RESUMO
Seeking of drugs is commonly evaluated in a specific environment for assessing drug preference. However, cognitive strategies involved in drug seeking are mostly unknown. To assess the strength of environmental cues that can be associated with nicotine in the zebrafish brain reward circuitry, we have designed herein a modified conditioned place preference (CPP) paradigm. This task was devised to identify salient environmental cues relevant for strong nicotine-environment association and drug seeking induction. During test sessions, background colors of the CPP tank chambers were shifted and preference for colors associated to nicotine was assessed. We have compared several tank designs and different compartment colors. Our findings indicated that zebrafish seeking behavior was strongly dependent on compartment color shades. Combination of red and yellow environments, which were preferred and avoided compartments, respectively, was the most effective design presenting the highest CPP-score. Interestingly, animals that stayed for longer periods in the environment conditioned to nicotine during a first testing interval were also able to follow the background color shade conditioned to nicotine to the other compartment immediately after background colors were relocated between compartments. During a second testing period, zebrafish also stayed for longer periods in the colored compartment paired to nicotine during conditioning. These findings suggest that under salient environmental conditions, zebrafish voluntarily followed a shifting visual cue previously associated with nicotine delivery. Furthermore, our findings indicate that zebrafish exhibit spatial associative learning and memory, which generates a repertoire of conspicuous locomotor behaviors induced by nicotine preference in the CPP task.
Assuntos
Nicotina , Peixe-Zebra , Animais , Condicionamento Clássico , Comportamento de Procura de Droga , Nicotina/farmacologia , RecompensaRESUMO
Sensitization of motor activity is a behavioural test to evaluate the effects of psychostimulants. Conditioned place preference (CPP) is an associative learning procedure to examine the rewarding properties of drugs. We aimed to assess whether motor sensitization to drugs of abuse can make zebrafish more vulnerable to establishing drug-induced CPP. We first evaluated sensitization of locomotor activity of zebrafish to repeated administrations of nicotine and cocaine during 5â¯days and after 5â¯days of withdrawal. After withdrawal, when zebrafish were re-exposed to the same dose of nicotine or cocaine locomotor activity was increased by 103% and 166%, respectively. Different groups of zebrafish were sensitized to nicotine or cocaine and trained on a nicotine-CPP task the day after withdrawal. The nicotine dose selected for sensitization was not effective for developing CPP in naïve zebrafish whereas it elicited CPP in zebrafish that were previously sensitized to nicotine or cocaine. Levels of nicotinic acetylcholine receptor ß2, α6 and α7 subunit, Pitx3, and tyrosine hydroxylase 1 (TH1) mRNAs were increased in the brain of nicotine- and cocaine-sensitized zebrafish. Nicotine-CPP performed with drug-sensitized zebrafish provoked further enhancements in the expression of α6 and α7 subunit, Pitx3, and TH1 mRNAs suggesting that the expression of these molecules in the reward pathway is involved in both processes. Our findings indicate that repeated exposures to low doses of drugs of abuse can increase subject's sensitivity to the rewarding properties of the same or different drugs. This further suggests that casual drug intake increases the probability of becoming addict.
Assuntos
Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Cocaína/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Nicotina/farmacologia , Receptores Nicotínicos/biossíntese , Peixe-Zebra , Animais , Encéfalo/metabolismo , Proteínas de Homeodomínio/biossíntese , Locomoção/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/biossíntese , Proteínas de Peixe-Zebra/biossínteseRESUMO
The rewarding properties of drugs in zebrafish can be studied using the conditioned place preference (CPP) paradigm. Most devices that have been used for CPP consist of two-half tanks with or without a central chamber. Here we evaluated the rewarding effects of nicotine and caffeine using a tank with five arms distributed radially from a central chamber that we have denoted Fish Tank Radial Maze (FTRM). Zebrafish were trained to associate nicotine or caffeine with a coloured arm. In testing sessions to assess CPP induction, between two and five different arms were available to explore. We found that when offering the two arms, one of them associated to the drug mediating conditioning for 14â¯days, zebrafish showed nicotine-induced CPP but not caffeine-induced CPP. When zebrafish had the option to explore drug-paired arms together with new coloured arms as putative distractors, the nicotine-CPP strength was maintained for at least three days. The presence of novel environments induced caffeine-CPP, which was still positive after three days of testing sessions. Complementary behavioural data supported these findings. Nicotine-CPP was prevented by the histone deacetylase inhibitor phenylbutyrate administered during conditioning; however, there were no effects on caffeine-CPP. The specific acetylation of lysine 9 in histone 3 (H3-K9) was increased in nicotine-conditioned zebrafish brains. This study suggests that novel environmental cues facilitate drug-environment associations, and hence, the use of drugs of abuse.
Assuntos
Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Recompensa , Acetilação/efeitos dos fármacos , Animais , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Testes Neuropsicológicos , Fenilbutiratos/farmacologia , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Peixe-ZebraRESUMO
RATIONALE: Zebrafish have a sophisticated color- and shape-sensitive visual system, so we examined color cue-based novel object recognition in zebrafish. We evaluated preference in the absence or presence of drugs that affect attention and memory retention in rodents: nicotine and the histone deacetylase inhibitor (HDACi) phenylbutyrate (PhB). OBJECTIVES: The objective of this study was to evaluate whether nicotine and PhB affect innate preferences of zebrafish for familiar and novel objects after short- and long-retention intervals. METHODS: We developed modified object recognition (OR) tasks using neutral novel and familiar objects in different colors. We also tested objects which differed with respect to the exploratory behavior they elicited from naïve zebrafish. RESULTS: Zebrafish showed an innate preference for exploring red or green objects rather than yellow or blue objects. Zebrafish were better at discriminating color changes than changes in object shape or size. Nicotine significantly enhanced or changed short-term innate novel object preference whereas PhB had similar effects when preference was assessed 24 h after training. Analysis of other zebrafish behaviors corroborated these results. CONCLUSIONS: Zebrafish were innately reluctant or prone to explore colored novel objects, so drug effects on innate preference for objects can be evaluated changing the color of objects with a simple geometry. Zebrafish exhibited recognition memory for novel objects with similar innate significance. Interestingly, nicotine and PhB significantly modified innate object preference.
Assuntos
Comportamento Exploratório/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Fenilbutiratos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Masculino , Memória/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Tempo , Percepção Visual/efeitos dos fármacos , Peixe-ZebraRESUMO
In rats, iron deficiency produces an alteration in myelin formation. However, there is limited information on the effects of this condition on oligodendroglial cell (OLGc) proliferation and maturation. In the present study, we further analyzed the hypomyelination associated with iron deficiency by studying the dynamics of oligodendrogenesis. Rats were fed control (40 mg Fe/kg) or iron-deficient (4 mg Fe/kg) diets from gestation day 5 until postnatal day 3 (P3) or 11 (P11). OLGc proliferation, migration and differentiation were investigated before and after an intracranial injection of apotransferrin at 3 days of age (P3). The proliferating cell population was evaluated at P3. Iron-deficient (ID) animals showed an increase in the oligodendrocyte precursors cell (OPC) population in comparison with controls. The overall pattern of migration of cells labeled with BrdU was investigated at P11. Iron deficiency increased the amount of BrdU(+) cells in the corpus callosum (CC) and decreased OLGc maturation and myelin formation. Changes in nerve conduction were analyzed by measuring visual evoked potentials. Latency and amplitude were significantly disturbed in ID rats compared with controls. Both parameters were substantially normalized when animals were treated with a single intracranial injection of 350 ng apotransferrin (aTf). The current results give support to the idea that iron deficiency increases the number of proliferating and undifferentiated cells in the CC compared with the control. Treatment with aTf almost completely reverted the effects of iron deficiency, both changing the migration pattern and increasing the number of mature cells in the CC and myelin formation.
Assuntos
Apoproteínas/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/patologia , Deficiências de Ferro , Oligodendroglia/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Transferrina/uso terapêutico , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Apoproteínas/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Peso Corporal/fisiologia , Encéfalo , Bromodesoxiuridina/metabolismo , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/fisiopatologia , Eletroencefalografia/métodos , Potenciais Evocados Visuais/efeitos dos fármacos , Potenciais Evocados Visuais/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hematócrito/métodos , Proteína Básica da Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Oligodendroglia/fisiologia , Estimulação Luminosa/métodos , Gravidez , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ácidos Siálicos/metabolismo , Transferrina/metabolismoRESUMO
Ca2+/calmodulin-dependent protein kinase II (CAMK II) and one of its target, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), glutamate receptors have been shown to participate in both long-term potentiation (LTP) in the hippocampus, and in spatial, as well as in a variety, of learning paradigms. Recently, we were able to demonstrate that the intrahippocampal infusion of a specific inhibitor of CAMK II (KN62) provoked full retrograde amnesia of an inhibitory avoidance learning in rats when given immediately, but not 120 or 240 min, after training. Furthermore, this task is accompanied by a rapid, selective and reversible increase in hippocampal [3H] AMPA receptor binding. Here we report the effect of this aversively motivated learning task on CAMK II activity, and AMPA GluR1 subunit phosphorylation and immunoreactivity in the hippocampus. One trial inhibitory avoidance training is associated with a learning-specific, time-dependent increase (25-78%) in both total and Ca2+-independent activities of CAMK II in the hippocampus of rats killed immediately (0 min), but not 120 min, after training. In addition, immunoblotting experiments showed an increment in the amount of the alpha-subunit of CAMK II at 0, 30 and 120 min after training. An increase in the in vitro phosphorylation of alpha- and beta-subunits of CAMK II was also observed in hippocampal synaptosomal membranes (SPM) of trained rats killed immediately and 30 min post-training. In addition, inhibitory avoidance is accompanied by a 20% increase in GluR1 phosphorylation and a 33% increase in GluR1 immunoreactivity 120 min after training. No significant changes were observed in shocked animals. Phosphorylation of hippocampal SPM from naive control animals in conditions suitable for CAMK II activation resulted in a large increase in the density of [3H] AMPA binding (+ 100%). Taken together, these findings confirm and extend previous data suggesting that CAMK II and AMPA glutamate receptors in the hippocampus participate in the early phase of memory formation of an inhibitory avoidance learning.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Hipocampo/metabolismo , Aprendizagem/fisiologia , Memória/fisiologia , Receptores de AMPA/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Dependentes de Cálcio-Calmodulina/fisiologia , Hipocampo/enzimologia , Immunoblotting , Potenciação de Longa Duração/fisiologia , Masculino , Fosforilação , Ratos , Ratos Wistar , Receptores de AMPA/fisiologia , Sinaptossomos/metabolismo , Fatores de Tempo , Trítio , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismoRESUMO
Training in step-down inhibitory avoidance (0.3-mA footshock) is followed by biochemical changes in rat hippocampus that strongly suggest an involvement of quantitative changes in glutamate AMPA receptors, followed by changes in the dopamine D1 receptor/cAMP/ protein kinase A (PKA)/CREB-P signalling pathway in memory consolidation. AMPA binding to its receptor and levels of the AMPA receptor-specific subunit GluR1 increase in the hippocampus within the first 3 h after training (20-70%). Binding of the specific D1 receptor ligand, SCH23390, and cAMP levels increase within 3 or 6 h after training (30-100%). PKA activity and CREB-P levels show two peaks: a 35-40% increase 0 h after training, and a second increase 3-6 h later (35-60%). The results correlate with pharmacological findings showing an early post-training involvement of AMPA receptors, and a late involvement of the D1/cAMP/PKA/CREB-P pathway in memory consolidation of this task.
Assuntos
Aprendizagem da Esquiva/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Hipocampo/química , Memória/fisiologia , Receptores de AMPA/fisiologia , Transdução de Sinais/fisiologia , Animais , Ratos , Receptores de Glutamato/fisiologiaRESUMO
Training in step-down inhibitory avoidance (0.3-mA footshock) is followed by biochemical changes in rat hippocampus that strongly suggest an involvement of quantitative changes in glutamate AMPA receptors, followed by changes in the dopamine D1 receptor/cAMP/protein kinase A (PKA)/CREB-P signalling pathway in memory consolidation. AMPA binding to its receptor and levels of the AMPA receptor-specific subunit GluR1 increase in the hippocampus within the first 3 h after training (20-70 per cent). Binding of the specific D1 receptor ligand, SCH23390, and cAMP levels increase within 3 or 6 h after training (30-100 per cent). PKA activity and CREB-P levels show two peaks: a 35-40 per cent increase 0 h after training, and a second increase 3-6 h later (35-60 per cent). The results correlate with pharmacological findings showing an early post-training involvement of AMPA receptors, and a late involvement of the D1/cAMP/PKA/CREB-P pathway in memory consolidation of this task.
Assuntos
Ratos , Animais , Aprendizagem da Esquiva/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Hipocampo/química , Memória/fisiologia , Receptores de AMPA/fisiologia , Transdução de Sinais/fisiologia , Receptores de Glutamato/fisiologiaRESUMO
Hippocampal cyclic GMP (cGMP) has been recently postulated to participate in an early phase of memory consolidation of an inhibitory avoidance learning in rats. Here we report on the effects of the intrahippocampal infusion of a soluble guanylyl cyclase inhibitor (LY 83583) in the consolidation of one-trial step-down inhibitory avoidance and on the effect of this task on hippocampal cGMP levels and cGMP-dependent protein kinase (PKG) activity. Bilateral intrahippocampal administration of LY 83583 (2.5 micrograms per side) caused full amnesia for inhibitory avoidance when given immediately (0 min) after training, but not 30 min post-training. Rats submitted to the inhibitory avoidance task showed a significant increase in both cGMP levels and in PKG activity in the hippocampus at 0 min after training. No changes were observed 30 min after training. These findings provide further evidence that the hippocampal cGMP/PKG cascade is involved in the early stages of memory formation of an inhibitory avoidance task in rats.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , GMP Cíclico/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Proteínas Quinases/metabolismo , Aminoquinolinas/farmacologia , Animais , Aprendizagem da Esquiva/fisiologia , Inibidores Enzimáticos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Proteínas Quinases/fisiologia , Ratos , Ratos WistarRESUMO
cAMP/cAMP-dependent protein kinase (PKA) signaling pathway has been recently proposed to participate in both the late phase of long term potentiation in the hippocampus and in the late, protein synthesis-dependent phase of memory formation. Here we report that a late memory consolidation phase of an inhibitory avoidance learning is regulated by an hippocampal cAMP signaling pathway that is activated, at least in part, by D1/D5 receptors. Bilateral infusion of SKF 38393 (7.5 microg/side), a D1/D5 receptor agonist, into the CA1 region of the dorsal hippocampus, enhanced retention of a step-down inhibitory avoidance when given 3 or 6 h, but not immediately (0 h) or 9 h, after training. In contrast, full retrograde amnesia was obtained when SCH 23390 (0.5 microg/side), a D1/D5 receptor antagonist, was infused into the hippocampus 3 or 6 h after training. Intrahippocampal infusion of 8Br-cAMP (1.25 microg/side), or forskolin (0.5 microg/side), an activator of adenylyl cyclase, enhanced memory when given 3 or 6 h after training. KT5720 (0.5 microg/side), a specific inhibitor of PKA, hindered memory consolidation when given immediately or 3 or 6 h posttraining. Rats submitted to the avoidance task showed learning-specific increases in hippocampal 3H-SCH 23390 binding and in the endogenous levels of cAMP 3 and 6 h after training. In addition, PKA activity and P-CREB (phosphorylated form of cAMP responsive element binding protein) immunoreactivity increased in the hippocampus immediately and 3 and 6 h after training. Together, these findings suggest that the late phase of memory consolidation of an inhibitory avoidance is modulated cAMP/PKA signaling pathways in the hippocampus.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Transdução de Sinais/fisiologia , Animais , Masculino , Ratos , Ratos WistarRESUMO
Several lines of evidence indicate that protein kinase C (PKC) is involved in long-term potentiation (LTP) and in certain forms of learning. Recently, we found a learning-specific, time-dependent increase in [3H]phorbol dibutyrate binding to membrane-associated PKC in the hippocampus of rats subjected to an inhibitory avoidance task. Here we confirm and extend this observation, describing that a one trial inhibitory avoidance learning was associated with rapid and specific increases in B-50/GAP-43 phosphorylation in vitro and in PKC activity in hippocampal synaptosomal membranes. The increased phosphorylation of B-50/GAP-43, was seen at 30 min (+35% relative to naive or shocked control groups), but not at 10 or 60 min after training. This learning-associated increase in the phosphorylation of B-50/GAP-43 is mainly due to an increase in the activity of PKC. This is based on three different sets of data: 1) PKC activity increased by 24% in hippocampal synaptosomal membranes of rats sacrificed 30 min after training; 2) B-50/GAP-43 immunoblots revealed no changes in the amount of this protein among the different experimental groups; 3) phosphorylation assays, performed in the presence of bovine purified PKC or in the presence of the selective PKC inhibitor CGP 41231, exhibited no differences in B-50/GAP-43 phosphorylation between naive and trained animals. In conclusion, these results support the contention that hippocampal PKC participates in the early neural events of memory formation of an aversively-motivated learning task.
Assuntos
Hipocampo/ultraestrutura , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteína Quinase C/metabolismo , Sinaptossomos/enzimologia , Animais , Aprendizagem da Esquiva/fisiologia , Bovinos , Inibidores Enzimáticos/farmacologia , Proteína GAP-43 , Membranas Intracelulares/enzimologia , Masculino , Fosforilação , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos WistarRESUMO
We have recently shown that inhibitory avoidance training produces a rapid, selective, and learning-specific increase in the number of 3H-AMPA glutamate receptors in several subfields of the dorsal hippocampal formation in the rat. In the present study we investigated the posttraining temporal course of this enhancement by quantitative autoradiography of 3H-AMPA binding. Confirming previous results, rats submitted to a step-down inhibitory avoidance paradigm showed a marked increase (50-90%) in hippocampal 3H-AMPA binding that peaked 2 h posttraining. In CA3 and dentate gyrus this increase persisted for at least 48 h following training. In contrast, 24 h after training the binding of 3H-AMPA in the CA1 subfield did not differ significantly from naive control values. In all hippocampal regions studied, the binding of 3H-AMPA at 168 h posttraining reached control values. No changes were observed in the shocked or free exploration groups in comparison with naive controls. The results suggest that hippocampal AMPA receptors undergo rapid and reversible changes after inhibitory avoidance learning and give further support to the hypothesis that changes in hippocampal AMPA receptors participate in the synaptic plasticity mediating certain forms of learning and memory.
Assuntos
Aprendizagem da Esquiva/fisiologia , Hipocampo/fisiologia , Inibição Neural/fisiologia , Receptores de AMPA/fisiologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo , Animais , Autorradiografia , Mapeamento Encefálico , Condicionamento Clássico/fisiologia , Potenciação de Longa Duração/fisiologia , Rememoração Mental/fisiologia , Ratos , Retenção Psicológica/fisiologiaRESUMO
Several lines of evidence indicate that protein kinase C (PKC) participates in long-term potentiation (LTP) and in certain forms of learning. Here we describe a rapid, specific and time-dependent increase in [3H]phorbol-12,13-dibutyrate ([3H]PDBu) binding to membrane-associated PKC in selected brain regions of rats submitted to an inhibitory avoidance task. A quantitative film autoradiographic method was used to determine the amount and distribution of membrane-bound PKC in rats sacrificed at various time intervals after training. At 0, 30 and 120 min following training there was a prominent increase (up to 200%) in the binding of [3H]PDBu throughout the hippocampus relative to naive, shocked or habituated control groups. No significant changes in [3H]PDBu binding in any brain region were found at 180 min after training. Similar training-specific increments in the binding of [3H]PDBu were observed in the frontal, parietal and entorhinal cerebral cortices, amygdala and cerebellum. The maximal effect was seen at 30 min in the CA2 region of the hippocampus (+200%) and at 30 and 120 min after training in the amygdala (+170%) in comparison to naive control values. No alterations in [3H]PDBu binding were found in the other brain regions studied. The present findings, together with previous data reporting a similar temporal course in the effects of intrahippocampal or intraamygdala infusion of specific PKC inhibitors on memory, suggest that PKC activation plays a role in the acquisition and consolidation of an inhibitory avoidance learning.
Assuntos
Aprendizagem da Esquiva/fisiologia , Encéfalo/enzimologia , Potenciação de Longa Duração , Dibutirato de 12,13-Forbol/metabolismo , Proteína Quinase C/metabolismo , Análise de Variância , Animais , Autorradiografia , Estudos de Avaliação como Assunto , Hipocampo/metabolismo , Masculino , Ensaio Radioligante , Ratos , Ratos Wistar , Fatores de Tempo , TrítioRESUMO
Nitric oxide (NO), an unconventional neurotransmitter in the brain, has been postulated as a retrograde intercellular messenger necessary for the induction, but not the maintenance phase, of activity-dependent forms of synaptic plasticity in the hippocampus. Here we report on the effects of an inhibitory avoidance learning task on hippocampal NO synthase (NOS) activity and on the effects of intrahippocampal infusion of a NOS inhibitor in the acquisition and consolidation of this task in rats. NOS activity increases by 45% in the hippocampus immediately after training (0 min) but not at 60 min after training. No changes were observed in cerebellar NOS activity. The bilateral intrahippocampal microinjection of nitro-arginine (NO-arg), an NOS inhibitor, provoked retrograde amnesia for the inhibitory avoidance when given 10 min before or immediately after training, but not 60 min after training. These results suggest that NO-regulated processes in the hippocampus play an important role at the time of training or very shortly thereafter of an inhibitory avoidance learning.
Assuntos
Arginina/análogos & derivados , Aprendizagem da Esquiva/fisiologia , Inibidores Enzimáticos/farmacologia , Hipocampo/fisiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico/fisiologia , Animais , Arginina/farmacologia , Infusões Parenterais , Masculino , Microinjeções , Nitroarginina , Ratos , Ratos WistarRESUMO
The venom of some Dendroaspis snakes contains small proteins (7500 mol. wt) that inhibit the binding of radiolabelled muscarinic antagonist to brain synaptomal membranes. There were no peptides described among muscarinic ligands until Adem et al. (Biochim. biophys. Acta 968, 340-345, 1988) reported that muscarinic toxins (MTxs), MTx1 and 2 were able to inhibit 3H-QNB binding to rat brain membranes. Since MTxs inhibit around half of specific binding of 3H-quinuclidinyl benzilate (3H-QNB) and 3H-N-methyl-scopolamine (3H-NMS), which do not discriminate between subtypes of muscarinic receptors, it has been proposed that MTxs might selectively bind to some subtype. MTx1 and 2 from Dendroaspis angusticeps almost completely inhibit the binding of 3H-pirenzepine (3H-PZ), a preferential M1 muscarinic receptor subtype ligand to cerebral cortex synaptosomal membranes. A much higher concentration was needed to inhibit partially 3H-PZ binding to atrial muscarinic receptors. These results support the hypothesis that MTx1 and 2 may be M1 selective muscarinic ligands. Similar activities have been found in Dendroaspis polylepis and D. viridis venoms, but with lower affinities. The Ki obtained from inhibition curves of the binding of 3H-PZ showed that MTx1 has higher affinity for the putative M1 muscarinic receptor subtype, followed by MTx2. DpMTx has lower affinity, while DvMTx seems to have the lowest affinity. All these peptides are devoid of anticholinesterase activity. Dendrotoxin and fasciculin from D. angusticeps venom do not inhibit the binding of muscarinic radioligands to cerebral cortex membranes. The injection of MTxs into dorsal hippocampus of rats immediately after training in an inhibitory avoidance task improves memory consolidation, as does oxotremorine.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Venenos Elapídicos/toxicidade , Agonistas Muscarínicos/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Técnicas In Vitro , Cinética , Ligantes , Memória/efeitos dos fármacos , N-Metilescopolamina , Pirenzepina/farmacocinética , Ratos , Ratos Wistar , Receptores Colinérgicos/efeitos dos fármacos , Receptores Colinérgicos/metabolismo , Derivados da Escopolamina/metabolismo , Especificidade da Espécie , Técnicas Estereotáxicas , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
Carbon monoxide (CO), produced through the action of haem oxygenase (HO) isoenzymes, has been recently postulated as a retrograde messenger in the early stages of long-term potentiation (LTP). In the present study, rats submitted to an inhibitory avoidance task there is a significant increase (+76%) in hippocampal HO activity immediately after training (0 min), but not at 60 min post-training. No changes were observed in cerebral cortical and cerebellar HO activity. Bilateral intrahippocampal infusion of the HO inhibitor zinc-protoporphyrin-IX (ZnPP) (2 micrograms side-1) caused full amnesia for inhibitory avoidance when given 10 min before training or immediately after training, but not 60 min after training. These findings provide evidence that CO production in the hippocampus is important for the early stages of memory processing of an inhibitory avoidance training.
Assuntos
Aprendizagem da Esquiva , Monóxido de Carbono/farmacologia , Hipocampo/fisiologia , Animais , Heme Oxigenase (Desciclizante) , Potenciação de Longa Duração , Masculino , Ratos , Ratos Wistar , Fatores de Tempo , Zinco/farmacologiaRESUMO
Zinc protoporhyrin-9 (ZnPP) is an inhibitor of heme oxygenase, the enzyme involved in the biosynthesis of carbon monoxide (CO). CO regulates the activity of glutamatergic synapses and has been proposed to play a role in the early phases of long-term potentiation. The present paper reports on the effect of ZnPP on memory of inhibitory avoidance and of habituation to a novel environment. The bilateral infusion of ZnPP (2 micrograms/side) into the dorsal hippocampus caused amnesia for the inhibitory avoidance task when given before training or 0 or 30 min, but not 60 or 100 min, after training. The immediate post-training intrahippocampal infusion of ZnPP also caused amnesia for the habituation task. The immediate post-training intra-amygdala infusion of ZnPP had no effect on retention of the avoidance task. The data are consistent with the hypotheses that memory involves long-term potentiation initiated at the time of training in the hippocampus, and that hippocampal but not amygdala long-term potentiation may be regulated by CO.