RESUMEN
We perfused iron as FeCl(3) directly into the striatum of normal rats and used the in vivo microdialysis technique to monitor striatal levels of dopamine (DA). KCl was perfused to assess the functional integrity of the DA receptors at the end of each dialysis experiment. Cu(+2) (as CuSO(4)) and Cl(-) (as NaCl) were perfused to compare the effects of Fe(+3) to that of other heavy metal and donors of Cl(-) anion. Perfusion of FeCl(3) (1 mM for 15 min) produced a 250% increase in striatal levels of DA. Perfusion of CuSO(4) (1 mM for 15 min) or NaCl (10 mM for 15 min) did not affect striatal DA levels. There was a significant increase in DA levels with KCl stimulation (56 mM for 15 min) after perfusion with FeCl(3). We conclude that iron releases DA from striatal nerve endings without the immediate destruction of the DA terminals. The implications of chronic release of dopamine as a cause of dopaminergic cell death are discussed.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Compuestos Férricos/farmacología , Animales , Cloruros , Sulfato de Cobre/farmacología , Espacio Extracelular/metabolismo , Masculino , Microdiálisis , Perfusión , Cloruro de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio/farmacologíaRESUMEN
L-dopa may be toxic to dopamine neurons, possibly due to catechol-autoxidation. Catechols are O-methylated by catechol-O-methyltransferase (COMT) in a SAM consuming reaction, preventing the initiation of catechol autoxidation. We hypothesized that SAM or SAM-precursors ameliorate L-dopa neurotoxicity, in a COMT-dependent fashion. We tested this hypothesis in primary mesencephalic cultures by adding 200 microM L-dopa with 2 mM methionine or 1 mM dimethionine or 0.5 mM SAM with or without 0.2 microM of the COMT-inhibitor 2', 5'-dinitrocatechol (OR 486). L-dopa was found to be neurotoxic as the surviving neurons had fewer and shorter processes. Methionine, dimethionine and SAM all protected DA neurons against damaged induced by L-dopa. The COMT inhibitor dinitrocatechol (DNC) completely abolished the protective effect against L-dopa toxicity. We conclude that supplementation with methionine, dimethionine or SAM ameliorates L-dopa neurotoxicity to dopamine neurons, while inhibition of COMT may aggravate or unmask L-dopa neurotoxicity.
Asunto(s)
Catecol O-Metiltransferasa/metabolismo , Levodopa/toxicidad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Animales , Inhibidores de Catecol O-Metiltransferasa , Catecoles/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dopamina/metabolismo , Inhibidores Enzimáticos/farmacología , Levodopa/antagonistas & inhibidores , Metionina/farmacología , Neuronas/citología , Ratas , S-Adenosilmetionina/farmacologíaRESUMEN
A paucity of studies are available concerning the comparative therapeutic effectiveness of presently available dopamine agonist agents in the control of Parkinson symptoms. To provide a basis for resolving this issue, we measured the circling response in unilaterally nigrotomized (6-OHDA) rats following the administration of ropinirole, pramipexole, pergolide, bromocriptine, and cabergoline. Cabergoline, and to a lesser extent pergolide, produced the most vigorous and longest lasting circling response. This response was sustained with administration of these agents over a nine day period. Bromocriptine, pramipexole and ropinirole were all less effective. These results suggest that dopamine agonists whose effect is primarily on D1 and D2 receptors are more effective than those whose actions do not include D1 activation.
Asunto(s)
Agonistas de Dopamina/farmacología , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Benzotiazoles , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Bromocriptina/farmacología , Cabergolina , Esquema de Medicación , Ergolinas/farmacología , Indoles/farmacología , Masculino , Actividad Motora/fisiología , Oxidopamina/farmacología , Trastornos Parkinsonianos/fisiopatología , Pergolida/farmacología , Pramipexol , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Tiazoles/farmacologíaRESUMEN
We report a patient with a parkinsonian syndrome induced by sertraline (Zoloft), an SSRI antidepressant, whose symptoms resolved after the drug was discontinued. This case prompted us to investigate the effect of sertraline on dopamine metabolism in animals. Sertraline (30 mg/kg, i.p.) or placebo (vehicle) was administered to two groups of six normal, anesthetized rats and using cerebral microdyalisis extracellular striatal levels of dopamine, the dopamine metabolites (HVA and DOPAC), as well as the serotonin metabolite 5-HIIA were monitored. In animals pre-treated with sertraline, DOPAC, HVA, and 5-HIAA levels were significantly decreased compared to control animals (p < 0.01). These data indicate that sertraline has an effect on dopamine metabolism, which may alter function in the striatum and induce a parkinsonian syndrome.
Asunto(s)
1-Naftilamina/análogos & derivados , Antidepresivos de Segunda Generación/efectos adversos , Antidepresivos de Segunda Generación/farmacología , Dopamina/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , 1-Naftilamina/efectos adversos , 1-Naftilamina/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Anciano , Animales , Cromatografía Líquida de Alta Presión , Femenino , Ácido Homovanílico/metabolismo , Humanos , Ácido Hidroxiindolacético/metabolismo , Microdiálisis , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Ratas , SertralinaRESUMEN
We tested the circling response to l-DOPA and apomorphine administration in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Rats demonstrated a progressively diminished circling response when l-DOPA-carbidopa was repeatedly administered at 120 min intervals. This decreasing response was not present when apomorphine was administered under the same conditions. We also perfused l-DOPA directly into the striatum in vivo of rats with an ipsilateral 6-OHDA nigrotomy at 60 min intervals and monitored striatal dopamine levels with the technique of brain microdialysis. Dopamine formation increased from the first to the fifth trial. This may be secondary to the decrease in uptake sites which accompanies the loss of striatal dopamine nerve terminals. We postulate that the continued presence of dopamine at striatal receptor sites conditions a short-term loss of dopamine receptor sensitivity and a consequent decreased circling response. The observation that desensitization (as measured by decreasing circling) was not present following repeated apomorphine administration may be attributable to its shorter duration of action. We also perfused l-DOPA into the striatum of normal rats and noted a progressive decrease in striatal dopamine levels from the first to the fifth trial. Since this occurred following direct administration of l-DOPA into the striatum, the decrease could not be accounted for by peripheral pharmacodynamics or bioavailability of l-DOPA in the striatum. Since this decrease in dopamine formation was seen only in the normal striatum, its relevance to the diminished behavioral response is unclear.
Asunto(s)
Apomorfina/farmacología , Dopaminérgicos/farmacología , Agonistas de Dopamina/farmacología , Dopamina/biosíntesis , Levodopa/farmacología , Neostriado/metabolismo , Conducta Estereotipada/efectos de los fármacos , Animales , Apomorfina/administración & dosificación , Cromatografía Líquida de Alta Presión , Dopaminérgicos/administración & dosificación , Agonistas de Dopamina/administración & dosificación , Electroquímica , Levodopa/administración & dosificación , Masculino , Microdiálisis , Neostriado/efectos de los fármacos , Oxidopamina/toxicidad , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/psicología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiologíaRESUMEN
The purpose of this study was to assess whether the presence and severity of psychiatric symptoms in stroke patients correlate with their length of stay (LOS) in a rehabilitation unit, with special emphasis on the role of negative symptoms (NS). Twenty-three stroke patients, consecutively recruited from the inpatient rehabilitation unit, were evaluated on admission with the Mini-Mental State Examination (MMSE), the Positive and Negative Symptom Scale (PANSS), the Hamilton Depression Rating Scale (HDRS), the Scale for Assessment of Negative Symptoms (SANS), and the Functional Independent Measure (FIM). NS scores significantly correlated with LOS, with SANS total score being the most informative, and the attentional impairment subscale the least. The group of patients with pronounced NS stayed in the hospital twice as long as patients with the score on the NS subscale of PANSS below 16. These two groups did not differ in their cognitive performance or in the positive symptom subscale of PANSS scores. Total FIM score on admission was lower and HDRS scores higher in patients with pronounced NS. However, these differences, unlike those of LOS, have not reached statistical significance. The presence and severity of NS in stroke patients are associated with a longer hospital stay. Identification and treatment of NS might lead to a faster discharge from rehabilitation unit.
Asunto(s)
Trastornos Cerebrovasculares/psicología , Trastornos Cerebrovasculares/rehabilitación , Tiempo de Internación , Trastornos Mentales/diagnóstico , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Anciano , Análisis de Varianza , Trastornos Cerebrovasculares/diagnóstico , Femenino , Unidades Hospitalarias , Hospitalización , Humanos , Masculino , Trastornos Mentales/psicología , Persona de Mediana Edad , Esquizofrenia/clasificación , Esquizofrenia/diagnóstico , Psicología del Esquizofrénico , Índice de Severidad de la EnfermedadRESUMEN
Inhibitors of the enzyme catechol-O-methyl transferase (COMT) may be useful adjuncts to L-DOPA in the treatment of Parkinson's disease as they offer the possibility of increasing the availability of the amino acid. It is unknown whether a COMT inhibitor which penetrates the blood-brain barrier is preferable to one restricted to extra-cerebral inhibition. We measured liver and brain COMT activity two hours following administration of two COMT inhibitors: entacapone (ENT), mainly peripherally acting, and dinitrocatechol (DNC), peripheral and central acting. As expected, the full spectrum inhibitor DNC (30 mg/kg) induced a near total inhibition of liver and brain COMT activity. Unexpectedly, however, ENT, at 30 mg/kg, produced the same degree of liver and brain COMT inhibition as DNC; using 10mg/kg, ENT still inhibited both liver and brain COMT activity by 80%. Only at 2.5 and 5 mg/kg did ENT achieve a differential inhibition of liver (80% inhibition) versus brain (10-30% inhibition) COMT activity. In a second series of experiments, we administered ENT (2.5, 10, and 30 mg/kg) and DNC (30 mg/kg) to rats and monitored extracellular striatal dopamine and dopamine metabolite levels with cerebral microdialysis both under basal conditions and following L-DOPA/carbidopa administration. No compound modified basal striatal levels of dopamine. ENT at 30 mg/kg (but not 2.5 or 10 mg), as well as DNC, decreased striatal levels of the methylated dopamine metabolite homovanillic acid (HVA). When L-DOPA/carbidopa was administered, dopamine formation was greatest and HVA formation least in animals pretreated with DNC and 30 mg/kg ENT (but not 2.5 or 10 mg/kg ENT). The finding that ENT at doses relatively specific for peripheral enzyme inhibition did not promote dopamine or inhibit HVA formation is most likely due to the 20% residual liver COMT activity present when the inhibitor was used at less than full doses. Our data indicate that DNC and ENT both inhibit striatal HVA formation and increase dopamine formation from exogenously administered L-DOPA. The dopamine promoting effect of ENT is only present, however, at doses which inhibit central as well as peripheral COMT activity.
Asunto(s)
Encéfalo/enzimología , Inhibidores de Catecol O-Metiltransferasa , Levodopa/metabolismo , Hígado/enzimología , Ácido 3,4-Dihidroxifenilacético/química , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Encéfalo/metabolismo , Catecol O-Metiltransferasa/química , Catecol O-Metiltransferasa/metabolismo , Catecoles/química , Catecoles/metabolismo , Catecoles/farmacología , Dopamina/análogos & derivados , Dopamina/química , Dopamina/metabolismo , Ácido Homovanílico/química , Ácido Homovanílico/metabolismo , Levodopa/farmacología , Hígado/metabolismo , Masculino , Nitrilos , Ratas , Ratas Sprague-DawleyRESUMEN
The D stereoisomer of dihydroxyphenylalanine (D-DOPA) and its alpha-keto acid metabolite 3,4-dihydroxyphenylpyruvic acid (DHPPA) when infused into the striatum, significantly increased in vivo extracellular dopamine levels. Following D-DOPA administration, the cumulative increase in dopamine levels was 30% of the increase following L-DOPA: following DHPPA it was 11% that of L-DOPA. Rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra demonstrated brisk contralateral turning following each compound. The turning, however, was delayed by 10-20 min and total turning was 40% less following D-DOPA and 57% less following DHPPA than it was following L-DOPA. These data indicate that exogenously administered D-DOPA can be metabolized in vivo within the brain to dopamine and suggest this may occur via a transamination pathway in which DHPPA is an intermediary metabolite. The possible relevance of these findings to the treatment of Parkinson's disease is discussed.
Asunto(s)
Conducta Animal/efectos de los fármacos , Dihidroxifenilalanina/farmacología , Dopaminérgicos/farmacología , Dopamina/metabolismo , Neostriado/metabolismo , Ácidos Fenilpirúvicos/farmacología , Animales , Levodopa/farmacología , Masculino , Microdiálisis , Neostriado/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Conducta Estereotipada/efectos de los fármacos , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
We used the technique of cerebral microdialysis to monitor the metabolism of exogenously administered L-dopa and compared dopamine and dopamine metabolite formation in the striatum (a site containing abundant dopamine nerve terminals and dopa-decarboxylase (DDC) activity) versus the cerebellum and occipital cortex (sites with limited dopaminergic innervation and DDC activity). The concentrations of dopamine and the major dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased in each brain region following L-dopa perfusion; however, dopamine formation was 90% less in the occipital cortex as compared to the striatum and 95% less in the cerebellum. DOPAC formation was 57% less in the occipital cortex and 74% less in the cerebellum. HVA formation was 42% less in the occipital cortex and 70% less in the cerebellum. The levels of the L-dopa metabolite 3-O-methyldopa and the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) were identical in the striatum, occipital cortex, and cerebellum both before and after L-dopa administration. We conclude that brain areas with marked reductions in dopamine nerve terminals and DDC activity have a diminished capacity to synthesize dopamine and also lack storage mechanisms to protect the newly synthesized dopamine from degradative metabolism. The relevance of these findings to the use of L-dopa in treating Parkinson's disease is discussed.
Asunto(s)
Química Encefálica/fisiología , Dopaminérgicos/farmacocinética , Dopamina/biosíntesis , Levodopa/farmacocinética , Neostriado/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Biotransformación , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Ácido Hidroxiindolacético/metabolismo , Masculino , Microdiálisis , Lóbulo Occipital/efectos de los fármacos , Lóbulo Occipital/metabolismo , Ratas , Ratas Sprague-Dawley , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
Dopamine (DA) is released in large quantities from the striatum during cerebral ischemia. Along with excitatory neurotransmitters, DA plays a role in cellular neuronal ischemic injury. In this study we examined the role of nitric oxide (NO) in the ischemia-induced release of DA. A microdialysis probe was stereotactically placed into the corpus striatum of 16 Sprague-Dawley rats for DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) level determinations. After probe stabilization, the animals received either NG-nitro-L-arginine-methyl ester (L-NAME), a NO synthase inhibitor, or vehicle through the microdialysis probe. Temporary global forebrain ischemia was induced using bilateral carotid artery ligature tightening and controlled hemorrhagic hypotension for 15 min. L-NAME administration caused a reduction in ischemic estimated extraneuronal DA concentration by 60% (P < 0.005) compared with control. There was an increase in both DOPAC and HVA concentrations during the recovery period compared to baseline values in the control group (P < 0.05). L-NAME also caused a reduction in HVA concentration compared to vehicle administration during the latter part of recovery (P < 0.05). These data support the concept that ischemic dopamine release may be mediated by NO. This NO-modulated DA release may contribute to the previously reported deleterious neurotoxic effects of NO during ischemia.
Asunto(s)
Dopamina/metabolismo , Ataque Isquémico Transitorio/metabolismo , Óxido Nítrico/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Arginina/análogos & derivados , Arginina/farmacología , Cuerpo Estriado/metabolismo , Ácido Homovanílico/metabolismo , NG-Nitroarginina Metil Éster , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Utilizing the cerebral microdialysis technique, we have compared in vivo the effects of selective MAO-A, MAO-B, and nonselective MAO inhibitors on striatal extracellular levels of dopamine (DA) and DA metabolites (DOPAC and HVA). The measurements were made in rats both under basal conditions and following L-DOPA administration. Extracellular levels of dopamine were enhanced and DA metabolite levels strongly inhibited both under basal conditions and following L-DOPA administration by pretreatment with the nonselective MAO inhibitor pargyline and the MAO-A selective inhibitors clorgyline and Ro 41-1049. The MAO-B inhibitor deprenyl had no effect on basal DA, HVA, or DOPAC levels. Nevertheless, deprenyl significantly increased DA and decreased DOPAC levels following exogenous L-DOPA administration, a finding compatible with a significant glial metabolism of DA formed from exogenous L-DOPA. We conclude that DA metabolism under basal conditions is primarily mediated by MAO-A. In contrast, both MAO-A and MAO-B mediate DA formation when L-DOPA is administered exogenously. The efficacy of newer, reversible agents which lack the "cheese effect" such as Ro 41-1049 are comparable to the irreversible MAO-A inhibitor clorgyline. The possible relevance of these findings for the treatment of Parkinson's disease is discussed.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Levodopa/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Clorgilina/farmacología , Ácido Homovanílico/metabolismo , Masculino , Microdiálisis , Pargilina/farmacología , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-Dawley , Selegilina/farmacologíaRESUMEN
We administered Ro 41-1049, an inhibitor of the enzyme monoamine oxidase type A (MAO-A) to rats and monitored extracellular catecholamine levels in the corpus striatum before and after the intraperitoneal (IP) administration of a bolus of L-dopa. Acute administration of Ro 41-1049 (1-50 mg/kg IP) produced a dose-dependent decrease in basal levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and an increase in basal levels of dopamine. In rats treated with Ro 41-1049 (20 mg/kg IP), L-dopa administration (100 mg/kg IP) produced a greater increase in striatal levels of dopamine than it did in controls, while DOPAC and HVA formation was attenuated. We conclude that inhibition of central MAO-A activity promotes synaptic accumulation of dopamine following administration of pharmacological doses of L-dopa.