RESUMO
The effect of aging on the binding parameters of 3H-SCH 23390, the most selective ligand of D-1 DA receptors, was studied in membrane preparations from the rat retina. DA-stimulated adenylate cyclase activity was also measured in order to better characterize the changes in retinal D-1 DA receptors induced by aging. The binding studies revealed that the density of 3H-SCH 23390 was increased (34 and 73%) in the retina of 14- and 26-month-old rats, when compared to young adult animals, respectively. In contrast, aging failed to alter the sensitivity of the adenylate cyclase to the action of DA. In fact, DA (10(-6) M to 10(-4) M) elicited a similar enhancement in cyclic AMP formation in retinal homogenates of both adult and senescent rats. Since dark adaptation increases the density of D-1 DA receptors in the retina of adult rats we studied the effect of light deprivation on 3H-SCH 23390 binding and DA-sensitive adenylate cyclase activity in the retina of senescent rats. As previously shown (25) light deprivation increased 3H-SCH 23390 binding and enhanced DA-sensitive adenylate cyclase activity in the retina of young adult rats. On the contrary, dark adaptation failed to increase 3H-SCH 23390 binding and to enhance DA-sensitive adenylate cyclase activity in the retina of senescent rats. Taken together these results indicate that D-1 DA receptors in the retina of aged rats have biochemical and functional properties different from those found in the retina of adult animals; these changes may result in an altered response to the physiological stimuli elicited by environmental lighting.
Assuntos
Envelhecimento/fisiologia , Adaptação à Escuridão , Receptores Dopaminérgicos/fisiologia , Retina/fisiologia , Regulação para Cima , Adenilil Ciclases/fisiologia , Fatores Etários , Animais , Benzazepinas/farmacologia , Sítios de Ligação/fisiologia , Masculino , Ratos , Ratos Endogâmicos , Retina/efeitos dos fármacosRESUMO
We studied the actions of D1 and D2 dopamine agonists and antagonists on the coupling of horizontal cell axons in the turtle retina by a combination of pharmacological and electrophysiological methods. Both D1 and D2 receptors were identified in membrane fractions by radioligand binding using [3H]-SCH 23390 and [3H]-spiperone, respectively. The KD of both receptor classes were identical (0.21 nM) but D1 receptor density exceeded that of D2 receptors by more than four-fold. D1 agonists increased the activity of adenylate cyclase in a dose-dependent manner, whereas D2 agonists were without significant effect by themselves, nor did D2 antagonists block the D1-mediated increase in adenylate cyclase activity. Intracellular recordings and Lucifer Yellow dye injections were used to characterize the modifications of the receptive field profile of horizontal cell axons (H1AT) exposed to different pharmacological agents. Dopamine or D1 agonists (0.05 - 10 microM) induced a marked constriction of the H1AT receptive field, whereas D2 agonists elicited a small expansion of the receptive field. However, in the presence of a D1 antagonist, as well as IBMX to inhibit phosphodiesterase, D2 agonists (10 - 70 microM) induced a marked increase in the receptive field profile. These results indicate that both D1 and D2 dopamine receptors play a role in shaping the receptive field profile of the horizontal cell axon terminal in the turtle retina.
RESUMO
The degeneration of the striato-nigral projection induced by the injection of kainic acid into the striatum produced a 30% increase in the density of type II benzodiazepine binding sites (measured as the proportion of [3H]flunitrazepam which remained after the addition of 2 X 10(-7) M CL 218872). The lesion did not change the number of type I benzodiazepine binding sites (measured using [3H]ethyl-beta-carboline-3-carboxylate). The increase of type II benzodiazepine binding sites persisted and was markedly enhanced in the substantia nigra, previously lesioned with kainic acid. In fact, the injection of kainic acid into the nigra caused, 3 weeks after the treatment, a 80% decrease in the total number of type I benzodiazepine binding sites, and no change in the number of type II benzodiazepine binding sites. The density of type II sites increased by 70% following a subsequent injection of kainic acid into the striatum, homolateral to the lesioned substantia nigra. The results suggest that type I benzodiazepine binding sites in the nigra are located on kainic acid-sensitive elements (probably intrinsic neurones), while type II benzodiazepine binding sites, the number of which increased after degeneration of the striato-nigral pathway, are localized on kainic acid-resistant structures (probably axons or terminals) that receive an input from striatal afferents and from interneurones in the nigra.
Assuntos
Corpo Estriado/efeitos dos fármacos , Ácido Caínico/farmacologia , Receptores de GABA-A/análise , Substância Negra/análise , Animais , Masculino , Vias Neurais/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Substância Negra/efeitos dos fármacosRESUMO
The effect of long-term treatment (three times daily for 3 weeks) with a behaviorally relevant dose of the benzodiazepine receptor partial agonist imidazenil (0.5 mg/kg, IP) on basal dopamine release in the nucleus accumbens of freely moving rats was compared with that of diazepam (3 mg/kg, IP), a benzodiazepine receptor full agonist. Challenge doses of imidazenil and diazepam decreased the extracellular dopamine concentration in the nucleus accumbens by approximately the same extent in animals repeatedly exposed to vehicle or to the respective drug. Moreover, the abrupt discontinuation of long-term treatment with diazepam or imidazenil failed to affect basal dopamine release in this brain area during the first 5 days of withdrawal. In contrast, administration of the benzodiazepine receptor antagonist flumazenil (4 mg/kg, IP) elicited a marked increase (95 or 60%) in dopamine release in the nucleus accumbens 6 h after withdrawal of diazepam or imidazenil, respectively. Flumazenil induced a similar but smaller effect (50% increase) 5 days after diazepam withdrawal but had no effect 5 days after discontinuation of imidazenil treatment. The results support an involvement of the mesoaccumbens dopaminergic neurons in the withdrawal syndrome precipitated by flumazenil and allow further differentiation of benzodiazepine receptor partial and full agonists with respect to dependence liability of dopaminergic neurons in the nucleus accumbens.
Assuntos
Benzodiazepinas/farmacologia , Diazepam/farmacologia , Dopamina/metabolismo , Sinergismo Farmacológico , Flumazenil/farmacologia , Imidazóis/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Animais , Moduladores GABAérgicos/farmacologia , Masculino , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Fifteen days after bilateral lesions of the substantia nigra by local infusion of kainic acid (0.75 microgram) or after intranigral injection of vehicle, rats were administered 0.1, 0.25, 1.0 and 2.5 mg/kg s.c. of apomorphine and the stereotyped items (locomotion, sniffing and gnawing) were recorded on an event-recorder and motility was measured by a photocell apparatus. After low doses of apomorphine (0.1, 0.2 mg/kg), rats lesioned in the substantia nigra with kainic acid showed a degree of stimulation of motility and of sniffing similar to controls; on the other hand, in rats lesioned with kainic acid in the nigra, a dramatic reduction of gnawing and its replacement by sniffing was observed after administration of higher doses of apomorphine (1.0, 2.5 mg/kg). Bilateral infusion of kainic acid (0.75 microgram) into the reticular information, 2.0 mm dorsal to the substantia nigra, had no effect on apomorphine-induced stereotyped behaviour. These results are in agreement with the concept that the substantia nigra, through non-DA pars reticulata neurons, mediates motor and behavioural syndromes of striatal origin.
Assuntos
Apomorfina/farmacologia , Comportamento/efeitos dos fármacos , Ácido Caínico/toxicidade , Pirrolidinas/toxicidade , Comportamento Estereotipado/efeitos dos fármacos , Substância Negra/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Locomoção/efeitos dos fármacos , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Substância Negra/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismoRESUMO
A unilateral kainate (KA) infusion (2 x 0.15 micrograms, 2 x 0.25 micrograms) in the ventral mesencephalic reticular formation (MRF) resulted in spontaneous contraversive turning lasting only a few days. Upon challenge with apomorphine (0.5 mg/kg s.c.) or amphetamine (5 mg/kg i.p.) the contraversive turning could be reinstated. The incidence, as well as the intensity, of the drug-induced response decreased over the 45 days of observation. KA infused in the ventral MRF induced typical lesions after doses of 2 x 0.15 micrograms but resulted in demyelination after 2 x 0.25 micrograms. These lesions failed to reduce noradrenaline (NA), serotonin (5 HT) or dopamine (DA) in various forebrain areas. Unilateral lesion of ascending NA projections by 6-OHDA infusion (4 micrograms) within the NA bundles coursing in the mesencephalon or near the locus coeruleus, failed to induce motor asymmetries. Unilateral selective lesion of the ventral NA bundle by local 6-OHDA (2 micrograms) infusion also failed to induce motor asymmetries, either spontaneously or in response to dopaminergic drugs. Unilateral lesion of ascending 5-HT projections by the tegmental infusion of 5,7-dihydroxytryptamine (10 micrograms) also failed to induce motor asymmetries in response to dopaminergic drugs but resulted in contraversive circling in response to 5-hydroxytryptophan. These data indicate that intrinsic neurones of the ventral MRF play a role in turning behaviour and exclude, in contrast with previous studies, a role of NA or 5-HT projections in the contraversive turning responses to DA receptor agonists obtained after lesions of the ventral MRF.
Assuntos
Mesencéfalo/fisiologia , Atividade Motora/fisiologia , Norepinefrina/fisiologia , Formação Reticular/fisiologia , Serotonina/fisiologia , Comportamento Estereotipado/fisiologia , 5,7-Di-Hidroxitriptamina/toxicidade , Animais , Dopamina/fisiologia , Humanos , Hidroxidopaminas/toxicidade , Ácido Caínico/toxicidade , Masculino , Mesencéfalo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Fibras Nervosas/fisiologia , Neurônios/fisiologia , Oxidopamina , Ratos , Ratos Endogâmicos , Formação Reticular/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Bilateral kainate-induced lesions of the substantia nigra prevented or dramatically reduced the catalepsy produced by haloperidol. In contrast, infusion of 1 or 4 micrograms 6-OHDA in the medial forebrain bundle, which decreased striatal DA by 30% and 80% respectively, failed to affect or actually potentiated haloperidol catalepsy. Since intranigral kainate, in contrast to 6-OHDA, destroys pars reticulata neurons it appears that these neurons are essential for the expression of haloperidol-catalepsy.
Assuntos
Catalepsia/induzido quimicamente , Haloperidol/farmacologia , Substância Negra/fisiologia , Animais , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Hidroxidopaminas/farmacologia , Ácido Caínico/toxicidade , Masculino , Feixe Prosencefálico Mediano/efeitos dos fármacos , Ratos , Receptores Dopaminérgicos/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologiaRESUMO
There is much debate on the role of the superior colliculus (SC) in turning behaviour. In order to clarify this issue, unilateral kainate lesions were made by infusing 0.25 microgram of kainate at two different anterior planes (0.8 mm apart), in the lateral or in the medial aspects of the deep collicular layers (DLSC), in the dorsal mesencephalic reticular formation (MRF), or in the lateral periaqueductal grey (PAG), both in normal rats and in rats made unilaterally supersensitive to DA-receptor agonists by unilateral infusion of 6-OHDA in the rostral substantia nigra. The effect of kainate lesions on spontaneous and apomorphine-induced motor behaviour was studied. In normal rats, unilateral kainate lesions of lateral DLSC or dorsal MRF resulted in short-lasting, spontaneous ipsiversive turning and persistent ipsiversive circling after peripheral administration of apomorphine. In 6-OHDA rats, kainate lesions of lateral DLSC or of dorsal MRF ipsilateral to 6-OHDA denervation reduced or even reversed the contralateral circling normally elicited in these rats by peripheral administration of apomorphine. Lesions of dorsal MRF, when compared with lesions of lateral DLSC, were more effective in producing these changes. Kainate lesions restricted to medial DLSC or to the PAG failed to elicit motor asymmetries in normal rats or to significantly modify the intensity of contralateral turning in 6-OHDA rats. These results clearly indicate that the SC plays an important role in turning behaviour. Failure of previous studies to research this conclusion probably derives from inadequate localization of collicular lesions and from the use of bilateral lesions.
Assuntos
Atividade Motora , Colículos Superiores/fisiologia , Animais , Apomorfina/farmacologia , Lateralidade Funcional , Hidroxidopaminas/farmacologia , Ácido Caínico/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Oxidopamina , Ratos , Ratos Endogâmicos , Rotação , Colículos Superiores/efeitos dos fármacosRESUMO
Kainate or electrolytic lesions were placed unilaterally in the dorsal mesencephalic reticular formation (MRF) or in the deep layers of the superior colliculus (DLSC) on the same side of a unilateral lesion of the medial forebrain bundle with 6-OHDA. Before the lesions the rats turned contralaterally when challenged with 0.25 mg/kg of apomorphine. After lesions of the MRF most rats turned ipsilaterally in response to the same dose of apomorphine. After lesions of the DLSC apomorphine-induced contralateral turning was significantly reduced but not abolished. The results indicate that the MRF and DLSC play a primary role in the expression of turning originated from the striatum.
Assuntos
Corpo Estriado/fisiologia , Mesencéfalo/fisiologia , Atividade Motora , Formação Reticular/fisiologia , Colículos Superiores/fisiologia , Animais , Estimulação Elétrica , Hidroxidopaminas/farmacologia , Ácido Caínico/farmacologia , Masculino , Mesencéfalo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Movimento , Ratos , Formação Reticular/efeitos dos fármacosRESUMO
Chronic administration of SCH 23390 (0.03 mg/kg s.c., three times daily), a selective D1 dopamine (DA) receptor blocker, markedly increased the [3H]SCH 23390 binding in the rat retina. As revealed by the Scatchard plot analysis of saturation data from retinal homogenates, chronic SCH 23390 increased the total number of binding sites by 34% when compared to tissue from solvent-treated rats but failed to change the apparent affinity of [3H]SCH 23390 for its binding sites. The up-regulation of [3H]SCH 23390 binding sites was paralleled by an increase in the sensitivity of retina DA-sensitive adenylate cyclase. In fact, DA (5 X 10(-6) M to 10(-4) M) produced a higher accumulation of cyclic AMP (from 58 to 128%) in the retina of SCH 23390-treated rats as compared to the accumulation (from 35 to 80%) found in tissue from solvent-treated rats. Since dark adaptation decreases dopaminergic function in the rat retina, the influence of environmental lighting on [3H]SCH 23390 binding and DA-sensitive adenylate cyclase activity was studied. After 4 h of dark adaptation the density of [3H]SCH 23390 binding sites was higher (32%) than that from light-adapted rats. On the other hand, dark adaptation failed to change the apparent affinity of [3H]SCH 23390 for its binding sites. Moreover, DA elicited a greater stimulation of adenylate cyclase activity in homogenates of retina from dark-adapted rats. Thus, the maximum adenylate cyclase response to DA resulted higher in the retina of dark-adapted rats (152%) than that found in the retina of light-adapted animals (97%).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Benzazepinas/farmacologia , Adaptação à Escuridão , Receptores Dopaminérgicos/metabolismo , Retina/metabolismo , Adaptação Fisiológica , Adenilil Ciclases/metabolismo , Animais , Benzazepinas/metabolismo , Dopamina/farmacologia , Luz , Masculino , Ratos , Ratos Endogâmicos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Dopamina D1 , Retina/enzimologia , Fatores de TempoRESUMO
The relationship between the postnatal development of dopaminergic (DAergic) nerve endings and the maturation of D1 DA receptors in the rat striatum was analyzed by measuring the content of DA and dihydroxyphenylacetic acid (DOPAC), two biochemical markers of DAergic nerve terminal proliferation, and the ontogenetic changes in [3H]SCH 23390 binding sites. DA-stimulated adenylate cyclase (AC) activity was also measured in order to characterize the coupling of [3H]SCH 23390 binding sites to the responses mediated by the activation of D1 DA receptors. Striatal levels of DA and DOPAC, as well as the density and affinity of [3H]SCH 23390 binding sites and DA-stimulated AC activity were also measured in senescent rats. The striatal content of DA increased slowly after birth, reaching adult levels by postnatal day 60 and remaining constant through adulthood and senescence (up to 20 months of age). The density of [3H]SCH 23390 binding sites increased 14-fold from birth to postnatal day 35, when a peak value was reached, whereas a significant decrease was observed in the striatum of aged rats. In contrast, the affinity of D1 DA receptors for [3H]SCH 23390 remained unchanged from birth through senescence. The stimulation of cyclic AMP formation induced by 100 microM DA increased 4-fold from birth to postnatal day 14, when the maximal responsiveness to DA was observed and then returned to adult levels. No significant alterations were observed in the Km values during development, whereas the stimulatory effect of 100 microM DA on AC activity was significantly decreased in senescent rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Envelhecimento/metabolismo , Corpo Estriado/metabolismo , Dopamina/metabolismo , Receptores Dopaminérgicos/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Adenilil Ciclases/metabolismo , Animais , Benzazepinas/metabolismo , Sítios de Ligação , Corpo Estriado/crescimento & desenvolvimento , Ratos , Ratos Endogâmicos , Receptores Dopaminérgicos/fisiologia , Receptores de Dopamina D1RESUMO
In order to investigate the role of dorsal mesencephalic reticular formation (MRF) and deep layers of superior colliculus (DLSC) as out-put areas for non-dopamine mediated behavioural functions arising in the substantia nigra, discrete unilateral kainate-lesions as well as sham-lesions were placed in the MRF and DLSC. Ten days later kainate (0.75 microgram) was microinjected into the substantia nigra pars reticulata. Lesions of MRF as well as lesions of DLSC reduced the contralateral turning induced by kainate lesions of pars reticulata ipsilateral to the MRF or DLSC lesions. The lesions of MRF were more effective than lesions of DLSC. Lesions of MRF or DLSC on the side contralateral to intranigral kainate were ineffective. The results indicate that the MRF-DLSC complex is an essential area for the expression of motor behaviour elicited from the substantia nigra.
Assuntos
Mesencéfalo/fisiologia , Formação Reticular/fisiologia , Comportamento Estereotipado/fisiologia , Substância Negra/fisiologia , Colículos Superiores/fisiologia , Animais , Dominância Cerebral/fisiologia , Dopamina/fisiologia , Humanos , Masculino , Atividade Motora/fisiologia , Vias Neurais/fisiologia , Ratos , Ácido gama-Aminobutírico/fisiologiaRESUMO
Kainic acid (50 nmol), applied intravitreally to the eyes of chicks, produces within 6 h a loss of more than 50% of biochemical markers for cholinergic and GABAergic neurons in the retina. Repeated peripheral administration of benzodiazepines, such as diazepam and clonazepam, protects from the kainate-induced loss of cholinergic and GABAergic markers in the retina. Histologically diazepam reduces the nuclear pyknosis induced by kainate particularly at the level of the amacrine cell-layer.
Assuntos
Benzodiazepinonas/farmacologia , Clonazepam/farmacologia , Diazepam/farmacologia , Ácido Caínico/farmacologia , Neurônios/fisiologia , Pirrolidinas/farmacologia , Retina/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Galinhas , Neurônios/efeitos dos fármacos , Retina/citologia , Retina/efeitos dos fármacosRESUMO
Locally applied kainic acid was used in order to destroy pallidal perikarya without damaging axons en passage, in an effort to clarify the role of the globus pallidus as a source of nigral GABAergic terminals. Rats were microinjected unilaterally with kainic acid in the globus pallidus, head, body and tail of the caudate and were sacrificed 7 days later. The forebrain of each rat was examined histologically in order to establish the extent of the lesion and nigral glutamate decarboxylase (GAD) was assayed as a marker of GABAergic terminals. Kainic acid produced in the globus pallidus loss of neuronal perikarya and reactive gliosis. Large multipolar neurons of the globus pallidus were characteristically absent on the lesioned-side. Lesions of the pallidum resulted in a non-significant (5.5%) reduction of nigral GAD. Kainate lesions restricted to the head of the caudate resulted in a significant (19%) drop of nigral GAD, while lesions of the caudate body provided the largest reductions of nigral GAD (53%). Lesions of the caudate tail were without effect. The results indicate that nigral GAD arises mostly from the body and, in part, also from the head of the caudate but not from the globus pallidus or from the tail of the caudate.
Assuntos
Carboxiliases/metabolismo , Núcleo Caudado/fisiologia , Globo Pálido/fisiologia , Glutamato Descarboxilase/metabolismo , Ácido Caínico/farmacologia , Pirrolidinas/farmacologia , Substância Negra/enzimologia , Animais , Núcleo Caudado/anatomia & histologia , Núcleo Caudado/efeitos dos fármacos , Globo Pálido/anatomia & histologia , Globo Pálido/efeitos dos fármacos , Masculino , Ratos , Substância Negra/anatomia & histologia , Substância Negra/efeitos dos fármacosRESUMO
Unilateral intranigral infusion of kainic acid (1.5 microgram) produced neuronal loss in the lateral two-thirds of the nigra while sparing axons en passage. Fink-Heimer silver impregnation revealed dense terminal degeneration in the nigra itself (both in the compacta and in the reticulata) and in areas of non-dopaminergic nigral projection such as the ventromedial (VM) nucleus of the thalamus, the superior colliculus and the reticular formation; only spare terminal degeneration was found in areas of dopaminergic projection such as the caudate and septum. In order to clarify the nature of the transmitter of the nigrothalamic and nigrocollicular neurons, the activity of glutamic decarboxylase (GAD), the marker of cholinergic neurons, was measured in the VM and ventrobasal (VB) thalamus and in the nigra of each side, 7 days after unilateral intranigral injection of kainic acid. GAD activity was reduced significantly in the VM-thalamus (-33%), in the superior colliculus (-40%) and in the substantia nigra (-18%) but not in the VB-thalamus of the lesioned side. CAT remained unchanged in these areas. Similar results were obtained in the thalamus and in the superior colliculus after electrocoagulative lesions of the nigra. The results indicate the existence of a nigrothalamic and of a nigrocollicular GABAergic pathway. This projection might play an important role in motor coordination and gaze control.
Assuntos
Substância Negra/anatomia & histologia , Colículos Superiores/anatomia & histologia , Tálamo/anatomia & histologia , Ácido gama-Aminobutírico/metabolismo , Animais , Colina O-Acetiltransferase/metabolismo , Glutamato Descarboxilase/metabolismo , Ácido Caínico/toxicidade , Masculino , Degeneração Neural/efeitos dos fármacos , Vias Neurais/anatomia & histologia , Vias Neurais/enzimologia , Ratos , Substância Negra/efeitos dos fármacos , Substância Negra/enzimologia , Colículos Superiores/enzimologia , Tálamo/enzimologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Chronic treatment with SCH 23390, a selective D-1 dopamine receptor antagonist, increased (40%) the density of [3H]SCH 23390 binding sites in striatal membrane preparations but failed to change the apparent KD of the ligand for its binding sites. Haloperidol, which preferentially blocks D-2 receptors, induced only a slight, not significant increase in the total number of [3H]SCH 23390 binding sites. (-)Sulpiride, a selective D-2 receptor blocker, also failed to change either Bmax or KD of [3H]SCH 23390 binding. Thus, chronic blockade of D-1 receptor sites by SCH 23390 can lead to an increase in their total number.
Assuntos
Benzazepinas/metabolismo , Receptores Dopaminérgicos/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Animais , Sítios de Ligação/efeitos dos fármacos , Haloperidol/farmacologia , Técnicas In Vitro , Cinética , Masculino , Membranas/metabolismo , Ratos , Ratos Endogâmicos , Receptores de Dopamina D1 , Sulpirida/farmacologiaRESUMO
In the rat substantia nigra Type II benzodiazepine recognition sites (measured as the portion of [3H]flunitrazepam binding which remain after the addition of 2 X 10(-7) M Cl 218872) represent 50% of the total benzodiazepine recognition sites. The density of Type II sites was increased by 35% following the degeneration of the striatonigral afferents induced by the intrastriatal injection of kainic acid. On the other hand the same lesion failed to change the density of the remaining nigral Type I sites. The results indicate that denervation induces supersensitivity to nigral Type II benzodiazepine recognition sites.
Assuntos
Receptores de GABA-A/metabolismo , Substância Negra/metabolismo , Animais , Carbolinas/metabolismo , Corpo Estriado/fisiologia , Denervação , Flunitrazepam/metabolismo , Ácido Caínico , Masculino , Vias Neurais/fisiologia , Piridazinas/farmacologia , Ratos , Ratos Endogâmicos , Substância Negra/fisiologiaRESUMO
The ability of an anticonvulsant dose (0.1 mg/kg i.p.) of imidazenil, a new partial agonist of benzodiazepine receptors, to antagonize the convulsions and the increase in t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to the gamma-aminobutyric acid type A (GABAA) receptor elicited by isoniazid, an inhibitor of central GABAergic function, was evaluated in mice chronically treated (3 times daily for 30 days) with the same dose of imidazenil. The challenge dose of imidazenil, administered 36 h after the last injection of the chronic treatment protocol, reduced both isoniazid-induced convulsions and the isoniazid-induced increase in [35S]TBPS binding to the same marked extent as in control mice. These results indicate that long-term treatment with a pharmacologically effective dose of imidazenil failed to induce tolerance to both the anticonvulsant effect and the positive modulatory action on GABAA receptor function of this drug in mouse brain.
Assuntos
Anticonvulsivantes/farmacologia , Benzodiazepinas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes , Imidazóis/farmacologia , Receptores de GABA/efeitos dos fármacos , Animais , Compostos Bicíclicos com Pontes/metabolismo , Tolerância a Medicamentos , Masculino , Camundongos , Receptores de GABA/fisiologiaRESUMO
The effects of long-term treatment (3 times a day for 4 weeks) with a pharmacologically active dose (0.1 mg/kg i.p.) of the novel anxiolytic, abecarnil, on exploratory behaviour and [35S]TBPS (t-butylbicyclophosphorothionate) binding were compared to those of diazepam (1 mg/kg i.p.) in mice. A challenge dose (0.1 mg/kg) of abecarnil given 12 h after the last administration of the treatment protocol markedly inhibited exploratory behaviour in animals treated chronically with abecarnil (-62%) or vehicle (-87%). Consistent with this behavioural effect, the same challenge dose of abecarnil significantly reduced [35S]TBPS binding to unwashed cerebral cortical membranes from mice treated chronically with abecarnil (-28%) or vehicle (-30%). In contrast, a challenge dose (1 mg/kg) of diazepam failed to affect motor behaviour and [35S]TBPS binding in mice chronically exposed to diazepam; in animals chronically treated with vehicle, diazepam markedly inhibited both exploratory behaviour (-55%) and [35S]TBPS binding (-21%). These results indicate that long-term treatment with abecarnil failed to induce tolerance to the effect of this drug on gamma-aminobutyric acid type A (GABAA) receptor function. Accordingly, [35S]TBPS binding was increased (+15-26%) 12 and 48 h after discontinuation of long-term diazepam administration while no such increase in [35S]TBPS binding was observed for mice chronically treated with abecarnil. Moreover, whereas a significant decrease (-15%) in [35S]TBPS binding was observed 96 h after discontinuation of long-term diazepam treatment, chronic treatment with abecarnil did not modify this parameter. Together, these data indicate that long-term treatment with a pharmacologically effective dose of abecarnil did not induce tolerance or the discontinuation syndrome in mice.
Assuntos
Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes , Carbolinas/farmacologia , Animais , Compostos Bicíclicos com Pontes/metabolismo , Tolerância a Medicamentos , Masculino , Camundongos , Receptores de GABA-A/efeitos dos fármacosRESUMO
The effect of SCH 23390, a selective blocker of D-1 receptors, on apomorphine-induced behavioural and EEG changes was studied in rats. In control rats, a low dose of apomorphine (50 micrograms/kg s.c.) produced sedation associated with EEG synchronization. A high dose of apomorphine (1 mg/kg s.c.) produced stereotypy associated with EEG desynchronization. At the dose of 1 mg/kg i.p., SCH 23390 decreased motor activity but failed to alter the EEG pattern. The administration of either the low or high dose of apomorphine to SCH 23390-treated rats elicited a marked sedative response associated with EEG synchronization. The EEG synchronization produced by apomorphine (50 micrograms/kg) in SCH 23390-treated rats was prevented by (-)-sulpiride (25 mg/kg i.p.), a D-2 receptor blocker. It is concluded that by preventing the excitatory response to apomorphine SCH 23390 discloses the existence of a population of D-2 receptors mediating sedation and sleep.