RESUMO
The metabotropic glutamate receptors 5 (mGluRs5) within the Nucleus Accumbens (NAc) have been implicated in the modulation of psychostimulant reward. We hypothesized that blockade of mGluR5 within the NAc shell would impair cocaine conditioning in rats. For this study, animals were implanted with cannulae within the NAc shell, and separate groups were exposed to a multimodal environment within activity chambers that signaled cocaine (cocaine-paired) or saline (controls, cocaine-unpaired) injections. Prior to placing the animals in the chambers, rats received systemic intraperitoneal injections of saline or cocaine for 10 consecutive sessions. In the test session (D12), animals were exposed to the multimodal environment without any cocaine or saline pre-treatment. Before placing the rats in the chambers, separate groups of animals were infused within the NAc shell with 2.5, 12 or 25 nmol/0.5 µl/side of 2-methyl-6-(phenylethynyl) pyridine (MPEP), an antagonist of mGluR5 or with vehicle. Blockade of the mGluR5 subtype at a 2.5 nmol dose showed no significant difference in either the ambulatory distance (AD) or the vertical plane move time (VPT). In contrast, mGluR5 blockade at 12 nmol and 25 nmol decreased conditioned locomotion in the cocaine-paired groups. An association of the environmental cues with the effects of cocaine implies the involvement of memory process during the conditioning response. Our results suggest that mGluR5 within the NAc shell could be modulating the expression of memory related to the association of environmental cues with the effects of cocaine. We suggest that mGluR5 could be taking into account to further studies related with cocaine exposure and cocaine addiction treatments.
Assuntos
Cocaína/farmacologia , Condicionamento Operante , Núcleo Accumbens/efeitos dos fármacos , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Relação Dose-Resposta a Droga , Masculino , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidoresRESUMO
Nurr1 expression is up-regulated in the brain following associative learning experiences, but its relevance to cognitive processes remains unclear. In these studies, rats initially received bilateral hippocampal infusions of control or antisense oligodeoxynucleotides (ODNs) 1 h prior to training in a holeboard spatial discrimination task. Such pre-training infusions of nurr1 antisense ODNs caused a moderate effect in learning the task and also impaired LTM tested 7 d later. In a second experiment, ODN infusions were given immediately after the animals had received two sessions of training, during which all animals showed normal learning. Although antisense treated rats were significantly impaired during the post-infusion stages of acquisition of the task, no group differences were observed during the LTM test given 7 d later. These animals were subjected 3 d later to reversal training in the same maze in the absence of any additional treatments. Remarkably, rats previously treated with antisense ODNs displayed perseveration: The animals were fixated with the previously learned pattern of baited holes, causing them to be significantly impaired in the extinction of acquired spatial preferences and future learning. We postulate that Nurr1 function in the hippocampus is important for normal cognitive processes.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Aprendizagem por Discriminação/fisiologia , Comportamento Exploratório/fisiologia , Hipocampo/metabolismo , Comportamento Espacial/fisiologia , Fatores de Transcrição/metabolismo , Análise de Variância , Animais , Extinção Psicológica/fisiologia , Masculino , Memória/fisiologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Oligonucleotídeos Antissenso/metabolismo , Ratos , Ratos Long-Evans , Percepção Espacial/fisiologia , Estatísticas não ParamétricasRESUMO
The involvement of neurotensin (NT) within the nucleus accumbens core (NAC) in behavior has been sparsely investigated. Moreover, little is known of what role NT within the ventral striatum has on spatial learning. The present study investigated whether NT receptors in the NAC are implicated in learning of spatial information. Male Long-Evans rats were trained on a food search spatial learning task. Rats were microinfused with either NT antagonist SR 48692 (50 nM/0.5 =L) or saline in the NAC before each training session. Rats treated with SR 48692 made more reference and working memory errors during the acquisition of spatial learning than did rats infused with saline. These results suggest that NT receptors contribute to NAC-mediated spatial learning.
Assuntos
Comportamento Apetitivo/efeitos dos fármacos , Neurotensina/antagonistas & inibidores , Núcleo Accumbens/efeitos dos fármacos , Orientação/efeitos dos fármacos , Pirazóis/farmacologia , Quinolinas/farmacologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Long-Evans , Receptores de Neurotensina/antagonistas & inibidoresRESUMO
An environment previously associated with cocaine use can elicit cravings, even in the absence of the drug, which may be due to the formation of strong associations between the environment and the drug. These associations can result from motor learning and reinforcing effects of cocaine, and may be mediated in part by ionotropic glutamate receptors in the nucleus accumbens (N.Acc.). To determine whether NMDA receptor activity in the N.Acc. affects the expression of conditioned locomotion, rats were trained using an environment-elicited cocaine-conditioning paradigm. Rats trained to pair a cocaine injection with an environment showed an increased locomotor activity when tested in the drug-paired environment, whereas rats injected with cocaine in their home cages did not exhibit greater locomotion. Significantly greater locomotor activity occurred in trained animals that received an infusion of AP-5, a NMDA receptor antagonist, into the N.Acc. These results suggest that animals trained to associate environmental cues with cocaine become conditioned to this environment. Furthermore, our finding demonstrates that NMDA receptor activation within the N.Acc. modulates cocaine-induced conditioning.
Assuntos
2-Amino-5-fosfonovalerato/farmacologia , Cocaína/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Locomoção/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Lithium (Li+) is a drug used for the treatment of neuropsychiatric disorders, whereas Nuclear receptor-related factor 1 (Nurr1) has been implicated in normal and aberrant cognitive processes. Li+'s effects on cognition and Nurr1 expression were examined. Rats were exposed to Li+ in their diet for 4 weeks and only those reaching Li+ blood concentrations within the established clinically therapeutic range were used. Li+ decreased rearing activity in rats, but did not affect horizontal locomotion nor object recognition memory. In contrast, Li+ treated animals were significantly impaired in the initial, but not late, stages of acquisition of a hippocampal-dependent spatial discrimination task. In agreement with the behavioral results, chronic Li+ caused a significant downregulation of basal Nurr1 expression in several brain regions. In particular, a significant negative correlation between Li+ blood levels and Nurr1 expression was identified in the CA1 hippocampal subregion, but not in CA3, perirhinal cortex or the dorsal endopiriform nucleus. Upregulation of hippocampal Nurr1 levels to those of controls were observed in Li+ treated rats following training in the spatial task. Overall, the results suggest that the effects of Li+ on the brain may be particularly relevant to hippocampal-dependent cognitive processes involving Nurr1 expression.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Aprendizagem por Discriminação/efeitos dos fármacos , Carbonato de Lítio/administração & dosagem , Comportamento Espacial/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Animais , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Aprendizagem por Discriminação/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Masculino , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Ratos , Ratos Long-Evans , Comportamento Espacial/fisiologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genéticaRESUMO
The nucleus accumbens (NAcc) has been shown to play a role in motor and spatial learning. Protein kinase C (PKC) has been implicated in the mechanisms of initiation and maintenance of long-term potentiation that is thought to be involved in the storage of long-term memory. In the present study, the importance of de novo synthesis of PKC-gamma within the NAcc in the acquisition and retention of spatial discrimination learning was assessed using an antisense knockdown approach. Separate groups of Long-Evans rats were exposed to acute microinfusions (6microg/microl) of PKC-gamma antisense oligodeoxynucleotide (AS-ODN), control oligodeoxynucleotide (C-ODN) or vehicle into the NAcc at 24 and 3h before each training session. Behavioral findings showed that the blockade of NAcc-PKC-gamma translation caused impairments in the early phase of learning and retention of spatial information. Biochemical experiments showed that PKC-gamma expression was reduced and Ca(2+)/phospholipid-dependent protein kinase C (PKC) activity was blocked significantly in the AS-ODN-treated rats in comparison with control rats. The present findings suggest that NAcc-PKC-gamma plays a role during the early acquisition of spatial learning. Also, retention test results suggest that NAcc-PKC-gamma may be working as an intermediate factor involved in the onset of molecular mechanisms necessary for spatial memory consolidation within the NAcc.