RESUMEN
We investigated whether the two output pathways of the striatum are differently affected by the novel atypical drug risperidone and the conventional typical antipsychotic drug haloperidol. To this end, changes in mRNA levels of preproenkephalin-A, preproenkephalin-B, and preprotachykinin were determined in the rat striatum following chronic drug treatment for 14 days, using quantitative in situ hybridization. Furthermore, we studied the contribution of the dopamine D2 and serotonin 5-HT2A antagonist components of risperidone in establishing its effects on neuropeptide mRNA levels in the striatum. The results showed that both risperidone and haloperidol had major effects on the preproenkephalin-A mRNA and thus on the indirect striatal output route, whereas they had minor effects on preproenkephalin-B and preprotachykinin mRNA, contained by the direct output route. When both drugs were administered in the same dose, preproenkephalin-A mRNA was much more elevated by haloperidol than by risperidone. However, when doses of risperidone and haloperidol were modified to attain comparable dopamine D2 receptor occupancy, the drugs had comparable effects on preproenkephalin-A mRNA levels. It was further found that 5-HT2A/C receptor blockade with ritanserin had only modest effects on preproenkephalin-B and preprotachykinin mRNA levels and did not affect preproenkephalin-A mRNA levels. We conclude that risperidone and haloperidol, administered in the same dose, differently affect the striatal output routes. Furthermore, the results suggest that the effects of risperidone on neuropeptide mRNA levels are fully accounted for by its D2 antagonism and that no indication exists for a role of 5-HT2A receptor blockade in this action.
Asunto(s)
Antipsicóticos/farmacología , Cuerpo Estriado/metabolismo , Encefalinas/metabolismo , Haloperidol/farmacología , Núcleo Accumbens/metabolismo , Precursores de Proteínas/metabolismo , Risperidona/farmacología , Taquicininas/metabolismo , Animales , Núcleo Caudado/metabolismo , Encefalinas/genética , Masculino , Precursores de Proteínas/genética , Putamen/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Ritanserina/farmacología , Taquicininas/genéticaRESUMEN
This paper describes the regional and cellular distribution of serotonin 5-hydroxytryptamine2a (5-HT2a) receptor mRNA in (sub)regions of the rat striatum by using in situ hybridization. Our results indicate that 5-HT2a mRNA is distributed heterogeneously in this brain region. Regional densitometry of autoradiograms from striatal sections hybridized with isotope-labeled cRNA probes showed that mRNA levels were highest in the olfactory tubercle, lower in the nucleus accumbens, and lowest in the caudate-putamen. In the nucleus accumbens, the average mRNA levels in the shell were higher than those in the core. These data suggest a particular relevance for the 5-HT2a receptor for olfactory tubercle- and shell-related functions. Therefore, in the nucleus accumbens and the olfactory tubercle, the cellular localization of 5-HT2a mRNA was investigated by determining the colocalization of 5-HT2a mRNA with enkephalin mRNA or dynorphin mRNA. 5-HT2a mRNA was found in enkephalinergic as well as dynorphinergic neurons. Thus, there does not seem to be a differential distribution of this receptor in the output routes of the ventral striatum. In all of the subregions investigated (core, medial shell, and lateral shell of the nucleus accumbens and the olfactory tubercle), only subpopulations of the total enkephalinergic and dynorphinergic populations were found to contain 5-HT2a mRNA. For enkephalin, the percentage colocalization was higher in the lateral shell (61%) compared with the other subregions (38-45%). For dynorphin, the percentage colocalization was higher in the olfactory tubercle (68%) than in the other subregions (34-43%). The differences in (sub)regional mRNA levels and in colocalization with opioids suggest a considerable regional differentiation in the effects of 5-HT2a-mediated neurotransmission in the striatum.
Asunto(s)
Núcleo Caudado/metabolismo , Núcleo Accumbens/metabolismo , Bulbo Olfatorio/metabolismo , Putamen/metabolismo , ARN Mensajero/biosíntesis , Receptores de Serotonina/biosíntesis , Animales , Núcleo Caudado/anatomía & histología , Dinorfinas/biosíntesis , Endorfinas/biosíntesis , Procesamiento de Imagen Asistido por Computador , Hibridación in Situ , Masculino , Núcleo Accumbens/anatomía & histología , Bulbo Olfatorio/anatomía & histología , Putamen/anatomía & histología , Ratas , Ratas WistarRESUMEN
The morphological plasticity of an identified population of synaptic boutons in the rat neostriatum was investigated 24 h (short-term treatment) or 14 days (long-term treatment) after administration of the depot neuroleptic, haloperidol decanoate. Specific methionine(5)-enkephalin antiserum was used to label bouton profiles in the dorsal neostriatum. The size and shape of these boutons was subsequently analysed with quantitative methods at the ultrastructural level. Immunoreactive synaptic bouton profiles were found to have a larger cross-sectional area, to be less circular in shape and to have a longer maximum diameter after long-term neuroleptic treatment. These parameters were not significantly affected by short-term neuroleptic treatment. The morphological parameters indicate that methionine(5)-enkephalin-immunoreactive boutons become enlarged, probably by elongating. This suggests that boutons containing methionine(5)-enkephalin increase their potential synaptic efficacy in the long term after neuroleptic treatment.
Asunto(s)
Cuerpo Estriado/metabolismo , Encefalina Metionina/metabolismo , Haloperidol/análogos & derivados , Sinapsis/metabolismo , Animales , Cuerpo Estriado/fisiología , Cuerpo Estriado/ultraestructura , Dendritas/fisiología , Dendritas/ultraestructura , Haloperidol/farmacología , Sueros Inmunes , Masculino , Microscopía Electrónica , Ratas , Ratas Wistar , Sinapsis/fisiología , Sinapsis/ultraestructuraRESUMEN
The ability of the novel antipsychotic drug risperidone to alter striatal neurotensin mRNA levels was investigated and compared with the typical antipsychotic drug haloperidol. Quantitative in situ hybridization studies revealed that risperidone treatment does not affect neurotensin mRNA levels in nucleus accumbens or caudate-putamen. This absence of effect contrasts with the dramatic increases in neurotensin mRNA seen after haloperidol treatment in these brain regions. Our results, while conforming the atypical nature of risperidone, do not support the notion that neurotensin elevation in the nucleus accumbens is necessary for the development of an antipsychotic effect.
Asunto(s)
Antipsicóticos/farmacología , Antagonistas de Dopamina/farmacología , Neurotensina/genética , ARN Mensajero/efectos de los fármacos , Risperidona/farmacología , Antagonistas de la Serotonina/farmacología , Animales , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Masculino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Putamen/efectos de los fármacos , Putamen/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
Previous immunocytochemical studies in rats have indicated that striatal dopamine depletion leads to an increase in enkephalin-immunoreactivity and a decrease in substance P-immunoreactivity in the striatum. Similar studies in primates have lead to contradictory results. In the present study changes in tyrosine hydroxylase-, met-enkephalin- and substance P-immunoreactivity were determined in the basal ganglia of 6 common marmosets Callithrix jacchus following dopamine depletion by unilateral intracerebral 6-hydroxydopamine (6-OHDA) injections using three different survival times. The non-lesioned side served as an intra-individual control. Tyrosine hydroxylase immunoreactivity was strongly reduced in the entire ipsilateral striatum. Enkephalin-immunoreactivity was increased throughout the striatum. Substance P-immunoreactivity was significantly increased in only one case in the caudate nucleus and in two cases in the putamen, while in other cases either a non-significant increase or decrease was found. Therefore, the results of the present study indicate that in marmosets dopamine has a inhibiting effect on the levels of striatal enkephalin, while its effect on substance P (SP) appears to be absent.
Asunto(s)
Ganglios Basales/metabolismo , Dopamina/fisiología , Neuropéptidos/metabolismo , Oxidopamina/toxicidad , Simpaticolíticos/toxicidad , Animales , Ganglios Basales/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Callithrix , Dopaminérgicos/toxicidad , Encefalina Metionina/metabolismo , Encefalinas/metabolismo , Inmunohistoquímica , Intoxicación por MPTP , Neostriado/metabolismo , Sustancia P/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
By combining immunocytochemistry for ChAT and in situ hybridization for dopamine D1 or D2 receptor mRNA in the striatum, it was found that (1) the percentage of ChAT/D2 mRNA co-localization is higher in the caudate-putamen than in the shell and core of the nucleus accumbens, (2) in the shell the degree of ChAT/D2 mRNA co-localization is higher rostrally than caudally, and 3) no significant regional differences exist in the degree of co-localization of ChAT and D1 mRNA.
Asunto(s)
Ganglios Basales/metabolismo , Cuerpo Estriado/metabolismo , Núcleo Accumbens/química , ARN Mensajero/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animales , Núcleo Caudado/metabolismo , Inmunohistoquímica , Hibridación in Situ , Núcleo Accumbens/metabolismo , ARN Mensajero/análisis , Ratas , Receptores de Dopamina D1/biosíntesis , Receptores de Dopamina D2/biosíntesisRESUMEN
In the present study, using quantitative receptor autoradiography and in situ hybridization histochemistry the effects of unilateral 6-hydroxydopamine lesions on the binding density levels of dopamine D1 and D2 receptors and the levels of mRNA encoding D1 and D2 receptors were investigated in the core and shell territories of the nucleus accumbens (Acb) and in the caudate-putamen (CP). The lesions induced contrasting effects on the D1 binding and D1 mRNA in the Acb and CP, i.e. an increase in binding and a decrease in the mRNA levels. For the D2 receptor an increase in both the binding density and mRNA levels was observed. The lesion-induced effects displayed regional differences. For D1 mRNA and D1 and D2 binding, the lesion effect was more pronounced in the core than in the shell of the Acb. For the D2 mRNA levels an increase was observed in the CP but not in the two territories of the Acb. Furthermore, the decrease in D1 mRNA was greater in the rostral than in the caudal parts of the core and shell of the Acb. These results indicate that the core and shell of the Acb and the CP respond differentially to dopamine depletion.
Asunto(s)
Dopamina/metabolismo , Núcleo Accumbens/metabolismo , ARN Mensajero/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animales , Autorradiografía , Hibridación in Situ , Masculino , Oxidopamina , Ratas , Ratas Wistar , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genéticaRESUMEN
Quantitative in situ hybridization histochemistry was used to examine the effects of unilateral 6-hydroxydopamine lesions of the ascending dopaminergic fibres on levels of mRNA encoding the neuropeptides enkephalin, dynorphin and substance P in subregions of the nucleus accumbens. The nucleus accumbens was divided into quadrants and changes in mRNA were measured along the rostrocaudal extent of the nucleus. Two weeks after the lesion an increase was found in enkephalin mRNA in the lesioned side compared to the non-lesioned side, whereas a decrease was observed for dynorphin and substance P mRNA. The changes in mRNA levels differed from quadrant to quadrant and were not uniformly distributed along the rostrocaudal axis. Both types of changes, i.e. increase and decrease, were much higher in rostral parts of the nucleus than in caudal parts, indicating regional differences in the effects of blockade of the dopaminergic neurotransmission. The lesion-induced increases and decreases in mRNA levels occurred in both the shell and the core subregions of the nucleus accumbens and were not specifically related to either of these areas. Factors are discussed that may contribute to the rostrocaudal gradient in the changes of enkephalin, substance P and dynorphin mRNA levels. On the basis of their afferent and efferent connections, the rostral and caudal parts of the nucleus accumbens are considered to be involved in different functions. The present results suggest that dopamine depletion may affect these functions in a differential manner.
Asunto(s)
Dopamina/metabolismo , Dinorfinas/biosíntesis , Encefalinas/biosíntesis , Núcleo Accumbens/metabolismo , Sustancia P/biosíntesis , Animales , Dinorfinas/genética , Encefalinas/genética , Masculino , Vías Nerviosas/fisiología , Oxidopamina , Precursores de Proteínas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores Dopaminérgicos/metabolismo , Sustancia P/genética , Taquicininas/genéticaRESUMEN
A subpopulation of projection neurons in the nucleus accumbens uses the neuropeptide enkephalin as a neurotransmitter. The synthesis of enkephalin in striatal neurons is regulated by dopaminergic inputs. In the present study quantitative in situ hybridization histochemistry was used to examine the effects of unilateral 6-hydroxydopamine lesions of the ascending dopaminergic fibres on levels of enkephalin mRNA in subregions of the nucleus accumbens. It was found that the levels of enkephalin mRNA were increased throughout the nucleus after the lesion. However, the increase appeared to be much higher in rostral parts of the nucleus than in caudal parts, indicating regional differences in the effects of blockade of the dopaminergic neurotransmission. Possible causative factors for these differences are discussed.