RESUMO
Systemically administered antipsychotics bind to dopamine (DA) D2 receptors expressed in both pre- and postsynaptic neurons of different striatal sites and present an amnestic effect on learning and memory of conditioned avoidance responses (CAR). The aim of this study was to test whether blockade of the pre- or post-synaptic D2 receptors of the dorsolateral striatum of rats is the mechanism by which systemically administered antipsychotics present this amnestic effect. CAR learning and memory was evaluated in rats that received i.p. administrations of pre- or postsynaptic doses of the antipsychotic sulpiride combined with intra-DLS infusion of the D2 agonist quinpirole. Intra-DLS quinpirole itself was not amnestic and this effect was prevented by co-administration of presynaptic dose of sulpiride. However, sulpiride was amnestic when administered systemically in a post- but not presynaptic dose. This amnestic effect of sulpiride was prevented by the co-administration of quinpirole into the DLS. These results show that a blockade of postsynaptic D2 receptors in the DLS is necessary and sufficient to produce the amnestic effect of neuroleptics on CARs.
Assuntos
Antipsicóticos/farmacologia , Corpo Estriado/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Memória/efeitos dos fármacos , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Animais , Antipsicóticos/administração & dosagem , Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Quimioterapia Combinada , Masculino , Neurônios/efeitos dos fármacos , Quimpirol/administração & dosagem , Quimpirol/farmacologia , Ratos , Ratos Wistar , Sulpirida/administração & dosagem , Sulpirida/farmacologia , Membranas Sinápticas/efeitos dos fármacosRESUMO
RATIONALE: Aversively motivated learning is more poorly understood than appetitively motivated learning in many aspects, including the role of dopamine receptors in different regions of the striatum. OBJECTIVES: The present study investigated the roles of the D1-like DA receptors in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) on learning and performance of conditioned avoidance responses (CARs). METHODS: Adult male Wistar rats received intraperitoneal (i.p.), intra-NAc, or intra-DLS injections of the D1 dopamine receptor agonist SKF 81297 or the D1 receptor antagonist SCH 23390 20 min before or immediately after a training session in the CAR task two-way active avoidance, carried out 24 h before a test session. RESULTS: Pre-training administration of SCH 23390, but not SKF 81297, caused a significant decrease in the number of CARs in the test, but not in the training session, when injected into the DLS, or in either session when injected into the NAc. It also caused a significant increase in the number of escape failures in the training session when injected into the NAc. Systemic administration caused a combination of these effects. Post-training administrations of these drugs caused no significant effect. CONCLUSIONS: The results suggest that the D1-like receptors in the NAc and DLS play important, though different, roles in learning and performance of CAR.
Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Psicológico/fisiologia , Corpo Estriado/fisiologia , Núcleo Accumbens/fisiologia , Receptores de Dopamina D1/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Masculino , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidoresRESUMO
The ventrolateral caudoputamen (VLCP) is well known to participate in the control of orofacial movements and forepaw usage accompanying feeding behavior. Previous studies from our laboratory have shown that insect hunting is associated with a distinct Fos up-regulation in the VLCP at intermediate rostro-caudal levels. Moreover, using the reversible blockade with lidocaine, we have previously suggested that the VLCP implements the stereotyped actions seen during prey capture and handling, and may influence the motivational drive to start attacking the roaches, as well. However, considering that (1) lidocaine suppresses action potentials not only in neurons, but also in fibers-of-passage, rendering the observed behavioral effect not specific to the ventrolateral caudoputamen; (2) the short lidocaine-induced inactivation period had left a relatively narrow window to observe the behavioral changes; and (3) that the restriction stress to inject the drug could have also disturbed hunting behavior, in the present study, we have examined the role of the VLCP in predatory hunting by placing bilateral NMDA lesions three weeks previous to the behavior testing. We were able to confirm that the VLCP serves to implement the stereotyped sequence of actions seen during prey capture and handling, but the study did not confirm its role in influencing the motivational drive to hunt. Together with other studies from our group, the present work serves as an important piece of information that helps to reveal the neural systems underlying predatory hunting.
Assuntos
Comportamento Predatório/fisiologia , Putamen/fisiologia , Análise de Variância , Anestésicos Locais/farmacologia , Animais , Agonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Privação de Alimentos , Lidocaína/farmacologia , Masculino , N-Metilaspartato/toxicidade , Proteínas Proto-Oncogênicas c-fos/metabolismo , Putamen/efeitos dos fármacos , Putamen/lesões , Ratos , Ratos Wistar , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
The multiple memory systems theory proposes that the hippocampus and the dorsolateral striatum are the core structures of the spatial/relational and stimulus-response (S-R) memory systems, respectively. This theory is supported by double dissociation studies showing that the spatial and cue (S-R) versions of the Morris water maze are impaired by lesions in the dorsal hippocampus and dorsal striatum, respectively. In the present study we further investigated whether adult male Wistar rats bearing double and bilateral electrolytic lesions in the dorsal hippocampus and dorsolateral striatum were as impaired as rats bearing single lesions in just one of these structures in learning both versions of the water maze. Such a prediction, based on the multiple memory systems theory, was not confirmed. Compared to the controls, the animals with double lesions exhibited no improvement at all in the spatial version and learned the cued version very slowly. These results suggest that, instead of independent systems competing for holding control over navigational behaviour, the hippocampus and dorsal striatum both play critical roles in navigation based on spatial or cue-based strategies.
Assuntos
Corpo Estriado/fisiologia , Hipocampo/fisiologia , Aprendizagem em Labirinto/fisiologia , Comportamento Espacial/fisiologia , Animais , Comportamento Animal/fisiologia , Masculino , Ratos , Ratos Wistar , Percepção Espacial/fisiologiaRESUMO
Recent studies have indicated that nearly half of all surgical patients still have inadequate pain relief; therefore, it is becoming increasingly more important to understand the mechanisms involved in postoperative pain in order to be better treated. Previous studies have shown that incisions can cause mast cell degranulation. Thus, the aim of this study was to investigate the involvement of mast cells in a model of postoperative pain in mice. The depletion of mast cell mediators produced by pre-treatment with compound 48/80 (intraplantar (i.pl.)) widely (98 ± 23% of inhibition) and extensively (up to 96 h) prevented postoperative nociception and reduced histamine and serotonin levels (88 ± 4% and 68 ± 10%, respectively) in operated tissue. Furthermore, plantar surgery produced immense mast cell degranulation, as assessed by histology and confirmed by the increased levels of serotonin (three-fold higher) and histamine (fifteen-fold higher) in the perfused tissue, 1h after surgery. Accordingly, pre-treatment with the mast cell membrane stabilizer cromoglycate (200 µg/paw, i.pl.) prevented mechanical allodynia (inhibition of 96 ± 21%) and an increase in histamine (44 ± 10% of inhibition) and serotonin (73 ± 5% of inhibition) levels induced by plantar surgery. Finally, local treatment with H(1) (promethazine, 100 µg/paw, i.pl.), 5-HT(3) (ondansetron, 10 µg/paw, i.pl.) or 5-HT(2A) (ketanserin, 5 µg/paw, i.pl.) receptor antagonists partially decreased postoperative nociception in mice, but when co-administered together it completely reversed the mechanical allodynia in operated mice. Thus, mast cell activation mechanisms are interesting targets for the development of novel therapies to treat postoperative pain.
Assuntos
Mastócitos/imunologia , Dor Pós-Operatória/imunologia , Animais , Degranulação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Masculino , Mastócitos/metabolismo , Camundongos , Nociceptividade/efeitos dos fármacos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/metabolismo , Dor Pós-Operatória/psicologia , Receptores Histamínicos H1/metabolismo , Serotonina/metabolismoRESUMO
The role of dopamine (DA) in rewarding motivated actions is well established but its role in learning how to avoid aversive events is still controversial. Here we tested the role of D2-like DA receptors in the nucleus accumbens (NAc) and the dorsolateral striatum (DLS) of rats in the learning and performance of conditioned avoidance responses (CAR). Adult male Wistar rats received systemic, intra-NAc or intra-DLS (pre- or post-training) administration of a D2-like receptor agonist (quinpirole) or antagonist ((-)sulpiride) and were given two sessions in the two-way active avoidance task. The main effects observed were: (i) sulpiride and lower (likely pre-synaptic) doses of quinpirole decreased the number of CARs and increased the number of escape failures; (ii) higher doses of quinpirole (likely post-synaptic) increased inter-trial crossings and failures; (iii) pre-training administration of sulpiride decreased the number of CARs in both training and test sessions when infused into the NAc, but this effect was observed only in the test session when it was infused into the DLS; (iv) post-training administration of sulpiride decreased CARs in the test session when infused into the NAc but not DLS. These findings suggest that activation of D2 receptors in the NAc is critical for fast adaptation to responding to unconditioned and conditioned aversive stimuli while activation of these receptors in the DLS is needed for a slower learning of how to respond to the same stimuli based on previous experiences.
Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Operante/fisiologia , Corpo Estriado/fisiologia , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Receptores de Dopamina D2/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Quimpirol/farmacologia , Ratos , Ratos Wistar , Sulpirida/farmacologiaRESUMO
The roles of the nigrostriatal pathway are far beyond the simple control of motor functions. The tonic release of dopamine in the dorsal and ventral striatum controls the choice of proper actions toward a given environmental situation. In the striatum, a specific action is triggered by a specific stimulus associated with it. When the subject faces a novel and salient stimulus, the phasic release of dopamine allows synaptic plasticity in the cortico-striatal synapses. Neurons of different regions of cortical areas make synapses that converge to the same medium spine neurons of the striatum. The convergent associations form functional units encoding body parts, objects, locations, and symbolic representations of the subject's world. Such units emerge in the striatum in a repetitive manner, like a mosaic of broken mirrors. The phasic release of dopamine allows the association of units to encode an action of the subject directed to an object or location with the outcome of this action. Reinforced stimulus-action-outcome associations will affect future decision making when the same stimulus (object, location, idea) is presented to the subject in the future. In the absence of a minimal amount of striatal dopamine, no action is initiated as seen in Parkinson's disease subjects. The abnormal and improper association of these units leads to the initiation of unpurposeful and sometimes repetitive actions, as those observed in dyskinetic patients. The association of an excessive reinforcement of some actions, like drug consumption, leads to drug addiction. Improper associations of ideas and unpleasant outcomes may be related to traumatic and depressive symptoms common in many diseases, including Parkinson's disease. The same can be said about the learning and memory impairments observed in demented and nondemented Parkinson's disease patients.
Assuntos
Cognição/fisiologia , Dopamina/metabolismo , Mesencéfalo/citologia , Neurônios/fisiologia , Animais , Aprendizagem por Associação/fisiologia , Comportamento Aditivo/metabolismo , Comportamento Aditivo/patologia , Depressão/metabolismo , Depressão/patologia , Humanos , Movimento/fisiologiaRESUMO
In the present review we propose a model to explain the role of the basal ganglia in sensorimotor and cognitive functions based on a growing body of behavioural, anatomical, physiological, and neurochemical evidence accumulated over the last decades. This model proposes that the body and its surrounding environment are represented in the striatum in a fragmented and repeated way, like a mosaic consisting of the fragmented images of broken mirrors. Each fragment forms a functional unit representing articulated parts of the body with motion properties, objects of the environment which the subject can approach or manipulate, and locations the subject can move to. These units integrate the sensory properties and movements related to them. The repeated and widespread distribution of such units amplifies the combinatorial power of the associations among them. These associations depend on the phasic release of dopamine in the striatum triggered by the saliency of stimuli and will be reinforced by the rewarding consequences of the actions related to them. Dopamine permits synaptic plasticity in the corticostriatal synapses. The striatal units encoding the same stimulus/action send convergent projections to the internal segment of the globus pallidus (GPi) and to the substantia nigra pars reticulata (SNr) that stimulate or hold the action through a thalamus-frontal cortex pathway. According to this model, this is how the basal ganglia select actions based on environmental stimuli and store adaptive associations as nondeclarative memories such as motor skills, habits, and memories formed by Pavlovian and instrumental conditioning.