RESUMEN
Direct intracerebral administration of sonic hedgehog (SHH) reduces 6-OHDA and MPTP toxicity to nigral dopaminergic cells in rats and primates. To determine whether transfection of the DNA sequence for SHH using viral vectors also protects against 6-OHDA toxicity, a type 2 adeno- associated virus (AAV) incorporating 600 base pairs of N-terminal SHH DNA was generated to induce SHH expression in rat striatum.AAV-SHH was injected into the striatum, 3 weeks prior to the initiation of an unilateral partial 6-OHDA nigro-striatal lesion. Animals receiving 4x10(7) viral particles of AAV-SHH showed a reduction in (+)-amphetamine induced ipsilateral turning over 4 weeks, when compared to animals receiving vehicle or a LacZ encoding vector. Following vehicle or AAV-LacZ administration, 6-OHDA caused a marked loss of striatal dopamine content and nigral tyrosine hydroxylase (TH) immunopositive cells. Following treatment with 4x10(7) viral particles of AAV-SHH the loss of striatal dopamine content was reduced and there was marked preservation of nigral dopaminergic cells. However, administration of 4x10(8) particles of AAV-SHH did not cause a significant change in (+)-amphetamine-induced rotation, striatal dopamine levels or the number of nigral TH immunoreactive cells following 6-OHDA lesioning compared to vehicle or AAV-LacZ treated animals. The results show that SHH delivered via a viral vector can protect dopaminergic neurons against 6-OHDA toxicity and suggest that this could be developed into a novel treatment for PD. However, the effects maybe dose limited due to uncoupling of hedgehog receptor signalling at higher levels of SHH expression.
Asunto(s)
Adrenérgicos/toxicidad , Degeneración Nerviosa/prevención & control , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Oxidopamina/toxicidad , Transactivadores/administración & dosificación , Adenoviridae/genética , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Vectores Genéticos , Proteínas Hedgehog , Humanos , Inmunohistoquímica , Inyecciones Intraventriculares , Masculino , Degeneración Nerviosa/inducido químicamente , Neuronas/metabolismo , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-Dawley , Transfección , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Sonic hedgehog (SHH) has trophic actions on dopaminergic cell cultures and protects them from MPP(+) toxicity but its in vivo actions have not been explored. We now investigate the effects of unilateral supranigral administration of SHH on nigro-striatal function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. SHH (0.1 or 1.0 microg) or vehicle was stereotaxically injected into the region of the right substantia nigra twice with an interval of 5 weeks between administrations. The first or second administration of low dose SHH (0.1 microg) did not significantly improve motor disability or locomotor activity compared to time-matched vehicle-treated animals. There was, however, an approximately 30% improvement in both motor disability and locomotor activity following the first administration of high dose SHH (1.0 microg). No further improvements occurred following the second high dose SHH treatment. Acute oral administration of L-3,4-dihydroxyphenylalanine (L-DOPA) produced a smaller increase in locomotor activity and greater reversal of motor disability in animals treated with SHH than occurred in vehicle-treated common marmosets. In the substantia nigra pars compacta, ipsilateral to SHH administration, the number of tyrosine hydroxylase-positive neurones was increased by 21% (P > 0.05) and 57% (P < 0.05) in low and high dose SHH groups respectively compared to the untreated contralateral hemisphere. There was no difference in the number of glial fibrillary acidic protein-positive cells. SHH may improve nigro-striatal function by restoring tyrosine hydroxylase positivity. This is reflected by an improvement in basal disability and a reduction in the lesion-induced response to L-DOPA.
Asunto(s)
Callithrix/metabolismo , Factores de Crecimiento Nervioso/farmacología , Neuronas/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Recuperación de la Función/efectos de los fármacos , Sustancia Negra/efectos de los fármacos , Transactivadores/farmacología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Callithrix/anatomía & histología , Recuento de Células , Dopamina/metabolismo , Interacciones Farmacológicas/fisiología , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas Hedgehog , Inmunohistoquímica , Levodopa/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Neuronas/metabolismo , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/fisiopatología , Recuperación de la Función/fisiología , Sustancia Negra/metabolismo , Sustancia Negra/fisiopatología , Resultado del Tratamiento , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Modafinil is a novel wake-promoting compound for which the mechanism and sites of action are unknown. We examined the neural substrates in the brain for the actions of modafinil using 2-deoxyglucose autoradiography and compared the findings to those obtained with amphetamine. Modafinil showed a relatively restricted pattern of changes in brain regional metabolic activity, while amphetamine altered glucose utilization in a wide variety of brain regions. Both modafinil and amphetamine increased glucose utilization in all subregions of the hippocampus (subiculum, CA1-CA3 and dentate gyrus) and in the centrolateral nucleus of the thalamus. Modafinil also increased glucose utilization in the central nucleus of the amygdala, but amphetamine had no effect in this region. Brain structures in which amphetamine increased metabolic rate but modafinil had no effect included regions of the basal ganglia, other nuclei of the thalamus, the frontal cortex, the nucleus accumbens, the ventral tegmental area and the pontine reticular fields. These findings suggest that, while both modafinil and amphetamine promote wakefulness, they act via distinctly different mechanisms. Modafinil appears to act on a specific subset of brain pathways which regulate sleep and wakefulness, whereas amphetamine affects a greater number of cerebral structures involved in the regulation of these behavioral states. Modafinil also lacks the pronounced effects on the extrapyramidal motor system which are characteristic of amphetamine and other psychomotor stimulants, implying that the effects of modafinil are not mediated by the dopamine system and that modafinil may selectively increase wakefulness with fewer side effects.
Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Desoxiglucosa , Dextroanfetamina/farmacología , Hipocampo/efectos de los fármacos , Vigilia/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Metabolismo Energético , Glucosa/metabolismo , Hipocampo/metabolismo , Masculino , Modafinilo , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Ratas , Ratas Sprague-Dawley , Sueño/fisiologíaRESUMEN
We examined the neuronal targets in the rat brain for the novel wakefulness-promoting agent modafinil and for amphetamine using c-Fos immunohistochemistry. Both modafinil and amphetamine induced neuronal expression of c-Fos-like immunoreactivity in the paraventricular nucleus of the hypothalamus, anterior hypothalamus and central nucleus of the amygdala. Modafinil also increased c-Fos-like immunoreactivity in the suprachiasmatic nucleus, while amphetamine had no effect. Brain regions in which amphetamine increased c-Fos-like immunoreactivity, but modafinil had no effect, included frontal cortex, striatum, lateral habenula, supraoptic nucleus and basolateral nucleus of the amygdala. These findings suggest that the mechanism of action of modafinil is different from that of amphetamine and that the neuronal targets for modafinil in the brain include nuclei of the hypothalamus and amygdala.
Asunto(s)
Anfetamina/farmacología , Compuestos de Bencidrilo/farmacología , Encéfalo/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Animales , Encéfalo/citología , Encéfalo/metabolismo , Inmunohistoquímica , Masculino , Modafinilo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , VigiliaRESUMEN
In vitro studies indicate that p42/p44MAPK phosphorylate both nuclear and cytoplasmic proteins. However, the functional targets of p42/p44MAPK activation in vivo remain unclear. To address this question, we localized activated p42/p44MAPK in hippocampus and cortex and determined their signaling effects after electroconvulsive shock treatment (ECT) in rats. Phosphorylated p42/p44MAPK content increased in the cytoplasm of hippocampal neurons in response to ECT. Consistent with this cytoplasmic localization, inhibition of ECT-induced p42/p44MAPK activation by the extracellular signal-regulated kinase kinase inhibitor PD098059 blocked phosphorylation of the cytoplasmic protein microtubule-associated protein 2c (MAP2c), but failed to inhibit the induction of the nuclear protein c-Fos in response to ECT. In contrast to hippocampal neurons, cortical neurons exhibited an increase in amount of phosphorylated p42/p44MAPK in both the nucleus and cytoplasm after ECT. Accordingly, PD098059 blocked the induction of Fos-like immunoreactivity in the nuclei of cortical neurons as well as MAP2c phosphorylation in the cytoplasm. Our data indicate that both nuclear and cytoplasmic substrates can be activated by p42/p44MAPK in vivo. However, the functional targets of p42/p44MAPK signaling depend on the precise location of p42/p44MAPK within different subcellular compartments of brain regions. These results indicate unique functional pathways of p42/p44MAPK-mediated signal transduction within different brain regions in vivo.
Asunto(s)
Encéfalo/fisiología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos , Proteínas Quinasas Activadas por Mitógenos , Transducción de Señal/fisiología , Animales , Proteínas Quinasas Dependientes de Calcio-Calmodulina/antagonistas & inhibidores , Núcleo Celular/fisiología , Corteza Cerebral/fisiología , Citoplasma/metabolismo , Electrochoque , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Hipocampo/fisiología , MAP Quinasa Quinasa 1 , Proteínas Asociadas a Microtúbulos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Especificidad de Órganos , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Ratas , Ratas Sprague-DawleyRESUMEN
Recent studies indicate that a daily s.c. injection of 1 mg/kg of recombinant human insulin-like growth factor-1 (rhIGF-1) for 17 days is efficacious in enhancing the functional recovery of injured sciatic nerves in CD-1 mice. To identify and characterize surrogate marker(s) that are altered in association with the administration of an efficacious dose of rhIGF-1, dose-response curves (0.1, 1 and 10 mg/kg) and time course effects (0, 0.5, 3, 6 and 24 hr) were determined after acute (single) and chronic (once daily for 17 days) injections of rhIGF-1 in CD-1 mice. Plasma glucose levels decreased in a dose-dependent fashion after either acute or chronic injections of rhIGF-1 with maximal effects at 0.5 to 1 hr after administration of rhIGF-1. Among the three insulin-like growth factor binding proteins (IGFBPs) evaluated in the study, only IGFBP2 levels were consistently increased in a dose-dependent fashion with maximal effects 3 hr after the last of a series of injections of rhIGF-1. Furthermore, IGFBP2 levels increased at a dose of rhIGF-1 (1 mg/kg) that enhances the regeneration of injured sciatic nerves in mice. Chronic administration of insulin at doses that cause comparable decreases in plasma glucose to that of rhIGF-1 did not alter IGFBP2 levels or enhance hindlimb function suggesting that the beneficial effects of rhIGF-1 occur via activation of the type-I IGF receptor rather than the insulin receptor. Based on these criteria, IGFBP2 appears to be useful as a surrogate marker for determining the in vivo effects of rhIGF-1.
Asunto(s)
Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/farmacología , Animales , Biomarcadores , Glucemia/análisis , Humanos , Insulina/farmacología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Proteínas Recombinantes/farmacologíaRESUMEN
The systemic administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, MK801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) , has previously been found to reverse the motor response alterations that develop during long-term levodopa treatment of parkinsonian rats. To determine whether co-administration of MK801 with levodopa might prevent the initial appearance of these response changes, rats, rendered parkinsonian by a 6-hydroxydopamine lesion of the medial forebrain bundle, received either levodopa alone or levodopa with the NMDA receptor antagonist. After four weeks of treatment with levodopa alone, the duration of the turning response declined by 37% (P < 0.05) and the number of ineffectual levodopa injections had more than doubled (P < 0.05). MK801 co-treatment completely blocked the shortening in response duration and prevented the frequency of ineffectual levodopa injection from exceeding baseline levels in animals receiving levodopa alone. The total magnitude of the turning response to levodopa was not affected. These results suggest that NMDA receptor blockade may act prophylactically to prevent the appearance of motor response alterations in levodopa-treated parkinsonian rodents that resemble those occurring in levodopa-treated patients with Parkinson's disease.
Asunto(s)
Antiparkinsonianos/farmacología , Maleato de Dizocilpina/farmacología , Levodopa/análogos & derivados , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/fisiopatología , Animales , Antiparkinsonianos/antagonistas & inhibidores , Benserazida/farmacología , Levodopa/antagonistas & inhibidores , Levodopa/farmacología , Masculino , Oxidopamina , Prosencéfalo , Ratas , Ratas Sprague-Dawley , RotaciónRESUMEN
Behavioral and biochemical responses to D1 and D2 dopamine (DA) agonists were used to evaluate the participation of striatal peptidergic mechanisms in the motor function alterations that attend chronic neuroleptic treatment. Rats, given haloperidol (1 mg/kg, i.c.) for 21 consecutive days, were randomly allocated to one of the following treatments: the D1 agonist SKF 38393, the D2 agonist quinpirole, their combination or saline. Stereotyped behavior and neuropeptide levels were evaluated after 5 days treatment and 4 days washout. Haloperidol increased most oral behaviors including licking, chewing and biting as well as striatal enkephalin and somatostatin levels. Subsequent treatment with SKF 38393 diminished the haloperidol-induced increase in licking and chewing; quinpirole reduced chewing behavior. The administration of both agonists together decreased chewing and biting. Neither DA agonist alone, nor their combination, reduced the haloperidol-induced increase in enkephalin levels. Both SKF 38393 and quinpirole, when given alone, tended to decrease the haloperidol-induced increase in somatostatin levels; when both D1 and D2 agonists were administered together, somatostatin levels declined significantly. These results suggest that somatostatin- but not enkephalin-containing striatal neurons contribute to the expression of haloperidol-induced stereotypies.
Asunto(s)
Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Neostriado/química , Neuropéptidos/metabolismo , Conducta Estereotipada/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Agonistas de Dopamina/farmacología , Dinorfinas/metabolismo , Encefalinas/metabolismo , Masculino , Neostriado/efectos de los fármacos , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Sensibilidad y Especificidad , Somatostatina/metabolismo , Sustancia P/metabolismo , Factores de TiempoRESUMEN
Striatal dynorphin-containing neurons receive dopaminergic inputs from the substantia nigra pars compacta and project primarily to the substantia nigra pars reticulata and entopeduncular nucleus. These neurons mainly express dopamine (DA) D1 receptors and thus dynorphin system stimulation might be expected largely to influence D1 receptor agonist or antagonist effects on motor function. It is well known the interaction existing between DA D1 and D2 drugs in the induction of behavioral effects. However, the effects of dynorphin on selective D1 and D2 DA agonist and antagonist-induced behaviors have not yet been investigated. Administration of the kappa agonists spiradoline (0.5, 1 and 5 mg/kg) or U50,488H (1, 10 and 25 mg/kg) decreased non-stereotyped grooming induced by the selective D1 agonist SKF38393. This effect was inhibited by the non-selective opioid receptor antagonist naloxone (20 mg/kg) and by the selective kappa antagonist nor-binaltorphimine (nor-BNI, 20 mg/kg). Stereotypies induced by the selective D2 agonist quinpirole were decreased by spiradoline (1 and 5 mg/kg) and by U50,488H (1, 10 and 25 mg/kg), while jerking movements of a type associated with increased D2 receptor and decreased D1 receptor stimulation emerged. Kappa agonist effects were inhibited by the prior administration of SKF38393 (10 mg/kg); these inhibitory effects were blocked by prior administration of the D1 antagonist SCH23390 (5 mg/kg). Naloxone reversed the effects of both kappa agonists on quinpirole-induced stereotypies. Kappa agonists increased D1 antagonist-induced catalepsy, but had no effect on D2 antagonist-induced catalepsy. Naloxone and nor-BNI inhibited this effect. These results suggest that the motoric effects of D1 receptor antagonists in part reflect stimulation of striatal dynorphin containing efferents.
Asunto(s)
Conducta Animal/efectos de los fármacos , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Receptores Opioides kappa/agonistas , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero , Animales , Catalepsia/inducido químicamente , Relación Dosis-Respuesta a Droga , Masculino , Pirrolidinas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Dopaminoceptive system alterations in the basal ganglia have been implicated in the pathogenesis of wearing-off fluctuations that complicate levodopa therapy of Parkinson's disease. To evaluate the contribution of glutamatergic mechanisms to the associated changes in striatal efferent pathway function, we examined the ability of N-methyl-D-aspartate (NMDA) receptor blockade to modify the motor response changes produced by chronic levodopa administration to hemiparkinsonian rats. Unilaterally 6-hydroxydopamine lesioned rats, given levodopa/benserazide (25/6.25 mg/kg) twice daily for 3 weeks, developed a progressive shortening in the duration of their motor response to levodopa similar to that occurring in parkinsonian patients with wearing-off phenomenon. The acute systemic administration of MK-801 (0.1 mg/kg) to these animals completely reversed the decrease in turning duration (P < 0.01). Intrastriatal injection of the NMDA antagonist was even more effective in prolonging the levodopa response (P < 0.01), while intranigrally injected MK-801 produced no statistically significant change in the duration of levodopa-induced rotation. Rotational intensity was unaffected by all routes of MK-801 administration. These results suggest that drugs capable of blocking NMDA receptors, especially in striatum, may help ameliorate motor fluctuations in patients with advanced Parkinson's disease.
Asunto(s)
Antiparkinsonianos/antagonistas & inhibidores , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Levodopa/antagonistas & inhibidores , Enfermedad de Parkinson Secundaria/fisiopatología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Antiparkinsonianos/farmacología , Apomorfina/farmacología , Benserazida/farmacología , Maleato de Dizocilpina/administración & dosificación , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Inyecciones , Inyecciones Intraventriculares , Levodopa/farmacología , Masculino , Movimiento/efectos de los fármacos , Oxidopamina , Ratas , Ratas Sprague-Dawley , Rotación , Conducta Estereotipada/efectos de los fármacos , Sustancia NegraRESUMEN
Motor fluctuations that ultimately complicate the response of most parkinsonian patients to levodopa therapy might represent a form of behavioral or neuronal plasticity. Since various forms of neuronal plasticity appear to be mediated by glutamate transmission through the N-methyl-D-aspartate (NMDA) receptor, the effect of NMDA receptor blockade on the development of alterations in the motor response to chronic levodopa was evaluated in hemiparkinsonian rats. Repeated levodopa administration decreased rotational behavior induced by a D1 dopamine receptor agonist, increased D2 agonist-induced rotation and progressively reduced the duration of the motor response to levodopa itself. Acute pretreatment with the noncompetitive NMDA antagonist MK-801 completely reversed all these changes. These findings suggest that NMDA receptor-mediated mechanisms contribute to the behavioral plasticity associated with chronic levodopa treatment and that NMDA antagonists might be effective in reversing the motor response complications of the long-term levodopa therapy.
Asunto(s)
Levodopa/farmacología , Actividad Motora/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Maleato de Dizocilpina/farmacología , Masculino , Enfermedad de Parkinson Secundaria/fisiopatología , Ratas , Ratas Sprague-Dawley , Rotación , Conducta Estereotipada/efectos de los fármacosRESUMEN
The pathogenesis of the motor fluctuations that complicate levodopa treatment of most parkinsonian patients remains uncertain. To evaluate the contribution of the degree of dopamine neuron loss and the duration of levodopa exposure, rats whose nigrostriatal system had been previously lesioned unilaterally by 6-hydroxydopamine received twice daily levodopa (25 mg/kg) injections for three weeks. The magnitude of the rotational response to levodopa more than doubled during the first week of treatment (P < 0.01), but remained essentially constant thereafter. Rats with over 95 percent loss of dopaminergic neurons evidenced a progressive shortening in the duration of levodopa's motor effects (P < 0.01) as well as a failure of nearly 8 percent of levodopa injections to elicit any response after the first week of treatment. In contrast, response changes resembling those associated with end of dose deterioration and on-off fluctuations in parkinsonian patients did not occur in the less severely lesioned rats. These results suggest that the extent of a dopamine neuron loss must exceed a relatively high threshold before intermittent levodopa treatment produces changes favoring the rapid appearance of motor fluctuations of the wearing-off and on-off types.
Asunto(s)
Levodopa/uso terapéutico , Movimiento/fisiología , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Anfetamina/farmacología , Animales , Apomorfina/farmacología , Desnervación , Inmunohistoquímica , Masculino , Haz Prosencefálico Medial/fisiología , Movimiento/efectos de los fármacos , Neostriado/patología , Oxidopamina , Enfermedad de Parkinson Secundaria/patología , Enfermedad de Parkinson Secundaria/fisiopatología , Ratas , Ratas Sprague-Dawley , Rotación , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Motor response complications that ultimately affect most parkinsonian patients appear related to altered dopaminergic mechanisms at both the presynaptic and postsynaptic levels. "Wearing-off" phenomena reflect a shortened duration of the antiparkinsonian action of levodopa, caused initially by the reduced capacity of the degenerating nigrostriatal system to store dopamine. Later, secondary changes in postsynaptic structures contribute substantially to these complications as well as to the changes in levodopa dose-antiparkinsonian response relation and the threshold for levodopa-induced dyskinesias that underlie "on-off" fluctuations and "peak-dose" dyskinesias. In parkinsonian rats, levodopa treatment not only fails to normalize striatal systems modified by the loss of dopaminergic afferents, but actually tends to exacerbate these alterations. Moreover, the vulnerability of these downstream systems to levodopa-induced change appears closely related to the severity of dopamine terminal loss and the intermittence of levodopa administration. In parkinsonian patients, switching from a standard intermittent levodopa regimen to a continuously infused dopaminomimetic alleviates motor fluctuations and widens the therapeutic window for levodopa. Taken together, currently available data support the view that continuous dopaminomimetic therapy has both immediate and delayed palliative value for advanced parkinsonian patients and potentially could confer prophylactic benefit to those at earlier stages of their disorder.
Asunto(s)
Antiparkinsonianos/efectos adversos , Dopaminérgicos/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Animales , Dopaminérgicos/administración & dosificación , Esquema de Medicación , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/prevención & control , Humanos , Cuidados Paliativos , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
Activation of dopamine D1 receptors is thought to stimulate release of striatal acetylcholine (ACh) indirectly, possibly through local release of substance P which, in turn, may enhance release of ACh. To test this hypothesis, in vivo microdialysis was used to assess the effect of neurokinin1 (NK1) receptor blockade on D1 agonist-induced increases in ACh release in the striatum of awake, freely moving rats with and without a unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal pathway. Local perfusion with the D1 agonist (+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine-7,8-diol hydrochloride (SKF 38393; 1-25 microM for 20 min) increased striatal ACh release in both intact rats and rats with a 6-hydroxydopamine-induced lesion, although the increase was greater in magnitude in rats with a lesion. Local application of the NK1 antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N- [(methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP-96,345; 10 and 25 microM), but not its less active enantiomer (2R,3R)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine (CP-96,344; 10 and 25 microM), decreased the elevation in ACh induced by SKF 38393 in both intact rats and rats treated with 6-hydroxydopamine. Systemic administration of the NK1 antagonist 17-beta-hydroxy-17-a-androstanol[3.2- b]pyrimidol[1,2-a]benzimidazole hydrochloride (WIN 51,708; 20 mg/kg i.p.) also reduced the increase in ACh release induced by local perfusion of SKF 38393.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Acetilcolina/metabolismo , Cuerpo Estriado/metabolismo , Receptores de Dopamina D1/fisiología , Receptores de Neuroquinina-1/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/análogos & derivados , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Androstanos/farmacología , Animales , Bencimidazoles/farmacología , Compuestos de Bifenilo/farmacología , Fenoldopam , Masculino , Oxidopamina , Ratas , Ratas Sprague-DawleyRESUMEN
Excitatory amino acid receptor antagonists have been proposed as novel therapeutic agents to be used with levopoda in the treatment of Parkinson's disease. We examined the neural substrates for the interaction between levodopa and antagonists of either the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or N-methyl-D-aspartate type of excitatory amino acid receptor using 2-deoxyglucose autoradiography. Thus, we compared the effects of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (10 mg/kg, i.v.) and the N-methyl-D-aspartate antagonist MK-801 (0.1 mg/kg, i.v.) on cerebral metabolic responses to levodopa (25 mg/kg, i.v., with 12.5 mg/kg benserazide) in rats with a unilateral nigrostriatal pathway lesion. Levodopa increased glucose utilization ipsilateral to the lesion in substantia nigra pars reticula (up to 104%), entopeduncular nucleus (up 90%) and subthalamic nucleus (up 30%), indicating that levodopa alters striatal output through the striatonigral, striatoentopeduncular and striatopallidal pathways. Levodopa also decreased metabolic rate in lateral habenula (down 39%), a target of projections from entopeduncular nucleus, implying a reduction in basal ganglia output. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and MK-801 by themselves did not affect glucose utilization in any of these regions. Pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline reduced the effect of levodopa in substantia nigra pars reticulata but not in entopeduncular nucleus or subthalamic nucleus, while MK-801 attenuated the effect of levodopa in all three of these structures; neither 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline nor MK-801 altered the effect of levodopa in lateral habenula. When given at the same doses to a separate group of lesioned animals, neither 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline nor MK-801 affected rotational behavior elicited by levodopa. These findings indicate that alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-D-aspartate receptor antagonists differentially modify dopamine receptor-mediated striatal output. alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor blockade may preferentially attenuate the effect of dopamine receptor activation on the striatonigral pathway, while N-methyl-D-aspartate blockade appears to reduce the actions of dopamine on the striatonigral, striatoentopeduncular and striatopallidal pathways.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Encéfalo/metabolismo , Desoxiglucosa/metabolismo , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores , Levodopa/farmacología , Quinoxalinas/farmacología , Animales , Autorradiografía , Encéfalo/efectos de los fármacos , Radioisótopos de Carbono , Masculino , Actividad Motora/efectos de los fármacos , Especificidad de Órganos , Oxidopamina , Ratas , Ratas Sprague-DawleyRESUMEN
Motor response complications eventually appear in most patients with advanced Parkinson's disease being treated with levodopa. The interval between onset of parkinsonism and emergence of these adverse events appears independent of the dose or the duration of therapy. Current evidence suggests that "wearing-off" fluctuations largely reflect the loss of normally functioning dopaminergic terminals, although postsynaptic alterations contribute somewhat to the underlying decline in the duration of levodopa's antiparkinsonian action. "On-off" fluctuations and peak-dose dyskinesias, on the other hand, appear to arise mainly as a consequence of postjunctional alterations that follow exposure to nonphysiologic intrasynaptic dopamine fluctuations in patients who have lost the buffering afforded by dopaminergic terminals. Studies in rats with 6-hydroxydopamine lesions indicate that striking functional alterations occur in striatal dopaminoceptive systems as a result of dopaminergic denervation and that levodopa replacement, particularly when given intermittently, fails to normalize these changes. To the extent that similar alterations contribute to the appearance of motor complications, the successful symptomatic therapy of Parkinson's disease may require continuous dopaminergic stimulation, as well as direct pharmacologic targeting of striatal dopaminoceptive systems.
Asunto(s)
Cuerpo Estriado/fisiopatología , Músculos/fisiopatología , Neuronas Eferentes/fisiología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Animales , Cuerpo Estriado/efectos de los fármacos , Humanos , Levodopa/efectos adversos , Levodopa/uso terapéutico , Músculos/efectos de los fármacos , Neuronas Eferentes/efectos de los fármacos , RatasRESUMEN
The potential antiparkinson activity of N-methyl-D-aspartate antagonists was investigated by examining the effects of dizocilpine (MK-801) on rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway. MK-801, when administered alone to these animals, elicited ipsilateral rotation, which could be blocked by haloperidol. MK-801, at doses that did not produce rotation when given alone, inhibited the contralateral rotation produced by the D2 receptor agonist quinpirole but had no effect on the rotation induced by the D1 agonist SKF 38393 [(+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8- diolhydrochloride]. However, exposure to levodopa 3 days previously resulted in a subsensitive rotational response to SKF 38393 and this subsensitivity to the D1 agonist was reversed by MK-801. The subsensitive rotational response to SKF 38393 was not evident 7 days after exposure to levodopa and MK-801 had no effect on the response to SKF 38393 at this time. These data suggest that N-methyl-D-aspartate receptor blockade can exert differential effects on dopamine agonist-induced rotational behavior that depend on which dopamine receptor subtype is activated and the previous exposure of the animal to dopamine agonists.
Asunto(s)
Encefalopatías/fisiopatología , Maleato de Dizocilpina/farmacología , Dopaminérgicos/farmacología , Levodopa/farmacología , Oxidopamina , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Encefalopatías/inducido químicamente , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Actividad Motora/efectos de los fármacos , N-Metilaspartato/antagonistas & inhibidores , Enfermedad de Parkinson/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacosRESUMEN
Microdialysis was used to study the effects of selective GABAergic agents on striatal acetylcholine (ACh) release in awake, freely moving rats. Local perfusion with the GABAA agonist muscimol dramatically reduced striatal ACh release, while the GABAB agonist baclofen caused only minor decreases in ACh release. Co-perfusion with the GABAA antagonist bicuculline diminished the muscimol-induced decrease in ACh release. Likewise, co-perfusion with the GABAB antagonist 2-hydroxysaclofen attenuated the baclofen-induced reduction in ACh release. Bicuculline alone markedly increased striatal ACh release, but 2-hydroxysaclofen by itself had no effect. These results suggest that GABA tonically regulates striatal ACh release primarily through stimulation of inhibitory GABAA receptors.
Asunto(s)
Acetilcolina/metabolismo , Baclofeno/farmacología , Cuerpo Estriado/metabolismo , Muscimol/farmacología , Receptores de GABA-A/fisiología , Receptores de GABA-B/fisiología , Animales , Baclofeno/administración & dosificación , Baclofeno/análogos & derivados , Bicuculina/administración & dosificación , Bicuculina/farmacología , Cuerpo Estriado/efectos de los fármacos , Antagonistas de Receptores de GABA-A , Antagonistas de Receptores de GABA-B , Cinética , Masculino , Microdiálisis , Muscimol/administración & dosificación , Ratas , Ratas Sprague-Dawley , Técnicas Estereotáxicas , Factores de TiempoRESUMEN
Little is known about the role that neuropeptides such as substance P play in cell-to-cell interactions in the striatum. The effect of locally perfused substance P on extracellular acetylcholine (ACh) in the dorsal striatum of awake, freely moving rats was examined using microdialysis. Neostigmine (1 microM) was included in the perfusate to improve recovery of ACh. Basal extracellular ACh was sensitive to Na(+)-channel blockade with tetrodotoxin (0.3 microM) and Ca(2+)-channel blockade with MgCl2 (10 mM) and therefore largely neuronal in origin. Local perfusion with 10 and 25 microM substance P for 20 min elevated extracellular ACh by 30% and 51%, respectively. The NK1 receptor antagonist, CP 96,345 (10 microM), which by itself had no effect on extracellular ACh, prevented the substance P-induced increase in extracellular ACh. These results suggest that stimulation of NK1 receptors by substance P enhances ACh release in the dorsal striatum and is consistent with anatomical evidence of a substance P-cholinergic circuit in this region.