RESUMO
Defensive behaviors of lower mammals confronted with a predatory stimulus provide an appropriate laboratory model for investigating behavior relevant to human emotional disorders. The mouse defense test battery (MDTB) has been developed because it combines many of the aspects of defense. Briefly, it consists of five tests either associated with potential threat (contextual defense) or the actual presence of an approaching threat (a rat). These latter focus on changes in flight, risk assessment and defensive threat and attack behaviors. Investigations with anxiolytic compounds have shown that these defense reactions may be used to differentiate between several classes of anxiolytic drugs. Here we used the MDTB to compare the behavioral profile of the benzodiazepine diazepam with that of neuropeptide receptor antagonists which have been shown to be involved in the modulation of stress response, namely the NK(2) receptor antagonists, SR48968 (0.01-1mg/kg) and SR144190 (1-10mg/kg), and the NT(1) receptor antagonist, SR48692 (1-30mg/kg). Results showed that all compounds decreased defensive threat/attack, but only diazepam and, to a lesser extent, SR48692 significantly modified risk assessment or flight. Further, none of the neuropeptide receptor antagonists modified contextual defense. Overall, the behavioral profile displayed by diazepam and these latter compounds in the MDTB are consistent with an anxiolytic-like action. However, our results suggest that, while NK(2) and NT(1) receptor antagonists may have limited efficacy on anxiety-related responses including cognitive aspects (i.e. risk assessment), they may have a potential against some forms of anxiety disorders which involve adaptative responses to extreme stress stimuli (e.g. direct confrontation with the threat stimulus).
Assuntos
Agressão/fisiologia , Comportamento Animal/efeitos dos fármacos , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores de Neurotensina/antagonistas & inibidores , Animais , Camundongos , Neurotensina/farmacologia , Pirazóis/farmacologia , Quinolinas/farmacologiaRESUMO
This study is designed to measure effects of serotonin 1A (5-HT1A) agonists on escape deficits produced by inescapable shock in rats--a model of learned helplessness. Rats were first exposed to 60 inescapable shocks (15-sec duration, 0.8 mA, every 1 min +/- 15 sec), and 48 hr later, they were subjected to daily 15-min shuttle-box sessions (30 trials/day) on 3 consecutive days. Twice daily intraperitoneal injection of buspirone (total daily dose of 0.5 and 1 mg/kg), gepirone (0.06 and 0.125 mg/kg), 8-OH dipropylamino-tetralin (8-OH-DPAT) (0.03, 0.06, 0.125, and 0.25 mg/kg), and ipsapirone (TVXQ 7821) (0.03 and 0.06 mg/kg) eliminated escape failures. This indicates that an antidepressant-like effect--reversal of helpless behavior--can be obtained with drugs assumed to stimulate serotonin 1A receptors.
Assuntos
Ansiolíticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Buspirona/farmacologia , Desamparo Aprendido , Naftalenos/farmacologia , Pirimidinas/farmacologia , Tetra-Hidronaftalenos/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina , Animais , Reação de Fuga , Masculino , Ratos , Ratos Endogâmicos , Receptores de Serotonina/efeitos dos fármacosRESUMO
In searching for reliable animal models of negative schizophrenic symptomatology, we considered the possibility that a deficient response to rewarding stimuli might be the basis for some features of the disease. Apomorphine (0.015 and 0.03 mg/kg) and 3-PPP (1 mg/kg) caused such a reward deficit when rats were shifted from continuous reinforcement to a fixed ratio (FR4) schedule of food delivery. Further experiments indicated that this effect could be accounted for by a decreased ability of secondary reinforcers to sustain responses, rather than by motor impairment, appetite loss, or reduced reward value of the food. If this deficit is due to decreased dopaminergic transmission produced by low doses of dopamine agonists, our model might suggest that some symptoms of schizophrenia (anhedonia for instance) are not incompatible with deficient dopaminergic transmission. Low to moderate doses of sulpiride, amisulpride, pimozide, and pipotiazine, but not fluphenazine, metoclopramide, haloperidol, thioridazine, and chlorpromazine, reversed the apomorphine-induced reward deficit. Although any extrapolation from animal data requires caution, it may be tentatively proposed that only some neuroleptics, at dosages insufficient to block dopamine transmission postsynaptically, can be effective in reducing negative schizophrenic symptoms.
Assuntos
Antipsicóticos/farmacologia , Modelos Animais de Doenças , Receptores Dopaminérgicos/efeitos dos fármacos , Psicologia do Esquizofrênico , Amissulprida , Animais , Apomorfina/farmacologia , Masculino , Fenotiazinas/farmacologia , Pimozida/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Endogâmicos , Receptores Dopaminérgicos/fisiologia , Esquema de Reforço , Reforço Psicológico/efeitos dos fármacos , Esquizofrenia/fisiopatologia , Sulpirida/análogos & derivados , Sulpirida/farmacologiaRESUMO
We intended to determine whether the effect of neurotensin (NT) on K+ and electrically evoked [3H]dopamine (DA) release from rat and guinea-pig striatal slices involved different mechanisms and/or receptors. In the two species, NT and three NT agonists were found to exhibit different relative potencies to enhance K+- and electrically-evoked [3H]DA release. NT(1-13) increased [3H]DA release with EC50 values in the nanomolar range and Emax values in the range of 100% of control. NT(8-13) and Eisai hexapeptide were both as active as NT(1-13) under K+ depolarization, but did not exceed 40% of the NT(1-13) effect under electrical depolarization. In rats, when [3H]DA release was stimulated with two successive K+ depolarizations, in the presence of NT(1-13), the NT effect during the second exposure to K+ was drastically decreased, suggesting that the NT receptor was desensitized. The desensitization process was essentially observed on Emax values, EC50 values being weakly affected. Similar results were obtained in guinea pig. In contrast, with two electrical depolarizations or with two different depolarizations (K+ followed by electrical), the NT effect during the second depolarization was not significantly affected. Concerning NT antagonists, SR 48692 antagonized with IC50 values in the nanomolar range the NT(1-13) stimulated K+-evoked [3H]DA release but did not affect, up to 10(-6) M, the NT(1-13) enhancement of electrically stimulated [3H]DA release. On the contrary, SR 142948A antagonized the NT(1-13) effect on K+- and electrically-evoked [3H]DA release. In conclusion, these results suggest the possible existence of potentially distinct neurotensin receptors differentially involved in the control exerted by NT on DA release under KCl vs electrical depolarization.
Assuntos
Dopamina/metabolismo , Potássio/fisiologia , Receptores de Neurotensina/agonistas , Córtex Visual/efeitos dos fármacos , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Relação Dose-Resposta a Droga , Cobaias , Imidazóis/farmacologia , Masculino , Neurotensina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Potássio/farmacologia , Pirazóis/farmacologia , Quinolinas/farmacologia , Ratos , Receptores de Neurotensina/efeitos dos fármacos , Córtex Visual/metabolismoRESUMO
Social behaviour is frequently impaired in schizophrenic patients, and current antipsychotics appear poorly effective in alleviating this deficit. SSR181507 is a selective dopamine D2 receptor antagonist and 5-HT1A receptor agonist [Neuropsychopharmacology 28 (2003) 2064] with an atypical antipsychotic profile and additional antidepressant/anxiolytic activities [Neuropsychopharmacology 28 (2003) 1889]. Here, we sought to assess the efficacy of SSR181507, and of reference antipsychotics and antidepressant/anxiolytics, to counteract phencyclidine (PCP)-induced social interaction deficit in rats. Pairs of unfamiliar rats were placed for 10 min each day into a dimly lit arena, during four consecutive days. On the test day (5th day), each pair was placed into the arena 30 min after i.p. treatment with PCP (or vehicle) and a challenge compound or vehicle (same for both rats, i.p. or s.c.). The time spent in social interaction was scored during 10 min. PCP (1 mg/kg) decreased social interaction time by about 35%. This effect was fully antagonized by pre-treatment with SSR181507 (1 mg/kg). In contrast, neither haloperidol (0.05 and 0.1 mg/kg) nor clozapine (0.3 and 1 mg/kg) antagonized this PCP-induced deficit. The selective 5-HT1A receptor agonist 8-OH-DPAT (0.025 and 0.05 mg/kg s.c.), but not the anxiolytic diazepam (0.75 and 1.5 mg/kg), also improved social interaction impairment in PCP-treated rats: this would indicate that the 5-HT1A receptor agonist properties of SSR181507 are responsible for the reversal of PCP-induced social deficit. These data suggest that, in addition to its atypical antipsychotic profile and antidepressant/anxiolytic activities, SSR181507 has a potential therapeutic activity in another key feature of schizophrenia poorly controlled by current antipsychotics, namely deterioration in social functioning.
Assuntos
Dioxanos/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Relações Interpessoais , Fenciclidina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina , Tropanos/farmacologia , Animais , Antipsicóticos/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/fisiologia , Receptores de Dopamina D2/fisiologia , Comportamento SocialRESUMO
The biochemical, electrophysiological and behavioural effects of SR 31742A, a novel and selective ligand of sigma sites in brain, labelled with (+)-[3H]3PPP (Ki = 5.3 +/- 0.3 nM), were investigated in rodents and compared with those of DA antagonists having (haloperidol) or not (spiroperidol) a high affinity for sigma sites. Like haloperidol but unlike spiroperidol, SR 31742A, (ED50 = 0.065 mg/kg, i.p., and 0.21 mg/kg, p.o.) antagonized sigma-dependent turning behaviour in mice and inhibited (0.5 mg/kg, i.v.) the spontaneous firing of hippocampal (CA3) neurones in urethane-anaesthetized rats. In chloral hydrate-anaesthetized rats, like classical antipsychotic compounds, SR 31742A (0.625-5 mg/kg, i.p.) increased the number of spontaneously active A9 and A10 DA cells after single administration and produced an opposite effect after repeated injections. The drug SR 31742A reduced (2.5, 5, 10 mg/kg, i.p.) the hyperactivity elicited by various drugs including that produced by injection of (+)-amphetamine into the nucleus accumbens and impaired avoidance responses at doses (5, 10 mg/kg, i.p.), sparing escape behaviour. SR 31742A lacked affinity for DA receptors and neither did the compound induce catalepsy nor antagonize such effects elicited by apomorphine as climbing, hypothermia, stereotypy or the inhibition of firing of DA neurones. SR 31742A did not affect the basal metabolism of DA but at 10 mg/kg (i.p.) it significantly reduced the amphetamine-induced rise in levels of 3-MT in the striatum of mice. Together, these results indicate a modulatory role for sigma sites upon the activity of hippocampal and DA systems and that sigma ligands exert effects, which suggest antipsychotic potential.
Assuntos
Azepinas/farmacologia , Receptores sigma/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Cinética , Masculino , Camundongos , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
SR 140333 (1-[2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl) piperidin-3-yl]ethyl]-4-phenyl-1-azonia-bicyclo[2.2.2]octane , chloride), a potent non peptide ligand of the substance P (SP) NK1 receptor subtype with high affinity for NK1 receptors from both rat cortical membranes and human IM9 cells (Ki = 0.02 nM and 0.01 nM, respectively) was studied in vivo on various effects induced by NK1 agonists in rats and mice. SR 140333 given intraperitoneally (i.p.) in mice antagonized dose-dependently and in a stereoselective manner the scratching responses induced by intracerebroventricular SP and septide (ID50 = 0.73 and 0.08 mg/kg, respectively) and the turning behavior elicited by intrastriatal SP and septide (ID50 = 0.07 and 0.06 mg/kg, respectively). This compound had little effect on the scratching responses and the turning behavior elicited by [Sar9, Met(O2)11]-SP. When SR 140333 was coadministered with the peptide agonist, the compound reduced the scratching responses elicited by SP, [Sar9, Met(O2)11]-SP and septide injected intrathecally (i.t.) in mice (ID50 = 72.0, 64.3 and 52.5 ng i.t., respectively). SR 140333 antagonized the salivation induced by SP, [Sar9, Met(O2)11]-SP and septide in rats (ID50 = 0.13, 0.18 and 0.09 mg/kg i.p., respectively). SR 140333 abolished the facilitation of the tail-flick reflex induced by noxious heat in rats (total reversal at 0.06 mg/kg, i.p.). This compound was also found to inhibit the turning behavior induced by intrastriatal apomorphine in mice (ID50 = 0.1 mg/kg, i.p.). In conclusion, these results indicate that SR 140333 behaves as a potent, selective and centrally active NK1 receptor antagonist.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Quinuclidinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Ratos , Salivação/efeitos dos fármacos , EstereoisomerismoRESUMO
In chronically implanted awake rats, microinjections of chlordiazepoxide (5 x 10(-7) M) into the dorsal raphé significantly attenuated the inhibition of lever-pressing for food elicited by a signal of punishment. This effect is abolished by prior application of 5,7-dihydroxytryptamine into the dorsal raphé (3 weeks after the infusion of the neurotoxin, dorsal raphé tryptophan hydroxylase activity was reduced to 25% of control values). Furthermore, the disinhibitory effect of intra raphé chlordiazepoxide can be mimicked or potentiated by intra raphé dorsalis application of serotonin (10(-7) or 10(-8) M, respectively). Further evidence for a crucial interaction between benzodiazepines and serotoninergic processes are provided by in vitro experiments showing that chlordiazepoxide or diazepam (10(-5) M) are able to facilitate the K+-evoked [3H]serotonin release from rat midbrain slices. Finally, a high density of [3H]flunitrazepam binding sites was found in the dorsal (and the median) raphé nucleus, the Kd and Bmax values being not altered by prior infusion of 5,7-dihydroxytryptamine. These in vitro data suggest possible means by which intra raphé (and perhaps peripherally administered) benzodiazepines may affect the activity of serotoninergic neurons and thereby produce their effects on experimental anxiety.
Assuntos
Nível de Alerta/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Clordiazepóxido/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Receptores de Droga/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , 5,7-Di-Hidroxitriptamina/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Flunitrazepam/metabolismo , Gânglios Espinais/efeitos dos fármacos , Masculino , Metergolina/farmacologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores de GABA-A , Serotonina/metabolismo , Serotonina/farmacologia , Triptofano Hidroxilase/metabolismoRESUMO
Electrophysiologically identified mesencephalic dopaminergic neurons were examined by means of extra- and intracellular microelectrodes in coronal slices of guinea-pig brain. Neurotensin and its C-terminal fragment (8-13) were equipotent in the enhancement of spontaneous neuronal firing rate (EC50 values 81.9 and 72.6nM, respectively). The duration of response was significantly longer and more variable for neurotensin compared to neurotensin fragment (8-13) (mean half-time of recovery 423+/-44 and 100+/-14 s, respectively, for peptides applied at 300 nM). The initial fast phase of excitatory responses to neurotensin receptor agonists was associated with membrane depolarization (when assessed in current-clamp mode) or with inward currents (when assessed in voltage-clamp mode), whereas prolonged excitation was associated with a slowly occurring and long-lasting change in the late afterhyperpolarization. Two kinetically distinct components were revealed in responses to neurotensin and neurotensin fragment (8-13) by the use of SR48692 and SR142948, two selective non-peptide neurotensin receptor antagonists. SR142948 (100 nM) potently antagonized responses to both agonists [response was reduced by 661 5% and 74+/-9% for neurotensin and neurotensin fragment (8-13), respectively] and caused a rightward shift in the concentration-response curve for neurotensin. On the other hand, SR48692 (100 nM) selectively inhibited the slow (late afterhyperpolarization-dependent) component, without altering the response amplitude; the half-time of recovery was reduced by 71+/-6% and 65+/-5% of control values for responses induced by neurotensin (300 nM) and neurotensin fragment (8-13) (300 nM), respectively. In addition, neurotensin, but not neurotensin fragment (8-13), provoked SR48692-sensitive and long-lasting attenuation of dopamine-induced inhibitory responses. It is suggested that two subtypes of neurotensin receptors are present in dopaminergic neurons, based on the differences in agonist and antagonist sensitivity, kinetic properties and the membrane mechanisms involved.
Assuntos
Potenciais de Ação/fisiologia , Dopamina/fisiologia , Mesencéfalo/fisiologia , Neurônios/fisiologia , Neurotensina/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptores de Neurotensina/fisiologia , Sulfonamidas , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Dopamina/farmacologia , Cobaias , Técnicas In Vitro , Isoquinolinas/farmacologia , Cinética , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Microeletrodos , Neurônios/efeitos dos fármacos , Neurotensina/química , Técnicas de Patch-Clamp , Pirazóis/farmacologia , Quinolinas/farmacologia , Receptores de Neurotensina/agonistas , Receptores de Neurotensina/antagonistas & inibidores , Sistemas do Segundo Mensageiro/fisiologiaRESUMO
The regulation of striatal cholinergic function by dopamine D1 receptor activation was examined in vivo in urethane-anaesthetized rats with microdialysis probes. Extracellular acetylcholine levels were enhanced by activation of D1 receptors either directly by a striatal application of the D1 receptor agonist (+)-SKF-38393 (3 microM) or indirectly by the release of dopamine evoked by striatal application of neurotensin (0.1 microM) under D2 receptor blockade. SR 144190, a new potent and selective non-peptide neurokinin-2 receptor antagonist (0.03-1 mg/kg, i.p.), dose-dependently reduced the acetylcholine release induced by (+)-SKF-38393 or neurotensin. Furthermore, intrastriatal application of SR 144190 (1 nM) blocked the increase in acetylcholine release induced by the local application of (+)-SKF-38393 (3 microM), neurokinin A (1 microM) or substance P (1 microM). Finally, a role for nitric oxide in mediating the effects of D1 neurokinin-2 receptor activation on acetylcholine release is proposed since local infusion of the competitive inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (0.01-10 microM), blocked the increase in acetylcholine release induced by (+)-SKF-38393 (3 microM), neurotensin (0.1 microM) or neurokinin A (1 microM) without affecting the enhancing effect of the neurokinin-1 agonist septide (0.1 microM).
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Acetilcolina/metabolismo , Corpo Estriado/fisiologia , Neurotensina/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico/fisiologia , Receptores de Dopamina D1/fisiologia , Receptores da Neurocinina-2/fisiologia , ômega-N-Metilarginina/farmacologia , Animais , Corpo Estriado/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2 , Inibidores Enzimáticos/farmacologia , Cinética , Masculino , Compostos de Metilureia/farmacologia , Microdiálise , Morfolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/fisiologia , Receptores da Neurocinina-2/antagonistas & inibidoresRESUMO
The effects of tachykinin receptor agonists and antagonists were investigated using intra- and extracellular recordings on spontaneously firing nigral neurons in guinea-pig brain slices. In 70 of 76 electrophysiologically identified dopaminergic neurons, a concentration-dependent increase in firing rate was induced by the selective neurokinin-3 tachykinin agonist senktide and by the natural tachykinin agonists neurokinin B and substance P, with EC50 values of 14.7, 31.2 and 12200 nM respectively. These responses were inhibited in a concentration- and time-dependent manner by the selective non-peptide neurokinin-3 receptor antagonist SR 142801 (1-100 nM; n=23), but neither by its S-enantiomer SR 142806 (100 nM; n=4) nor by selective antagonists of neurokinin-1 (SR 140333) or neurokinin-2 (SR 48968) receptors (both at 100 nM; n=3). The selective neurokinin-1 agonist [Sar9,Met(O2)11]substance P (30-100 nM; n=23) and the selective neurokinin-2 agonist [Nle10]neurokinin A(4-10)(30-100 nM; n=13) were without any effect on dopaminergic cells. In 13 of 21 electrophysiologically identified, presumably GABAergic neurons located in the pars compacta of the substantia nigra, excitatory responses were evoked concentration dependently by substance P and [Sar9,Met(O2)11]substance P, with EC50 values of 18.6 and 41.9 nM respectively. These responses were inhibited by SR 140333 (100 nM; n=3), but neither by its R-enantiomer SR 140603 nor by SR 142801 (both at 100 nM; n=3). Senktide and [Nle10]neurokinin A(4-10) (both at 30-100 nM; n=10) were without effect on these presumed GABAergic neurons. A small population (12%) of pars compacta neurons was insensitive to any of the three selective tachykinin agonists. In the nigral pars reticulata, 12 neurons were recorded which had an electrophysiological profile similar to that of presumed GABAergic neurons in the pars compacta. Of these 12 cells, seven did not respond to any of the selective tachykinin agonists tested, while five were excited by senktide in a concentration-dependent manner (EC50=98.5 nM). Although this value was significantly higher than that found for dopaminergic neurons in the pars compacta, senktide-evoked responses were inhibited by SR 142801 (100 nM; n=3). We conclude that, in the guinea-pig substantia nigra, tachykinins evoke excitatory responses in both dopaminergic and non-dopaminergic neurons; however, the sensitivity to tachykinin agonists (neurokinin-1 versus neurokinin-3) depends on both neuronal type and localization.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-1/agonistas , Receptores da Neurocinina-3/agonistas , Receptores da Neurocinina-3/antagonistas & inibidores , Substância Negra/fisiologia , Taquicininas/farmacologia , Animais , Dopamina/fisiologia , Eletrofisiologia , Cobaias , Técnicas In Vitro , Masculino , Piperidinas/farmacologia , Quimpirol/farmacologia , Substância Negra/efeitos dos fármacosRESUMO
Ejections of 10(-5)-10(-3)M neurotensin into the ventral tegmental area increased dopamine efflux measured by electrochemical approaches in the prefrontal cortex of anaesthetized rats. In the same conditions, the effects evoked on dopamine efflux by 10(-5)M neurotensin(8-13) and [D-Tyr(11)]neurotensin were different from each other and depended on the explored area: the prefrontal cortex and the caudal and rostral nucleus accumbens. In the prefrontal cortex, neurotensin(8-13) was as potent as neurotensin, whereas [D-Tyr(11)]neurotensin was ineffective. In the caudal nucleus accumbens, when considering the initial intensity of the effect, neurotensin(8-13) and neurotensin appeared more potent than [D-Tyr(11)]neurotensin. In contrast, in the rostral nucleus accumbens, neurotensin(8-13) was less potent than [D-Tyr(11)]neurotensin and neurotensin. These results support the differential involvement of two pharmacologically distinct neurotensin receptor entities on ventral tegmental area neurons in the modulation of mesolimbic and mesocortical dopaminergic activity.
Assuntos
Dopamina/metabolismo , Neurotensina/farmacologia , Núcleo Accumbens/metabolismo , Fragmentos de Peptídeos/farmacologia , Córtex Pré-Frontal/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Eletroquímica , Espaço Extracelular/metabolismo , Masculino , Microinjeções , Neurotensina/análogos & derivados , Ratos , Ratos Sprague-DawleyRESUMO
Psychostimulants and antipsychotic drugs increase mRNA expression of the neuropeptide neurotensin (NT) in the striatum and nucleus accumbens. In the present study, we used mice lacking the dopamine transporter (DAT) to investigate the consequences of a chronic hyperdopaminergic state on NT gene expression. NT mRNA expression was examined under basal conditions and after administration of haloperidol or amphetamine using in situ hybridization with a digoxigenin-labeled NT cRNA probe. DAT-/- mice exhibited a striking increase in the number of NT mRNA-expressing perikarya in the substantia nigra and ventral tegmental area, as well as a less pronounced increase in the lateral septum compared with wild-type littermates. No changes were detected in other regions expressing NT mRNA. Acute administration of haloperidol (1 mg/kg) induced a significant increase in the number of NT mRNA-expressing neurons in the dorsomedial and dorsolateral striatum of wild-type mice but failed to stimulate NT gene expression in DAT mutants. In contrast, a higher dose of haloperidol (5 mg/kg) stimulated striatal NT mRNA expression both in DAT+/+ and DAT-/- mice. Amphetamine (10 mg/kg) increased the number of hybridized neurons in the nucleus accumbens shell and fundus striati of wild-type and DAT-/- mice, indicating that the drug acted through a target other than DAT, such as the serotonin or the norepinephrine transporters. The up-regulation of NT mRNA observed in DAT-/- mice may represent an adaptive mechanism in response to constitutive hyperdopaminergia. These results illustrate the profound alterations in the NT system induced by chronic stimulation of DA receptors and underscore the potential clinical relevance of NT/DA interactions in schizophrenia and drug abuse.
Assuntos
Encéfalo/fisiologia , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras/deficiência , Transtornos Mentais/fisiopatologia , Proteínas do Tecido Nervoso , Neurotensina/biossíntese , Anfetamina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Dopaminérgicos/farmacologia , Antagonistas de Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Expressão Gênica/efeitos dos fármacos , Haloperidol/farmacologia , Hibridização In Situ , Camundongos , Neurotensina/efeitos dos fármacos , Neurotensina/genética , RNA Mensageiro/análise , RNA Mensageiro/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The effects of SR140333 and SR48968 (neurokinin1 and neurokinin2 tachykinin receptor antagonists, respectively) on the N-methyl-D-aspartate-evoked release of [3H]acetylcholine (previously formed from [3H]choline) were investigated in striosome-enriched areas and in the matrix of the rat striatum using an in vitro microsuperfusion method. In both striatal compartments, SR140333 and SR48968 did not modify the 50 microM N-methyl-D-aspartate-evoked release of [3H]acetylcholine. However, in low concentrations, both SR140333 (0.1 microM to 1 pM) and SR48968 (0.1 microM to 0.1 nM) markedly enhanced the 1 mM N-methyl-D-aspartate (+10 microM D-serine)-evoked release of [3H]acetylcholine in striosome-enriched areas. These responses were dopamine-dependent since they were not observed any more following the local blockade of D2 receptors by sulpiride or of dopamine synthesis by alpha-methyl-p-tyrosine. A dopamine-dependent disinhibitory effect (of lower amplitude) on the 1 mM N-methyl-D-aspartate (+10 microM D-serine)-evoked release of [3H]acetylcholine was also induced by SR48968 (0.1 microM to 0.1 nM) (but not by SR140333) in the matrix. In addition, in the matrix, as shown only in the presence of alpha-methyl-p-tyrosine, both SR140333 and SR48968 reduced the 1 mM N-methyl-D-aspartate (+10 microM D-serine)-evoked response and these non-dopamine-mediated inhibitory effects only occurred at the highest tested concentration (0.1 microM) of the antagonists. Indicating the specificity of these responses, the effects of SR140333 were reproduced by RP67580, another neurokinin1 receptor antagonist and, as expected from previous binding studies, corresponding SR140333 and SR48968 enantiomers were without effect. These results suggest that under potent stimulation of N-methyl-D-aspartate receptors, endogenously released substance P and neurokinin A (or related tachykinins) regulate differently the N-methyl-D-aspartate-evoked release of [3H]acetylcholine in striosomes and in the matrix. The inhibitory effects of these tachykinins on the evoked release of [3H]acetylcholine are mediated by dopamine. On the contrary, their facilitatory responses are only observed in the matrix under blockade of dopamine transmission.
Assuntos
Acetilcolina/metabolismo , Benzamidas/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , N-Metilaspartato/farmacologia , Neostriado/metabolismo , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Quinuclidinas/farmacologia , Receptores da Neurocinina-2/antagonistas & inibidores , Animais , Dopamina/fisiologia , Técnicas In Vitro , Masculino , Neostriado/efeitos dos fármacos , Neurocinina A/farmacologia , Neurocinina B/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Estimulação Química , Substância P/farmacologiaRESUMO
Unilateral microinjection of neurotensin in the ventral tegmental area of the rat (2.5 micrograms/0.5 microliter) produced behavioural excitation illustrated by contralateral circling. Given orally, SR 48692, a selective and potent non-peptide neurotensin receptor antagonist, significantly reduced these rotations with a triphasic dose-effect relationship. Inhibition occurred at 0.12 mg/kg; further increases in dose up to 2.5 mg/kg produced no significant antagonism, then at doses > or = 5 mg/kg, a second phase of antagonism was observed. Bilateral injection of neurotensin (0.5 microgram each side) into the nucleus accumbens antagonized the increase in locomotor activity following intraperitoneal injection of amphetamine. Given orally, SR 48692 reduced dose-dependently (0.1-1 mg/kg) these intra-accumbens neurotensin effects. Using high pressure liquid chromatography with electrochemical detection, we showed that microgram amounts of neurotensin injected into the ventral tegmental area increased dihydroxyphenylacetate/dopamine ratios in the nucleus accumbens. Using in vivo voltammetry techniques, we found that the injection of nanogram and picogram amounts of neurotensin in the ventral tegmental area stimulated dopamine efflux in the nucleus accumbens. None of these biochemical changes were affected by SR 48692 (0.1-10 mg/kg). These results indicate complex interactions between neurotensin and the mesolimbic dopamine system. More particularly, the differential ability of SR 48692 to affect neurotensin-evoked behavioural versus biochemical changes supports the concept of neurotensin receptor heterogeneity.
Assuntos
Dopamina/fisiologia , Atividade Motora/efeitos dos fármacos , Neurotensina/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Pirazóis/farmacologia , Quinolinas/farmacologia , Receptores de Neurotensina/antagonistas & inibidores , Transmissão Sináptica , Tegmento Mesencefálico/efeitos dos fármacos , Ácido 3,4-Di-Hidroxifenilacético/análise , Anfetamina/farmacologia , Animais , Dopamina/análise , Masculino , Atividade Motora/fisiologia , Núcleo Accumbens/fisiologia , Ratos , Ratos Sprague-Dawley , Tegmento Mesencefálico/fisiologiaRESUMO
The objective of the present in vitro and in vivo experiments was to examine the involvement of neurokinin NK3 receptors in the regulation of the noradrenergic function in gerbils and guinea-pigs. Application of senktide, a peptide NK3 receptor agonist, on guinea-pig locus coeruleus slices increased the firing rate of presumed noradrenergic neurons (EC50 = 26 nM) in a concentration-dependent manner. Given i.c.v., senktide (0.5-2 micrograms) and (MePhe7)neurokinin B (1-10 micrograms), another NK3 receptor agonist, reduced exploratory behaviour in gerbils in a dose-dependent manner (2 micrograms of senktide producing a 50% reduction of locomotor activity and rearing). In vivo microdialysis experiments in urethane-anaesthetized guinea-pigs showed that senktide (2-8 micrograms i.c.v.) induced a dose-dependent increase in norepinephrine release in the medial prefrontal cortex. The electrophysiological, behavioural and biochemical changes elicited by senktide were concentration- or dose-dependently reduce by SR 142801, the selective non-peptide NK3 receptor antagonist. In the locus coeruleus slice preparation, complete antagonism of senktide (30 nM) was observed with 50 nM of SR 142801, while injected i.p. (0.1-1 mg/kg) it abolished the senktide-induced norepinephrine release in guinea-pigs. In gerbils, SR 142801 (1-10 mg/kg i.p.) reversed the reduction of exploratory behaviour induced by senktide (1 microgram). By contrast, the 100-fold less active enantiomer, SR 142806, did not exert any antagonism in these models. Finally, the reduction of exploratory behaviour in gerbils was found to be reversed by prazosin (0.25-2.56 micrograms/kg i.p.) and to some extent by clonidine, drugs known to depress noradrenergic function. All these experiments strongly support the hypothesis that brain noradrenergic neurons can be activated by stimulation of neurokinin NK3 receptors.
Assuntos
Fibras Adrenérgicas/fisiologia , Encéfalo/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores da Neurocinina-3/efeitos dos fármacos , Substância P/análogos & derivados , Animais , Relação Dose-Resposta a Droga , Gerbillinae , Cobaias , Microdiálise , Neuropeptídeos/farmacologia , Norepinefrina/farmacologia , Piperidinas/farmacologia , Prazosina/farmacologia , Substância P/farmacologiaRESUMO
The time-course of variations in extracellular dopamine concentration following local pressure ejection of 10(-7) to 10(-3) M neurotensin into the ventral tegmental area of the rat was determined in the minute range in the nucleus accumbens by means of differential normal pulse voltammetry associated with carbon fibre electrodes. The effects of neurotensin ejection into the ventral tegmental area were further investigated on the firing activity of the corresponding dopaminergic neurons. The lowest concentration of neurotensin (10(-7) M) enhanced the extracellular dopamine concentration throughout the nucleus accumbens and stimulated the discharge activity of ventral tegmental area dopaminergic neurons. The two highest concentrations of neurotensin (10(-5) M and 10(-3) M) evoked two patterns of responses on the extracellular dopamine concentration and on the discharge activity of dopaminergic neurons. The extracellular dopamine concentration was increased above basal levels in the caudal part of the nucleus accumbens. In the rostral part, the evoked changes exhibited a multiphasic time-course characterized by a decreasing phase below baseline. The firing rate of dopaminergic neurons was either increased or decreased, depending on the neuron being tested. In fact, neurotensin ejection was always followed by an exacerbation of bursting activity, the resulting effect on the mean firing rate being related to the duration of the interburst intervals. Indeed, short interburst intervals permitted an increase in mean firing rate whereas long interburst intervals, indicative of excessive depolarization, led to a decrease in mean firing rate. These results suggest that variations in extracellular dopamine concentration evoked by neurotensin administration into the ventral tegmental area are the result of neurotensin-evoked changes in dopaminergic activity. Moreover, the differential effects evoked by high concentrations of neurotensin could be attributable to two subpopulations of ventral tegmental area dopaminergic neurons which could project differentially to the caudal and the rostral parts of the nucleus accumbens.
Assuntos
Dopamina/metabolismo , Neurotensina/farmacologia , Núcleo Accumbens/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Eletroquímica , Eletrofisiologia , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Masculino , Neurônios/efeitos dos fármacos , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Área Tegmentar Ventral/fisiologiaRESUMO
The present study investigated, in rats, whether blockade of cannabinoid CB1 receptors may alter Fos protein expression in a manner comparable to that observed with antipsychotic drugs. Intraperitoneal administration of the selective CB1 receptor antagonist, SR141716, dose-dependently (1.0, 3.0 and 10 mg/kg) increased Fos-like immunoreactivity in mesocorticolimbic areas (prefrontal cortex, ventrolateral septum, shell of the nucleus accumbens and dorsomedial caudate-putamen), while motor-related structures such as the core of the nucleus accumbens and the dorsolateral caudate-putamen were unaffected. In the ventrolateral septum, taken as a representative structure, the Fos-inducing effect of SR141716 (10 mg/kg) was maximal 2 h after injection and returned to near control levels by 4 h. Within the prefrontal cortex, SR141716 increased the number of Fos-positive cells predominantly in the infralimbic and prelimbic cortices, presumptive pyramidal cells being the major cell types in which Fos was induced. The D1-like receptor antagonist, SCH23390 (0.1 mg/kg), did not prevent the Fos-inducing effect of SR141716 in any brain region examined (prefrontal cortex, nucleus accumbens, ventrolateral septum and dorsomedial caudate-putamen), although SCH23390 significantly reduced Fos expression induced by cocaine (20 mg/kg) in all these regions. By contrast, the dopamine D2-like agonist, quinpirole (0.25 mg/ kg), counteracted SR141716-induced Fos-like immunoreactivity in the ventrolateral septum, the nucleus accumbens and the dorsomedial caudate-putamen, while no antagonism was observed in the prefrontal cortex. Microdialysis experiments in awake rats indicated that SR141716, at doses which increased Fos expression (3 and 10 mg/kg), did not alter dopamine release in the shell of the nucleus accumbens. Finally, SR141716 increased the levels of neurotensin-like immunoreactivity in the nucleus accumbens, but not in the caudate-putamen. Collectively, the present results show that blockade of cannabinoid receptors increases Fos- and neurotensin-like immunoreactivity with characteristics comparable to those reported for atypical neuroleptic drugs.
Assuntos
Encéfalo/fisiologia , Regulação da Expressão Gênica/fisiologia , Genes fos/efeitos dos fármacos , Sistema Límbico/fisiologia , Piperidinas/farmacologia , Córtex Pré-Frontal/fisiologia , Pirazóis/farmacologia , Receptores de Dopamina D2/fisiologia , Receptores de Droga/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Canabinoides/antagonistas & inibidores , Dopamina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Sistema Límbico/efeitos dos fármacos , Masculino , Microdiálise , Neurotensina/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Canabinoides , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Droga/antagonistas & inibidores , RimonabantoRESUMO
Compounds possessing neurotrophic properties may represent a possible treatment for neurodegenerative disorders such as Alzheimer's disease. SR 57746A, 1-[2-(naphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,5,6- tetrahydropyridine hydrochloride, is a new compound with neurotrophic activity in a number of in vitro preparations. The neurotrophic effects of this compound have been evaluated in vivo using four distinct rat models of neurodegeneration: transient global ischaemia produced by a four-vessel occlusion; septohippocampal lesion produced by injection of vincristine sulphate into the medial septum; sciatic nerve crushing; and acrylamide-induced peripheral neuropathy. Rats were administered vehicle or 2.5-10 mg/kg p.o. SR 57746A, after initiation of the degenerative process, then once daily for 10 days in the first two models, 16 days in the third and 26 days in the fourth model. Median scores for ischaemia-induced neuronal damage were reduced by 30-40% by SR 57746A treatment in hippocampal CA1, CA2, and CA3 regions, and in the dorsal striatum. Twelve days after intraseptal vincristine administration, there was a marked loss of septohippocampal cholinergic neurons, as indicated by reduced choline acetyltransferase activity in both the septum and hippocampus. SR 57746A dose-dependently reversed this reduction in both areas. These results were confirmed by histoenzymological evaluation of hippocampal acetylcholinesterase content. SR 57746A also reversed the loss of hippocampal choline acetyltransferase induced by intraseptal vincristine in marmosets. Behavioral deficits in these models (exploratory behaviour in the former and short-term social memory in the latter) were also significantly reduced by SR 57746A treatment. In the sciatic crush model, sensorimotor function improved more rapidly in rats treated with 10 mg/kg SR 57746A. In this same model, SR 57746A (10 mg/kg/day) also significantly increased the length of regenerated nerve eight days after the crush, as measured using the pinch test. Finally, SR 57746A retarded the onset, reduced the amplitude and accelerated the recovery of acrylamide-induced peripheral neuropathy. Thus, SR 57746A possesses notable neurotrophic activity in a variety of neurodegenerative models in vivo, suggesting that the compound may possess therapeutic potential for the treatment of neurodegenerative diseases.
Assuntos
Degeneração Neural/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Acetilcolinesterase/análise , Acrilamida , Acrilamidas/toxicidade , Animais , Biomarcadores , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/fisiopatologia , Callithrix , Colina O-Acetiltransferase/análise , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Naftalenos/farmacologia , Compressão Nervosa , Fatores de Crescimento Neural/farmacologia , Regeneração Nervosa , Proteínas do Tecido Nervoso/análise , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/prevenção & controle , Desempenho Psicomotor/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de Serotonina/classificação , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Nervo Isquiático/lesões , Nervo Isquiático/fisiologia , Septo Pelúcido/efeitos dos fármacos , Septo Pelúcido/fisiologia , Especificidade da Espécie , Vincristina/toxicidadeRESUMO
1. Neurotensin stimulated inositol monophosphate (IP1) formation in both human colonic carcinoma HT29 cells and in mouse neuroblastoma N1E115 cells with EC50 values of 3.5 +/- 0.5 nM (n = 4) and 0.46 +/- 0.02 nM (n = 3), respectively. Neurotensin also stimulated cyclic GMP production with an EC50 of 0.47 +/- 1.2 nM and inhibited cyclic AMP accumulation induced by forskolin (0.5 microM) with an IC50 of 1.33 +/- 1.5 nM (n = 3) on the N1E115 cell line. 2. The competitive antagonism by the non-peptide neurotensin receptor antagonist, SR48692 of neurotensin-induced IP1 formation revealed pA2 values of 8.7 +/- 0.2 (n = 3) for HT29 and 10.1 +/- 0.2 (n = 3) for N1E115 cells. SR48692 also antagonized the cyclic GMP and cyclic AMP responses induced by neurotensin in the N1E115 cell line with pA2 values of 10.7 +/- 0.7 (n = 3) and 9.8 +/- 0.3 (n = 3), respectively. 3. In CHO cells transfected with the rat neurotensin receptor, neurotensin stimulated IP1 and cyclic AMP formation with EC50 values of 3.0 +/- 0.5 nM (n = 3) and 72.2 +/- 20.7 nM (n = 3), respectively. Both effects were antagonized by SR48692, giving pA2 values of 8.4 +/- 0.1 (n = 3) for IP1 and 7.2 +/- 0.4 (n = 3) for cyclic AMP responses. 4. Radioligand binding experiments, performed with [125I]-neurotensin (0.2 nM), yielded IC50 values of 15.3 nM (n = 2) and 20.4 nM (n = 2) for SR48692 versus neurotensin receptor binding sites labelled in HT29 and N1E115 cells, respectively. 5 In conclusion, SR48692 appears to be a potent, species-independent antagonist of the signal transduction events triggered by neurotensin receptor activation in both neuronal and non-neuronal cell systems.