Estudo dos efeitos de infusões de um agonista e um antagonista de receptores dopaminérgicos D2 no núcleo accumbens e estriado dorsolateral sobre o aprendizado e performance de ratos na esquiva ativa de duas vias

Orientador : Prof. Dr. Cláudio da CunhaDissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia. Defesa: Curitiba, 21/02/2011Bibliografia: fls. 61-65ResumoResumo: O papel da dopamina em ações motivadas pela recompensa está bem esclarecido, entretanto seu papel no aprendizado de como evitar eventos aversivos ainda é controverso. Testamos, neste estudo, o papel de receptores dopaminérgicos D2 no núcleo accumbens (NAc) e no estriado dorsolateral (DLS) de ratos no aprendizado e performance de respostas condicionadas de esquiva (CAR, do inglês conditioned avoidance response). Ratos Wistar machos adultos receberam administrações sistêmicas, intra-NAc ou intra-DLS (pré ou pós-treino) do agonista de receptores D2 (quimpirole) ou do antagonista ((-)sulpiride) e foram submetidos a duas sessões da esquiva ativa de duas vias. Os principais efeitos observados foram: (i) sulpiride e quimpirole nas doses pré-sinápticas (mais baixas) reduziram o número de CAR e aumentaram o número de falhas de fuga; (ii) doses pós-sinápticas de quimpirole aumentaram o número de cruzamentos inter-tentativas e de falhas de fuga; (iii) a administração pré-treino de sulpiride reduziu o número de CAR nas sessões de treino e teste na infusão intra-NAc, efeito que foi observado somente na sessão de teste para infusão intra-DLS; (iv) a administração pós-treino de sulpiride reduziu o número de CAR na sessão teste quando infundido no NAc, mas não no DLS. Esses achados sugerem que a ativação de receptores D2 no NAc é crítica para a adaptação rápida da resposta ao estímulo aversivo condicionado e incondicionado enquanto a ativação desses receptores no DLS é necessária para o aprendizado lento de como responder a esses mesmos estímulos baseado em experiências prévias.Abstract: The role of dopamine in rewarding motivated actions is well established, but its role in learning of how to avoid aversive events is still controversial. Here we tested the role of D2 dopamine receptors in the nucleus accumbens (NAc) and the dorsolateral striatum (DLS) of rats in 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 receptor agonist (quinpirole) or antagonist ((-)sulpiride), and were given 2 sessions in the 2-way active avoidance task. The main effects observed were the following: (i) sulpiride and presynaptic (lower) doses of quinpirole decreased the number of CARs and increased the number of escape failures; (ii) Postsynaptic (higher) doses of quinpirole 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 infused into the DLS; (iv) Post-training administration of sulpiride decreased CARs in the test session when infused into the Nac, but not in the DLS. These findings suggest that activation of D2 receptors in the Nac is critical for a fast adaptation of the responding to unconditioned and conditioned aversive stimuli while activation of these receptors in the DLS is needed for a slow learning of how to respond to the same stimuli based on previous experiences

Antipsicótico típico produz efeitos amnésicos pelo bloqueio de receptores D2 pós-sinápticos no estriado dorsolateral de ratos, mas não afeta a dessensibilização de receptores D2 pré-sinápticos no núcleo accubens em modelo animal de esquizofrenia

Orientador : Prof. Dr. Claudio da CunhaTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia. Defesa: Curitiba, 22/01/2015Inclui referênciasResumo: A esquizofrenia é um transtorno mental tipicamente caracterizado pelo quadro psicótico representado por delírios e alucinações. Sua causa está associada ao aumento da dopamina (DA) mesolímbica e da expressão de receptores D2 estriatais, os quais constituem o principal alvo terapêutico do tratamento com antipsicóticos. Os antipsicóticos típicos são muito efetivos na redução dos sintomas psicóticos, porém apresentam efeitos amnésicos significativos que dificultam a adesão dos pacientes ao tratamento. Por esta razão, a compreensão dos mecanismos pelos quais os antipsicóticos típicos atuam na produção dos seus efeitos pode favorecer a descoberta de alvos terapêuticos mais efetivos no tratamento dessa doença. Nesta tese, investigamos o papel dos receptores dopaminérgicos D2 pré- e pós-sinápticos do DLS no aprendizado e memória de respostas condicionadas de esquiva (CAR); e o papel dos autoreceptores D2 na regulação da neurotransmissão dopaminérgica mesolímbica. A administração de uma dose pré- e pós-sináptica, mas não pré-sináptica, do antipsicótico típico sulpiride foi amnésica sobre CAR. Esse efeito foi revertido pela infusão intra-DLS do agonista D2 quimpirole em uma dose que não afetou o aprendizado e memória de CAR per se. Esses resultados mostram que o bloqueio de receptores D2 pós-sinápticos no DLS é necessário e suficiente para produzir os efeitos amnésicos dos antipsicóticos típicos. No segundo estudo, a técnica de amperometria de potencial fixo foi utilizada para evocar a liberação de DA no NAc para avaliar os mecanismos de inibição de liberação de DA e a dessensibilização de curto-prazo de autoreceptores D2 em um modelo animal de esquizofrenia. As doses sistêmicas pré- e pré- e pós-sináptica de sulpiride bloquearam a inibição da liberação de DA. A infusão intra-NAc de quimpirole não afetou a inibição de liberação de DA per se, mas reverteu o aumento da DA extracelular induzido por sulpiride. Por outro lado, a dessensibilização de curto-prazo induzida pelo aumento de DA eletricamente evocada não foi afetada por sulpiride ou quimpirole. Portanto, a ativação de autoreceptores D2 inibe a liberação de DA, mas não afeta a dessensibilização de curto-prazo desses receptores. Esses resultados auxiliam no entendimento de como antipsicóticos atuam nos receptores D2 pré e pós-sinápticos estriatais na produção dos seus efeitos terapêuticos e adversos.Abstract: Schizophrenia is a mental disorder typically characterized by psychotic symptoms such as delusions and hallucinations. Its etiology is associated to increased mesolimbic dopamine (DA) and striatal D2 receptors, which are the main target of antipsychotics treatment. Typical antipsychotics are effective in alleviate psychotic symptoms, but usually present amnestic side effects that difficult schizophrenic patients adherence to treatment. Hence, understanding how typical antipsychotics promote their effects may help discovery of new and more effective treatments. Here, we investigated the role of DLS pre- and postsynaptic D2 dopaminergic receptors in conditioned avoidance response (CAR) learning and memory; and the role of NAc presynaptic D2 receptors in the regulation of the mesolimbic dopaminergic neurotransmission. Systemic administration of pre- and postsynaptic, but not presynaptic, dose of the typical antipsychotic sulpiride was amnestic over CAR. Such effect was reverted by intra-DLS infusion of the D2 agonist quinpirole in a dose that did not affect CAR learning and memory per se. These results show that blockade of postsynaptic D2 receptors in the DLS is necessary and sufficient to produce the amnestic effect of typical antipsychotics. In the second study, fixed potential amperometry was used to electrically evoke DA release in the NAc to evaluate the mechanisms of DA release inhibition and D2 autoreceptors short-term desensitization in a schizophrenia animal model. Systemic presynaptic and pre- and postsynaptic doses of sulpiride blocked DA release inhibition. Intra-NAc quinpirole did not affect DA release inhibition per se, but reverted the increased extracellular DA induced by sulpiride. On the other hand, D2 autoreceptor short-term desensitization induced by electrically evoked DA was not affected by sulpiride or quinpirole. Therefore, activation of D2 autoreceptors regulates DA release from presynaptic terminals but does not induce short-term desensitization of D2 autoreceptors. Results presented in this thesis help understanding how antipsychotics act on pre- and postsynaptic striatal D2 receptors to yield their therapeutics and adverse effects

Both the dorsal hippocampus and the dorsolateral striatum are needed for rat navigation in the Morris water maze

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 hippocarnpus 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. (C) 2011 Elsevier B.V. All rights reserved.CNPqCNPqCAPESCAPESFundacao AraucariaFundacao AraucariaFAPESPFAPES

The role of the ventrolateral caudoputamen in predatory hunting

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. (C) 2011 Elsevier Inc. All rights reserved.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [05/59286-4]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq

The role of nucleus accumbens and dorsolateral striatal D2 receptors in active avoidance conditioning

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