (nbm) produced a nearly complete loss of cholinergic markers in the ipsilateral frontal and parietal cortices with no recovery at 6 months. The loss was associated with compensatory increases in AChE-positive fibre density in the contralateral cortex, in ipsilateral cortical regions not receiving their cholinergic innervation from the nbm and in the size of cholinergic magnocellular neurones in the contralateral nbm. The hypertrophy and increase in AChE-positive fibre density were apparent at 4-6 weeks after lesion and increased with time. Cholinergic transplants to cholinergically deafferented cortex prevented development of the compensatory increases in AChE-positive fibre density and restored AChE-positive fibre density and ChAT activity to control levels in ipsilateral cholinergically deafferented regions, partially after 6-8 weeks and completely after 6 months. In contrast, when cholinergic grafts were placed into unlesioned cortex, axonal outgrowth was localized to the vicinity of the transplant and did not develop with time. These results support the concept that vacant synapses promote and direct axonal outgrowth from transplanted neurones and that grafted cholinergic neurones integrate into the lesioned forebrain cholinergic projections system and prevent the lesion-induced changes in AChE-positive fibre density and ChAT activity.

Asunto(s)

Corteza Cerebral/fisiología , Corteza Cerebral/cirugía , Trasplante de Tejido Fetal , Tejido Nervioso/trasplante , Plasticidad Neuronal , Sistema Nervioso Parasimpático/fisiología , Prosencéfalo/fisiología , Animales , Corteza Cerebral/metabolismo , Colina O-Acetiltransferasa/metabolismo , Agonistas de Aminoácidos Excitadores/farmacología , Masculino , Tejido Nervioso/embriología , Prosencéfalo/efectos de los fármacos , Prosencéfalo/embriología , Ratas , Ratas Sprague-Dawley , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología

RESUMEN

Unilateral S-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) lesions of the nucleus basalis magnocellularis (nbm), which produced persistent and extensive ChAT-positive cell loss within the nbm and depletion of cortical cholinergic markers in the frontal cortex, increased both the number and sensitivity of individual frontal cortical neurones responding to iontophoretic administration of ACh. The lesion also increased the sensitivity of individual neurones to carbachol but the increase in the number of neurones responding to carbachol was transient and had returned to normal 4 weeks after lesion. The sensitivity of individual neurones to glutamate was unchanged by the lesion. The percentage of cortical neurones responding to ACh, but not the sensitivity of individual neurones was restored to the prelesion level, 6-8 weeks after cholinergic transplants to the lesioned frontal cortex; cholinergic transplants to the more distant parietal cortex were only effective after 6 months whereas noncholinergic transplants were ineffective at both time intervals. Cholinergic transplants placed in the frontal cortex 6-8 weeks or 6 months before nbm lesion offered some protection from the effects of the lesion, particularly at 6 months but were ineffective when placed into the parietal cortex. Lesion of the nbm also reduced basal firing rate of spontaneously active neurones and this was not restored by any of the transplants. The results are discussed in the light of quantitative measurements of acetylcholinesterase-positive fibre outgrowth from the transplant into the recording area, which are described in the preceding manuscript [20].

Asunto(s)

Acetilcolina/farmacología , Corteza Cerebral/trasplante , Lóbulo Frontal/efectos de los fármacos , Prosencéfalo/trasplante , Sustancia Innominada/efectos de los fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología , Animales , Masculino , Ratas , Ratas Sprague-Dawley

RESUMEN

(-)-Nicotine tartrate (2 mg/kg), and a nicotinic agonist, RJR 2403 (1.4 mg/kg), and antagonist, mecamylamine (1 mg/kg), were administered to separate groups of rats SC twice daily for 10 days. Two other groups received the same doses of nicotine or RJR 2403 for 1 day followed by saline for 9 days. Twenty-four hours after the final injection, the rats were compared to a 10-day saline-injected group on acquisition of a hidden platform position in the Morris water maze (20 trials, 30-min inter-trial interval). The rats were killed 48 h after the last drug injection and frontal, entorhinal and posterior cingulate cortex and dorsal and ventral hippocampus assayed for [3H]-nicotine binding density. Chronic nicotine significantly increased the number of frontal and entorhinal cortical and dorsal hippocampal, but not posterior cingulate cortical or ventral hippocampal, nicotinic receptors, and improved rate of learning. Chronic mecamylamine and RJR 2403 also significantly increased the number of nicotinic receptors in frontal cortex, though not other regions, but retarded rate of learning. Nicotine given for 1 day 11 days earlier marginally increased nicotinic receptors in entorhinal cortex (but not other regions) and significantly increased rate of learning, though significantly less than 10-day nicotine. Entorhinal cortical and dorsal hippocampal nicotinic receptor numbers were positively associated with rate of learning but not performance at asymptote. Thus cognitive enhancement after chronic nicotine is in part a delayed consequence of nicotine administration 11 days earlier, and may reflect regional changes in nicotinic receptor up-regulation.

Asunto(s)

Encéfalo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Mecamilamina/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/efectos de los fármacos , Animales , Encéfalo/metabolismo , Masculino , Nicotina/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/metabolismo , Regulación hacia Arriba

RESUMEN

The effects of chronic nicotine treatment and of unilateral AMPA lesion of the nucleus basalis magnocellularis (nbm) on the sensitivity of frontal cortical neurones to iontophoretically applied nicotine were studied. Chronic nicotine treatment increased the number of [3H]nicotine binding sites from 2.9 to 3.9 pmol g-1 wet weight, and increased the proportion of cortical neurones responding to nicotine from 32.3% to 60.0%. After unilateral nbm lesions, the densities of AChE-positive fibers and [3H]nicotine binding sites were reduced by approximately 97% and 55%, respectively, and the proportion of neurones responding to nicotine increased from 32.3% to 53.8%. The two treatments, chronic nicotine administration and nbm lesion, also increased the size of individual neuronal responses, prolonged their duration, and shortened the response latency. Responses to glutamate were unaffected by either procedures. The results show that the increase in [3H]nicotine binding produced by chronic nicotine administration is associated with an increased response to iontophoretically applied nicotine, suggesting that the receptor upregulation induced by the chronic treatment were functional. Less easily explained is the association between increased sensitivity of frontal cortical neurons to nicotine after nbm lesion with a decreased receptor density. It is suggested that a substantial proportion of nicotinic receptors are located presynaptically, and that their loss after lesion concealed an upregulation at postsynaptic sites.

Asunto(s)

Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Neuronas/efectos de los fármacos , Nicotina/metabolismo , Nicotina/farmacología , Sustancia Innominada/fisiología , Animales , Sitios de Unión , Lóbulo Frontal/citología , Ácido Glutámico/farmacología , Masculino , Nicotina/administración & dosificación , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Tritio

RESUMEN

The present study investigated the performance of rats at 3-4 months and 21 months of age in the Morris water maze and correlated age-related cognitive deficits with changes in both cholinergic and GABAergic systems in the frontal cortex. The older rats were divided into two groups, unimpaired old and impaired old according to their ability to find a hidden submerged platform in the water maze, for electrophysiological, neurochemical, and morphological studies. The firing rate of frontal cortical neurones was recorded from the motor area of the frontal cortex under urethane anaesthesia and was found to be significantly slower in the two aged groups of rats compared to the young rats, but there were no differences between the two aged groups. The sensitivity of frontal cortex neurones of the impaired and unimpaired old age groups to ACh and to carbachol was significantly lower than that of the young group, but there were no differences between the two old age groups. In contrast, sensitivity of frontal cortex neurones to bicuculline was significantly higher in the aged rats compared with the young rats and was significantly greater in the impaired old rats than in the unimpaired old rats. The sensitivity of cortical neurones to glutamate was unaffected by age. There were also significant correlations between the percentages of cortical neurones responding to ACh and bicuculline and different parameters of water maze acquisition during days 7-8, but not during days 2-3, when spatial learning had not begun, and days 13-14, when spatial learning was complete. Biochemical and morphological analyses did not show any significant differences in ChAT activity and AChE-positive fibre density in the frontoparietal cortices of the three groups of rats. The results demonstrate that the learning deficit observed in old age rats cannot be adequately explained solely by a reduction in cholinergic receptor sensitivity and that an age-related increase in GABAergic tone may be a more important determinant of cognitive impairment.

Asunto(s)

Envejecimiento/psicología , Aprendizaje por Laberinto/fisiología , Sistema Nervioso Parasimpático/fisiología , Prosencéfalo/fisiología , Ácido gamma-Aminobutírico/fisiología , Acetilcolina/metabolismo , Acetilcolina/farmacología , Acetilcolinesterasa/metabolismo , Animales , Bicuculina/farmacología , Carbacol/farmacología , Colina O-Acetiltransferasa/metabolismo , Estimulación Eléctrica , Electrofisiología , Ácido Glutámico/farmacología , Iontoforesis , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Sistema Nervioso Parasimpático/anatomía & histología , Sistema Nervioso Parasimpático/efectos de los fármacos , Prosencéfalo/anatomía & histología , Prosencéfalo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Percepción Espacial/efectos de los fármacos , Percepción Espacial/fisiología

RESUMEN

One week after unilateral alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) lesions of nucleus basalis magnocellularis, rats showed significant lateralised bias in spontaneous turning and in turning induced by tail pinch or by placing the rat on a 45 degrees grid. Turning was biased to the lesioned side and this side also showed increased responsiveness to pin-prick stimulation of the skin (somaesthesia), snout and whisker stimulation and ammonia olfaction. Arecoline (0.5 mg/kg), at a dose which did not affect responses to sensorimotor stimulation in sham-operated rats, corrected the lesion-induced biased turning to tail pinch and the 45 degrees grid test and reduced the bias in the open field. In contrast, nicotine (0.05 mg/kg), at a dose which also did not substantially affect responses to sensorimotor stimulation in sham-operated rats, switched the lesion-induced turning bias towards the contralateral side. Neither cholinoceptor agonist reduced the lesion-induced increased sensory responsiveness. The effects of nicotine were blocked by the centrally acting nicotinic antagonist, mecamylamine (1.0 mg/kg), but not by hexamethonium (1.0 mg/kg), or ondansetron (0.01 mg/kg). Amphetamine (up to 1.0 mg/kg) did not affect the lesion-induced motor asymmetry. The results confirm that the basal forebrain cholinergic system plays a role in sensorimotor cortical functions, but suggest different functional roles for muscarinic and nicotinic receptors.

Asunto(s)

Arecolina/farmacología , Fibras Colinérgicas/efectos de los fármacos , Dominancia Cerebral/efectos de los fármacos , Nicotina/farmacología , Desempeño Psicomotor/efectos de los fármacos , Receptores Colinérgicos/efectos de los fármacos , Sustancia Innominada/efectos de los fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Anfetamina/farmacología , Animales , Mapeo Encefálico , Fibras Colinérgicas/fisiología , Dominancia Cerebral/fisiología , Masculino , Orientación/efectos de los fármacos , Orientación/fisiología , Desempeño Psicomotor/fisiología , Ratas , Ratas Sprague-Dawley , Receptores Colinérgicos/fisiología , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/fisiología , Olfato/efectos de los fármacos , Olfato/fisiología , Conducta Estereotipada/efectos de los fármacos , Conducta Estereotipada/fisiología , Sustancia Innominada/fisiología

RESUMEN

Unilateral lesions of the nucleus basalis magnocellularis (NBM) produced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid in rats caused, 8-10 weeks after the lesion, a 94% reduction in cortical acetylcholinesterase fibres and reduced activities of acetylcholinesterase and choline acetyltransferase by 70-80% in the frontal cortex ipsilateral to the lesion. In anaesthetized unlesioned control rats, iontophoretic administration of acetylcholine and carbachol produced atropine-sensitive inhibition and excitation of frontal cortical neurones, effects similar to those produced by electrically stimulating the NBM. The lesion reduced cortical neuronal firing rates but increased the percentage and sensitivity of neurones responding to acetylcholine, the predominant response changing from inhibition to excitation; response duration increased but latency was unaffected. The size of the response of individual neurones to carbachol, but not the percentage of sensitive neurones, was also increased in lesioned animals. The proportion of neurones responding to bicuculline and their individual sensitivities were increased by the lesion, suggesting that the lesion increased GABAergic tone; responses to glutamate were unchanged. The lesion did not affect the proportion of neurones in which acetylcholine modulated neuronal responses but reversed the nature of the modulation to predominantly excitatory; excitation was the predominant response to electrical forepaw stimulation in unlesioned control animals. This suggests a possible interaction between GABAergic and cholinergic mechanisms in selective attention and processing of cognitive information. Acute administration of di-isopropyl fluorophosphate to unlesioned animals significantly increased the number of frontal cortical neurones responding to acetylcholine, without affecting individual neuronal sensitivity or responses to carbachol and glutamate. The similarity of these effects to those of acetylcholine in lesioned animals suggests that the increased sensitivity to acetylcholine in the latter was due to loss of acetylcholinesterase, enabling diffusion of acetylcholine to more distant neurones. However, acetylcholinesterase does not hydrolyse carbachol and therefore it is necessary to postulate a different post-synaptic mechanism to explain the lesion-induced increases in the sensitivities of individual neurones to carbachol and to acetylcholine; interpretation of experimental findings should take these two mechanisms into account.

Asunto(s)

Lóbulo Frontal/fisiología , Isoxazoles/farmacología , Bulbo Raquídeo/efectos de los fármacos , Bulbo Raquídeo/fisiología , Sistema Nervioso Parasimpático/fisiología , Propionatos/farmacología , Ácido gamma-Aminobutírico/fisiología , Acetilcolina/farmacología , Animales , Bicuculina/farmacología , Carbacol/farmacología , Lóbulo Frontal/citología , Lóbulo Frontal/metabolismo , Glutamatos/farmacología , Ácido Glutámico , Iontoforesis , Masculino , Bulbo Raquídeo/patología , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley

RESUMEN

True Blue, a retrograde fluorescent tracer, was used to investigate axonal outgrowth after grafting embryonic forebrain cholinergic tissue into the cholinergically-deafferented rat frontal cortex. Unilateral deafferentation was achieved by injecting alpha-amino-3-OH-4-isoxozole propionic acid (AMPA) into the ipsilateral nucleus basalis magnocellularis. Grafting occurred 3 weeks after the lesion. Eight to 10 weeks later, True Blue was injected bilaterally into the cortex at a superficial site which, on the transplanted side, was located at least 2 mm away from the transplant. Forty-eight h later, retrogradely labelled fluorescent neurones could be seen in the deepest part of the transplants. Some of these neurones were shown to be ChAt-positive, providing evidence of axonal outgrowth from transplanted cholinergic neurones into cholinergically-deafferented frontal cortex.

Asunto(s)

Axones/fisiología , Corteza Cerebral/crecimiento & desarrollo , Neuronas Aferentes/fisiología , Sistema Nervioso Parasimpático/crecimiento & desarrollo , Acetilcolina/farmacología , Animales , Ganglios Basales/citología , Ganglios Basales/efectos de los fármacos , Benzofuranos , Trasplante de Tejido Encefálico , Corteza Cerebral/citología , Trasplante de Tejido Fetal , Colorantes Fluorescentes , Lóbulo Frontal/citología , Lóbulo Frontal/crecimiento & desarrollo , Histocitoquímica , Ácido Iboténico/análogos & derivados , Ácido Iboténico/toxicidad , Masculino , Sistema Nervioso Parasimpático/citología , Ratas , Ratas Sprague-Dawley , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico