Gabriela Acosta | Unne - Academia.edu (original) (raw)
Papers by Gabriela Acosta
General Pharmacology: The Vascular System, 1998
1. The effect of the intraperitoneal administration of cholecystokinin sulphated octapeptide (CCK... more 1. The effect of the intraperitoneal administration of cholecystokinin sulphated octapeptide (CCK-8S) (10 nmol/kg i.p.) on endogenous levels of several amino acids in five areas of the rat brain was analyzed. The olfactory bulb, hypothalamus, hippocampus, cerebral frontal cortex, and corpus striatum were evaluated. In addition, the effects of CCK-8S and PD 135,158 (1 mg/kg), a selective CCK(B) antagonist, on the performance of rats submitted to a dark/light transition test were also studied. 2. Upon administration of CCK-8S, the concentration of glutamate was reduced (27%) in the olfactory bulb. The same was observed when the levels of glycine (31%) or alanine (43%) were determined. No significant effects were produced by CCK-8S on cortical and hypothalamic levels. In the hippocampus, the concentration of both glutamate (27%) and taurine (29%) were reduced, whereas the levels of GABA in the striatum (29%) were increased. 3. After a single injection of CCK-8S, the time spent by the rats in the illuminated site of the dark/light transition test box, was not changed. On the contrary, the administration of PD 135,158 increased the time spent in the lighted compartment. 4. These results show that systemic administration of CCK-8S produced regional specific changes in brain amino acids, without producing any significant behavioral modification in the rat exposed to a dark/light box. In contrast, the selective CCKB receptor antagonist, PD 135,158, induces anxiolytic-like action in an animal model of anxiety.
Stress, 2015
Postnatal stress alters stress responses for life, with serious consequences on the central nervo... more Postnatal stress alters stress responses for life, with serious consequences on the central nervous system (CNS), involving glutamatergic neurotransmission and development of voluntary alcohol intake. Several drugs of abuse, including alcohol and cocaine, alter glutamate transport (GluT). Here, we evaluated effects of chronic postnatal stress (CPS) on alcohol intake and brain glutamate uptake and transporters in male adolescent Wistar rats. For CPS from postnatal day (PD) 7, pups were separated from their mothers and exposed to cold stress (4 °C) for 1 h daily for 20 days; controls remained with their mothers. Then they were exposed to either voluntary ethanol (6%) or dextrose (1%) intake for 7 days (5-7 rats per group), then killed. CPS: (1) increased voluntary ethanol intake, (2) did not affect body weight gain or produce signs of toxicity with alcohol exposure, (3) increased glutamate uptake by hippocampal synaptosomes in vitro and (4) reduced protein levels (Western measurements) in hippocampus and frontal cortex of glial glutamate transporter-1 (GLT-1) and excitatory amino-acid transporter-3 (EAAT-3) but increased glutamate aspartate transporter (GLAST) levels. We propose that CPS-induced decrements in GLT-1 and EAAT-3 expression levels are opposed by activation of a compensatory mechanism to prevent excitotoxicity. A greater role for GLAST in total glutamate uptake to prevent enlarged extracellular glutamate levels is inferred. Although CPS strongly increased intake of ethanol, this had little impact on effects of CPS on brain glutamate uptake or transporters. However, the impact of early life adverse events on glutamatergic neurotransmission may underlie increased alcohol consumption in adulthood.
Accumulation of [3H]L-serine in crude synaptosomal fractions freshly prepared from rat brain has ... more Accumulation of [3H]L-serine in crude synaptosomal fractions freshly prepared from rat brain has been found to be temperature-sensitive and to consist of both Na(+)-dependent and Na(+)-independent components. The accumulation of [3H]L-serine measured at submicromolar concentrations had a distinct substrate selectivity, different from the uptake of [3H]L-proline, [3H]L-glutamate and [3H]GABA. It was fully inhibited by L-glutamine, L-asparagine, L-cysteine, L-alanine, L-leucine, L-isoleucine, L-tyrosine, L-phenylalanine, L-threonine and by the synthetic marker for the large neutral amino acid transport systems 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid, but not influenced by beta-alanine, taurine, glycine nor was it inhibited by the marker for the A system, L-2-methylamino isobutyric acid. D-Serine at 1 mM concentration produced no significant inhibition of the accumulation of 10 nM [3H]L-serine. We conclude that L-serine uptake observed in the present study is mediated by at least two distinct transport systems: a Na(+)-dependent one of lower affinity (K(m) in mM range) and a Na(+)-independent system of higher affinity (K(m) approximately 20-100 micro M). Characteristics of [3H]L-serine accumulation displayed at low substrate concentrations suggest that it was mediated neither by the typical 'A', nor by the 'large neutral', amino acid transport systems but predominantly by transporters belonging to the recently identified LAT (L-amino acid transporter) family.
Vertex (Buenos Aires, Argentina)
Although several hypothesis and theories have been advanced as explanations for the functions of ... more Although several hypothesis and theories have been advanced as explanations for the functions of sleep, a unified theory of sleep function remains elusive. Sleep has been implicated in the plastic cerebral changes that underlie learning and memory, in particular those related to memory consolidation of recently acquired new information. Despite steady accumulations of positive findings over the last ten years, the precise role of sleep in memory and brain plasticity is unproven at all. This situation might be solved by more integrated approaches that combine behavioral and neurophysiological measurements in well described in vivo models of neuronal activity and brain plasticity.
General Pharmacology: The Vascular System, 1992
1 The function of the gamma-ammobutync acid (GABA)-erglc system m certain areas of the rat brain ... more 1 The function of the gamma-ammobutync acid (GABA)-erglc system m certain areas of the rat brain was investigated after chrome chemical stress (exposure to ether vapours 30 sec/day for 20 days) 2 GABA concentrauon, [3H]-GABA uptake and the acUwty of the synthesis enzyme glutamate decarhoxylase (GAD) were measured 3 Chromc stress (a) reduced neuronal uptake of [3H]-GABA m the frontal cerebral cortex (43%) and increased non-neuronal uptake of [3H]-GABA m the hypothalamus (62%), (b) enhanced the activity of GAD (under subsaturatmg substrate concentraUon) m the frontal cortex (91%) and m the corpus smatum (69%); (c) did not modify GABA endogenous concentratson; (d) did not affect the ammals' body weight increase or produce any s~gns of toxicity 4 The stlmulat~on of GAD and reductton of [3H]-GABA neuronal uptake in the frontal cortex might suggest the stimulation of GABAerglc neurotransm~ss~on reduced by chromc stress m this area of the rat brain Together w~th previous findings the frontal cortex would appear to be a key area m chrome stress processing
General Pharmacology: The Vascular System, 1996
1. The in vitro effect of valproic acid (VA) (10 =6 to 10 -3 M) on glutamic acid decarboxytase (G... more 1. The in vitro effect of valproic acid (VA) (10 =6 to 10 -3 M) on glutamic acid decarboxytase (GAD) activity in whole brain and cerebral cortex (CC) of neonates and of adult rats was examined.
Journal of Neuroscience, 2007
Initially, memory is labile and requires consolidation to become stable. However, several studies... more Initially, memory is labile and requires consolidation to become stable. However, several studies support that consolidated memories can undergo a new period of lability after retrieval. The mechanistic differences of this process, termed reconsolidation, with the consolidation process are under debate, including the participation of hippocampus. Up to this point, few reports describe molecular changes and, in particular, transcription factor (TF) involvement in memory restabilization. Increasing evidence supports the participation of the TF nuclear factor-B (NF-B) in memory consolidation. Here, we demonstrate that the inhibition of NF-B after memory reactivation impairs retention of a hippocampal-dependent inhibitory avoidance task in mice. We used two independent disruptive strategies to reach this conclusion. First, we administered intracerebroventricular or intrahippocampal sulfasalazine, an inhibitor of IKK (IB kinase), the kinase that activates NF-B. Second, we infused intracerebroventricular or intrahippocampal B decoy, a direct inhibitor of NF-B consisting of a double-stranded DNA oligonucleotide that contains the B consensus sequence. When injected immediately after memory retrieval, sulfasalazine or B decoy (Decoy) impaired long-term retention. In contrast, a one base mutated B decoy (mDecoy) had no effect. Furthermore, we also found NF-B activation in the hippocampus, with a peak 15 min after memory retrieval. This activation was earlier than that found during consolidation. Together, these results indicate that NF-B is an important transcriptional regulator in memory consolidation and reconsolidation in hippocampus, although the temporal kinetics of activation differs between the two processes.
PLoS ONE, 2013
We have previously shown marked upregulation of the mRNA and corresponding protein for the cellul... more We have previously shown marked upregulation of the mRNA and corresponding protein for the cellular motor molecule myosin VI (Myo6) after an extremely traumatic stress experience, along with a delayed decrease in 5-bromo-29-deoxyuridine incorporation in the murine hippocampus, a brain structure believed to undergo adult neurogenesis. In this study, we investigated the role of Myo6 in both proliferation and differentiation in pluripotent P19 cells by using stable transfection and RNA interference techniques.
Pharmacology Biochemistry and Behavior, 2001
The pharmacological response to benzodiazepines has been demonstrated to be different in aged ind... more The pharmacological response to benzodiazepines has been demonstrated to be different in aged individuals in comparison to adults. We studied the age-dependent changes in some of the in vitro and behavioral effects of diazepam in aged (24 months old) rats, comparing them to adults (3 months old). We evaluated the in vitro gamma-aminobutyric acid (GABA)-induced 36Cl- uptake and the diazepam potentiation of GABA-stimulated 36Cl- uptake in microsacs from cerebral cortex of both groups of animals. We found no differences in the GABA-stimulated 36Cl- uptake between adult and aged animals, and diazepam failed to potentiate GABA-induced 36Cl- flux in the aged cortical microsacs. We also examined the effect of 0.03-10 mg of diazepam on locomotor activity in an open-field test and the anxiolytic-like action of diazepam in doses ranging from 0.03 to 1 in a dark-light transition test. We observed no anxiolytic-like action of the drug in the dark-light transition test in the aged rats, while there was a shift to the left in the diminution of locomotor activity evaluated by the open-field test. We conclude that the pharmacodynamic changes observed in cortical GABA(A) receptors in aged rats could partially explain the lack of anxiolytic-like action but not the oversedation evidenced in this group of animals.
Neuroscience Letters, 2004
Gabapentin (GBP), an anticonvulsant drug, 10 mg/kg, i.p., but not 100 mg/kg, i.p., enhanced reten... more Gabapentin (GBP), an anticonvulsant drug, 10 mg/kg, i.p., but not 100 mg/kg, i.p., enhanced retention of an inhibitory avoidance task when given 20 min after training, as indicated by retention performance 48 h later. The immediate post-training administration of pentylenetetrazol (PTZ, 45 mg/kg, i.p.) impaired retention performance. The amnesic effects of the convulsant drug PTZ were not influenced by GBP at any level of doses. However, GBP 100 mg/kg, but not 10 mg/kg, delayed the latency to first clonic body seizures and decreased the duration of convulsion induced by PTZ. The enhancing effect of GBP on retention was not prevented by the opiate receptor antagonist, naltrexone (0.01 mg/kg, i.p.), which completely prevented the impairment of retention caused by PTZ. Further, naltrexone did not modify the convulsions induced by PTZ. In mice pretreated with naltrexone and that received PTZ, the administration of GBP again, enhanced retention performance during the retention test. Since previous results indicate that the amnesic action of PTZ are due to an effect on memory retrieval, the present results provide additional pharmacological evidence suggesting that GBP influenced memory consolidation and not memory retrieval of an inhibitory avoidance task in mice.
Neuroscience Letters, 2012
Neuroscience Letters, 2001
Male CF-1 mice were tested 48 h after training on a one trial step-through inhibitory avoidance t... more Male CF-1 mice were tested 48 h after training on a one trial step-through inhibitory avoidance task. Immediately posttraining, intraperitoneal (i.p.) injections of the antiepileptic gabapentin (1-(aminomethyl) cyclohexaneacetic acid) (GBP, 10 mg/kg) enhanced retention performance. The effect was prevented by atropine, a central muscarinic cholinergic receptor antagonist (0.5 mg/kg, i.p.) administered after training but 10 min prior to GBP treatment. In contrast, neither methylatropine (0.5 mg/kg, i.p.), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training GBP on retention performance. Low subeffective doses of the central acting anticholinesterase physostigmine (35 mg/kg, i.p.) administered immediately after training, and GBP (5 mg/kg, i.p.), given 10 min after training, significantly enhanced retention performance. The effects of GBP (5 mg/kg, i.p.) were not influenced by the peripherally acting anticholinesterase neostigmine (150 mg/kg, i.p.). Considered together, these findings suggest a disinhibitory action of GBP on the activity of central muscarinic cholinergic mechanisms that are involved in memory consolidation. q
Neuroscience Letters, 2003
Immediate post-training intraperitoneal administration of the centrally acting anticholinesterase... more Immediate post-training intraperitoneal administration of the centrally acting anticholinesterase physostigmine (70.0, or 150.0 mg/kg) enhanced retention of male CF-1 mice tested 48 h after training in a one-trial step-through inhibitory avoidance task (0.8 mA, 50 Hz, 1 s footshock). The effect was observed in mice that received saline 30 min before the retention test; on the contrary, the pre-test administration of the centrally active muscarinic cholinergic antagonist, atropine (1.0 mg/kg, i.p.), but not methylatropine (1.0 mg/kg, i.p.), instead of saline, prevents the enhancement of retention induced by both doses of the anticholinesterase when given immediately after training. The high retention performance caused by post-training physostigmine was recovered following a second administration of the same doses of the drug, 10 min after the pre-test injections of atropine. Since, physostigmine do not influence memory retrieval when given prior to the retention test, and its post-training effects are not due to the induction of state-dependency, the recover of the high retention performance was probably due to a classical interaction between a muscarinic competitive antagonist and an indirect cholinergic agonist. Further, atropine probably does not modify the memory trace by erasing it, but by producing a poor retrieval. q
Neuroscience Letters, 1994
(1) This study shows the effects of bicuculline pretreatment on the GABAergic system in certain a... more (1) This study shows the effects of bicuculline pretreatment on the GABAergic system in certain areas of the rat brain after acute ether and cold stress. (2) The spontaneous locomotor activity was diminished by either ether stress or cold stress or bicuculline. (3) Acute ether stress enhanced GABA concentration in the hypothalamus (69%) and in the frontal cerebral cortex (26%). Bicuculline prevented the increase in GABA levels induced by ether stress in both areas. (4) Acute cold stress decreased GABA concentration in the corpus striatum (29%). Bicuculline prevented the decrease in GABA levels induced by cold stress. (5) It is concluded that there is a GABAA receptor involved in stress induced changes on endogenous GABA levels as well as on locomotor activity.
Neuroscience Letters, 1993
(1) The function of the gamma-aminobutyric acid (GABA)ergic system in certain areas of the rat br... more (1) The function of the gamma-aminobutyric acid (GABA)ergic system in certain areas of the rat brain was investigated after acute and chronic cold stress. (2) GABA concentration, [3H]GABA uptake and the activity of the synthesis enzyme glutamate decarboxylase (GAD) were measured. (3) Acute stress: (a) reduced GABA concentration in the corpus striatum (29%); (b) decreased GAD activity (under non-saturating substrate concentration) in the olfactory bulbs (24%); (c) diminished neuronal uptake of [3H]GABA in the frontal cerebral cortex (65%), hypothalamus (86%) and olfactory bulbs (82%). (4) Chronic stress: (a) reduced the endogenous levels of GABA in the frontal cerebral cortex (51%), hypothalamus (26%) and olfactory bulbs (15%); (b) decreased GAD activity in the corpus striatum (32%) and olfactory bulbs (34%); (c) decreased neuronal uptake of [3H]GABA in the hypothalamus (83%). (5) These findings suggest that compensatory changes may develop in the GABAergic system after chronic stress.
Neurochemical Research, 2009
The naturally occurring toxin rottlerin has been used by other laboratories as a specific inhibit... more The naturally occurring toxin rottlerin has been used by other laboratories as a specific inhibitor of protein kinase C-delta (PKC-d) to obtain evidence that the activitydependent distribution of glutamate transporter GLAST is regulated by PKC-d mediated phosphorylation. Using immunofluorescence labelling for GLAST and deconvolution microscopy we have observed that D-aspartate-
Neurochemical Research, 2010
It is well known that animals exposed to stressful stimuli during their early life develop differ... more It is well known that animals exposed to stressful stimuli during their early life develop different neurological disorders when they become adults. In this study, we evaluated the effect of acute cold stress on gamma-aminobutyric acid (GABA) and L-Serine (L-Ser) transporters in vitro, using the uptake of [(3)H]-GABA and [(3)H]L-Ser by synaptosomes-enriched fractions isolated from rat cerebral cortex during postnatal development. GABA and L-Ser uptake studies in vitro will be used in this investigation as a colateral evidence of changes in the expression of transporters of GABA and L-Ser. We observed that the maximum velocity (V (max)) in L-Ser and GABA uptake after stress session increased in all stages studied. In contrast, K (m) values of L-Ser uptake enhancent in almost age calculated, excluding at PD21 after cold stress during development, at the same time as K (m) (uptake affinity) values of GABA increased in just about age considered but not at PD5 compared with the control group. Finally we investigated the mechanism by which cells regulate the substrate affinity of L-Ser and GABA transporters. We demonstrated a significantly increase in total PKC activity to PD5 from PD21. Pretreatment with PKC inhibitor: staurosporine (SP) led to a restoration of control uptake in several postnatal-days suggesting a relationship between amino acids system and PKC activation. These findings suggest that a single exposure to postnatal cold stress at different periods after birth modifies both GABA and L-Ser transporters and the related increase in total PKC activity could be intracellular events that participate in neuronal plasticity by early life stress, which could be relevant to function of transporters in the adult rat brain.
Neurobiology of Learning and Memory, 2008
It is accepted that once consolidation is completed memory becomes permanent. However, it has als... more It is accepted that once consolidation is completed memory becomes permanent. However, it has also been suggested that reactivation (retrieval) of the original memory, again, makes it sensitive to the same treatments that affect memory consolidation when given after training. Previous results demonstrated that the immediate post-training intraperitoneal administration of N x -nitro-L-arginine methyl ester (L-NAME), a non-specific inhibitor of nitric oxide synthase (NOS), impairs retention test performance of a one-trial step-through inhibitory avoidance response in adult mice. The effect of L-NAME on retention was attributed to an action on memory consolidation of the original learning. For the first time, we report that the administration of L-NAME after the first retention test (memory reactivation) of the inhibitory avoidance response impairs retention performance over six consecutive days. This impairment effect is dose-and-time dependent and could not be attributed to a retrieval deficit since a mild footshock did not reinstate the original avoidance response and no spontaneous recovery was observed at least 21 days after training. Further support for a storage deficit interpretation as opposed to a retrieval deficit was obtained from the fact that L-NAME's effects after retrieval were not due to state-dependency. The impairment effect of L-NAME was dependent on the age of the original memory. That is, there was an inverse correlation between the susceptibility of the memory trace when reactivated and the time elapsed between training and the first retrieval session. We suggest an action of L-NAME on memory reactivation-induced processes that are different from memory extinction of the original learning extending the biological significance of nitric oxide on memory.
European Journal of Neuroscience, 2005
Although it is generally accepted that memory consolidation requires regulation of gene expressio... more Although it is generally accepted that memory consolidation requires regulation of gene expression, only a few transcription factors (TFs) have been clearly demonstrated to be specifically involved in this process. Increasing research data point to the participation of the Rel/nuclear factor-kappaB (NF-kappaB) family of TFs in memory and neural plasticity. Here we found that two independent inhibitors of NF-kappaB induced memory impairment in the one-trial step-through inhibitory avoidance paradigm in mice: post-training administration of the drug sulfasalazine and 2 h pretraining administration of a double-stranded DNA oligonucleotide containing the NF-kappaB consensus sequence (kappaB decoy). Conversely, one base mutation of the kappaB decoy (mut-kappaB decoy) injection did not affect long-term memory. Accordingly, the kappaB decoy inhibited NF-kappaB in hippocampus 2 h after injection but no inhibition was found with mut-kappaB decoy administration. A temporal course of hippocampal NF-kappaB activity after training was determined. Unexpectedly, an inhibition of NF-kappaB was found 15 min after training in shocked and unshocked groups when compared with the naïve group. Hippocampal NF-kappaB was activated 45 min after training in both shocked and unshocked groups, decreasing 1 h after training and returning to basal levels 2 and 4 h after training. On the basis of the latter results, we propose that activation of NF-kappaB in hippocampus is part of the molecular mechanism involved in the storage of contextual features that constitute the conditioned stimulus representation. The results presented here provide the first evidence to support NF-kappaB activity being regulated in hippocampus during consolidation, stressing the role of this TF as a conserved molecular mechanism for memory storage.
Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 2007
Postnatal development changes in mechanisms of synaptosomal amino acid transport have been studie... more Postnatal development changes in mechanisms of synaptosomal amino acid transport have been studied in rat cerebral cortex. Specific uptake of radiolabeled L-serine was examined and compared with that of radiolabeled GABA using synaptosomes-enriched fractions freshly prepared from cerebral cortex at different postnatal days from the birth to young adulthood. The preparations were incubated with 10 nM of [ 3 H]L-serine and 10 nM of [ 3 H]-GABA in either the presence or absence of NaCl, KCl or choline chloride, at 2 and 30°C, for different periods up to 30 min. The uptake of [ 3 H]L-serine was temperature dependent in synaptosomal fractions prepared from cerebral cortex of rats in postnatal days 5, 7, 13 and 21, but stronger dependence was observed in adult brain, irrespective of the presence of Na + , K + or choline ions. At all postnatal ages studied, [ 3 H]-GABA uptake showed a high activity in the presence of Na + ions and at 30°C. The values of K m were 90-489 μM in L-serine uptake. However, in the uptake of GABA the values of K m were 80-150 μM. The highest values of V max were obtained at 5 and 21 postnatal days for both transport systems. These results indicate that the uptake of L-serine and GABA are regulated differentially during postnatal development.
General Pharmacology: The Vascular System, 1998
1. The effect of the intraperitoneal administration of cholecystokinin sulphated octapeptide (CCK... more 1. The effect of the intraperitoneal administration of cholecystokinin sulphated octapeptide (CCK-8S) (10 nmol/kg i.p.) on endogenous levels of several amino acids in five areas of the rat brain was analyzed. The olfactory bulb, hypothalamus, hippocampus, cerebral frontal cortex, and corpus striatum were evaluated. In addition, the effects of CCK-8S and PD 135,158 (1 mg/kg), a selective CCK(B) antagonist, on the performance of rats submitted to a dark/light transition test were also studied. 2. Upon administration of CCK-8S, the concentration of glutamate was reduced (27%) in the olfactory bulb. The same was observed when the levels of glycine (31%) or alanine (43%) were determined. No significant effects were produced by CCK-8S on cortical and hypothalamic levels. In the hippocampus, the concentration of both glutamate (27%) and taurine (29%) were reduced, whereas the levels of GABA in the striatum (29%) were increased. 3. After a single injection of CCK-8S, the time spent by the rats in the illuminated site of the dark/light transition test box, was not changed. On the contrary, the administration of PD 135,158 increased the time spent in the lighted compartment. 4. These results show that systemic administration of CCK-8S produced regional specific changes in brain amino acids, without producing any significant behavioral modification in the rat exposed to a dark/light box. In contrast, the selective CCKB receptor antagonist, PD 135,158, induces anxiolytic-like action in an animal model of anxiety.
Stress, 2015
Postnatal stress alters stress responses for life, with serious consequences on the central nervo... more Postnatal stress alters stress responses for life, with serious consequences on the central nervous system (CNS), involving glutamatergic neurotransmission and development of voluntary alcohol intake. Several drugs of abuse, including alcohol and cocaine, alter glutamate transport (GluT). Here, we evaluated effects of chronic postnatal stress (CPS) on alcohol intake and brain glutamate uptake and transporters in male adolescent Wistar rats. For CPS from postnatal day (PD) 7, pups were separated from their mothers and exposed to cold stress (4 °C) for 1 h daily for 20 days; controls remained with their mothers. Then they were exposed to either voluntary ethanol (6%) or dextrose (1%) intake for 7 days (5-7 rats per group), then killed. CPS: (1) increased voluntary ethanol intake, (2) did not affect body weight gain or produce signs of toxicity with alcohol exposure, (3) increased glutamate uptake by hippocampal synaptosomes in vitro and (4) reduced protein levels (Western measurements) in hippocampus and frontal cortex of glial glutamate transporter-1 (GLT-1) and excitatory amino-acid transporter-3 (EAAT-3) but increased glutamate aspartate transporter (GLAST) levels. We propose that CPS-induced decrements in GLT-1 and EAAT-3 expression levels are opposed by activation of a compensatory mechanism to prevent excitotoxicity. A greater role for GLAST in total glutamate uptake to prevent enlarged extracellular glutamate levels is inferred. Although CPS strongly increased intake of ethanol, this had little impact on effects of CPS on brain glutamate uptake or transporters. However, the impact of early life adverse events on glutamatergic neurotransmission may underlie increased alcohol consumption in adulthood.
Accumulation of [3H]L-serine in crude synaptosomal fractions freshly prepared from rat brain has ... more Accumulation of [3H]L-serine in crude synaptosomal fractions freshly prepared from rat brain has been found to be temperature-sensitive and to consist of both Na(+)-dependent and Na(+)-independent components. The accumulation of [3H]L-serine measured at submicromolar concentrations had a distinct substrate selectivity, different from the uptake of [3H]L-proline, [3H]L-glutamate and [3H]GABA. It was fully inhibited by L-glutamine, L-asparagine, L-cysteine, L-alanine, L-leucine, L-isoleucine, L-tyrosine, L-phenylalanine, L-threonine and by the synthetic marker for the large neutral amino acid transport systems 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid, but not influenced by beta-alanine, taurine, glycine nor was it inhibited by the marker for the A system, L-2-methylamino isobutyric acid. D-Serine at 1 mM concentration produced no significant inhibition of the accumulation of 10 nM [3H]L-serine. We conclude that L-serine uptake observed in the present study is mediated by at least two distinct transport systems: a Na(+)-dependent one of lower affinity (K(m) in mM range) and a Na(+)-independent system of higher affinity (K(m) approximately 20-100 micro M). Characteristics of [3H]L-serine accumulation displayed at low substrate concentrations suggest that it was mediated neither by the typical 'A', nor by the 'large neutral', amino acid transport systems but predominantly by transporters belonging to the recently identified LAT (L-amino acid transporter) family.
Vertex (Buenos Aires, Argentina)
Although several hypothesis and theories have been advanced as explanations for the functions of ... more Although several hypothesis and theories have been advanced as explanations for the functions of sleep, a unified theory of sleep function remains elusive. Sleep has been implicated in the plastic cerebral changes that underlie learning and memory, in particular those related to memory consolidation of recently acquired new information. Despite steady accumulations of positive findings over the last ten years, the precise role of sleep in memory and brain plasticity is unproven at all. This situation might be solved by more integrated approaches that combine behavioral and neurophysiological measurements in well described in vivo models of neuronal activity and brain plasticity.
General Pharmacology: The Vascular System, 1992
1 The function of the gamma-ammobutync acid (GABA)-erglc system m certain areas of the rat brain ... more 1 The function of the gamma-ammobutync acid (GABA)-erglc system m certain areas of the rat brain was investigated after chrome chemical stress (exposure to ether vapours 30 sec/day for 20 days) 2 GABA concentrauon, [3H]-GABA uptake and the acUwty of the synthesis enzyme glutamate decarhoxylase (GAD) were measured 3 Chromc stress (a) reduced neuronal uptake of [3H]-GABA m the frontal cerebral cortex (43%) and increased non-neuronal uptake of [3H]-GABA m the hypothalamus (62%), (b) enhanced the activity of GAD (under subsaturatmg substrate concentraUon) m the frontal cortex (91%) and m the corpus smatum (69%); (c) did not modify GABA endogenous concentratson; (d) did not affect the ammals' body weight increase or produce any s~gns of toxicity 4 The stlmulat~on of GAD and reductton of [3H]-GABA neuronal uptake in the frontal cortex might suggest the stimulation of GABAerglc neurotransm~ss~on reduced by chromc stress m this area of the rat brain Together w~th previous findings the frontal cortex would appear to be a key area m chrome stress processing
General Pharmacology: The Vascular System, 1996
1. The in vitro effect of valproic acid (VA) (10 =6 to 10 -3 M) on glutamic acid decarboxytase (G... more 1. The in vitro effect of valproic acid (VA) (10 =6 to 10 -3 M) on glutamic acid decarboxytase (GAD) activity in whole brain and cerebral cortex (CC) of neonates and of adult rats was examined.
Journal of Neuroscience, 2007
Initially, memory is labile and requires consolidation to become stable. However, several studies... more Initially, memory is labile and requires consolidation to become stable. However, several studies support that consolidated memories can undergo a new period of lability after retrieval. The mechanistic differences of this process, termed reconsolidation, with the consolidation process are under debate, including the participation of hippocampus. Up to this point, few reports describe molecular changes and, in particular, transcription factor (TF) involvement in memory restabilization. Increasing evidence supports the participation of the TF nuclear factor-B (NF-B) in memory consolidation. Here, we demonstrate that the inhibition of NF-B after memory reactivation impairs retention of a hippocampal-dependent inhibitory avoidance task in mice. We used two independent disruptive strategies to reach this conclusion. First, we administered intracerebroventricular or intrahippocampal sulfasalazine, an inhibitor of IKK (IB kinase), the kinase that activates NF-B. Second, we infused intracerebroventricular or intrahippocampal B decoy, a direct inhibitor of NF-B consisting of a double-stranded DNA oligonucleotide that contains the B consensus sequence. When injected immediately after memory retrieval, sulfasalazine or B decoy (Decoy) impaired long-term retention. In contrast, a one base mutated B decoy (mDecoy) had no effect. Furthermore, we also found NF-B activation in the hippocampus, with a peak 15 min after memory retrieval. This activation was earlier than that found during consolidation. Together, these results indicate that NF-B is an important transcriptional regulator in memory consolidation and reconsolidation in hippocampus, although the temporal kinetics of activation differs between the two processes.
PLoS ONE, 2013
We have previously shown marked upregulation of the mRNA and corresponding protein for the cellul... more We have previously shown marked upregulation of the mRNA and corresponding protein for the cellular motor molecule myosin VI (Myo6) after an extremely traumatic stress experience, along with a delayed decrease in 5-bromo-29-deoxyuridine incorporation in the murine hippocampus, a brain structure believed to undergo adult neurogenesis. In this study, we investigated the role of Myo6 in both proliferation and differentiation in pluripotent P19 cells by using stable transfection and RNA interference techniques.
Pharmacology Biochemistry and Behavior, 2001
The pharmacological response to benzodiazepines has been demonstrated to be different in aged ind... more The pharmacological response to benzodiazepines has been demonstrated to be different in aged individuals in comparison to adults. We studied the age-dependent changes in some of the in vitro and behavioral effects of diazepam in aged (24 months old) rats, comparing them to adults (3 months old). We evaluated the in vitro gamma-aminobutyric acid (GABA)-induced 36Cl- uptake and the diazepam potentiation of GABA-stimulated 36Cl- uptake in microsacs from cerebral cortex of both groups of animals. We found no differences in the GABA-stimulated 36Cl- uptake between adult and aged animals, and diazepam failed to potentiate GABA-induced 36Cl- flux in the aged cortical microsacs. We also examined the effect of 0.03-10 mg of diazepam on locomotor activity in an open-field test and the anxiolytic-like action of diazepam in doses ranging from 0.03 to 1 in a dark-light transition test. We observed no anxiolytic-like action of the drug in the dark-light transition test in the aged rats, while there was a shift to the left in the diminution of locomotor activity evaluated by the open-field test. We conclude that the pharmacodynamic changes observed in cortical GABA(A) receptors in aged rats could partially explain the lack of anxiolytic-like action but not the oversedation evidenced in this group of animals.
Neuroscience Letters, 2004
Gabapentin (GBP), an anticonvulsant drug, 10 mg/kg, i.p., but not 100 mg/kg, i.p., enhanced reten... more Gabapentin (GBP), an anticonvulsant drug, 10 mg/kg, i.p., but not 100 mg/kg, i.p., enhanced retention of an inhibitory avoidance task when given 20 min after training, as indicated by retention performance 48 h later. The immediate post-training administration of pentylenetetrazol (PTZ, 45 mg/kg, i.p.) impaired retention performance. The amnesic effects of the convulsant drug PTZ were not influenced by GBP at any level of doses. However, GBP 100 mg/kg, but not 10 mg/kg, delayed the latency to first clonic body seizures and decreased the duration of convulsion induced by PTZ. The enhancing effect of GBP on retention was not prevented by the opiate receptor antagonist, naltrexone (0.01 mg/kg, i.p.), which completely prevented the impairment of retention caused by PTZ. Further, naltrexone did not modify the convulsions induced by PTZ. In mice pretreated with naltrexone and that received PTZ, the administration of GBP again, enhanced retention performance during the retention test. Since previous results indicate that the amnesic action of PTZ are due to an effect on memory retrieval, the present results provide additional pharmacological evidence suggesting that GBP influenced memory consolidation and not memory retrieval of an inhibitory avoidance task in mice.
Neuroscience Letters, 2012
Neuroscience Letters, 2001
Male CF-1 mice were tested 48 h after training on a one trial step-through inhibitory avoidance t... more Male CF-1 mice were tested 48 h after training on a one trial step-through inhibitory avoidance task. Immediately posttraining, intraperitoneal (i.p.) injections of the antiepileptic gabapentin (1-(aminomethyl) cyclohexaneacetic acid) (GBP, 10 mg/kg) enhanced retention performance. The effect was prevented by atropine, a central muscarinic cholinergic receptor antagonist (0.5 mg/kg, i.p.) administered after training but 10 min prior to GBP treatment. In contrast, neither methylatropine (0.5 mg/kg, i.p.), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training GBP on retention performance. Low subeffective doses of the central acting anticholinesterase physostigmine (35 mg/kg, i.p.) administered immediately after training, and GBP (5 mg/kg, i.p.), given 10 min after training, significantly enhanced retention performance. The effects of GBP (5 mg/kg, i.p.) were not influenced by the peripherally acting anticholinesterase neostigmine (150 mg/kg, i.p.). Considered together, these findings suggest a disinhibitory action of GBP on the activity of central muscarinic cholinergic mechanisms that are involved in memory consolidation. q
Neuroscience Letters, 2003
Immediate post-training intraperitoneal administration of the centrally acting anticholinesterase... more Immediate post-training intraperitoneal administration of the centrally acting anticholinesterase physostigmine (70.0, or 150.0 mg/kg) enhanced retention of male CF-1 mice tested 48 h after training in a one-trial step-through inhibitory avoidance task (0.8 mA, 50 Hz, 1 s footshock). The effect was observed in mice that received saline 30 min before the retention test; on the contrary, the pre-test administration of the centrally active muscarinic cholinergic antagonist, atropine (1.0 mg/kg, i.p.), but not methylatropine (1.0 mg/kg, i.p.), instead of saline, prevents the enhancement of retention induced by both doses of the anticholinesterase when given immediately after training. The high retention performance caused by post-training physostigmine was recovered following a second administration of the same doses of the drug, 10 min after the pre-test injections of atropine. Since, physostigmine do not influence memory retrieval when given prior to the retention test, and its post-training effects are not due to the induction of state-dependency, the recover of the high retention performance was probably due to a classical interaction between a muscarinic competitive antagonist and an indirect cholinergic agonist. Further, atropine probably does not modify the memory trace by erasing it, but by producing a poor retrieval. q
Neuroscience Letters, 1994
(1) This study shows the effects of bicuculline pretreatment on the GABAergic system in certain a... more (1) This study shows the effects of bicuculline pretreatment on the GABAergic system in certain areas of the rat brain after acute ether and cold stress. (2) The spontaneous locomotor activity was diminished by either ether stress or cold stress or bicuculline. (3) Acute ether stress enhanced GABA concentration in the hypothalamus (69%) and in the frontal cerebral cortex (26%). Bicuculline prevented the increase in GABA levels induced by ether stress in both areas. (4) Acute cold stress decreased GABA concentration in the corpus striatum (29%). Bicuculline prevented the decrease in GABA levels induced by cold stress. (5) It is concluded that there is a GABAA receptor involved in stress induced changes on endogenous GABA levels as well as on locomotor activity.
Neuroscience Letters, 1993
(1) The function of the gamma-aminobutyric acid (GABA)ergic system in certain areas of the rat br... more (1) The function of the gamma-aminobutyric acid (GABA)ergic system in certain areas of the rat brain was investigated after acute and chronic cold stress. (2) GABA concentration, [3H]GABA uptake and the activity of the synthesis enzyme glutamate decarboxylase (GAD) were measured. (3) Acute stress: (a) reduced GABA concentration in the corpus striatum (29%); (b) decreased GAD activity (under non-saturating substrate concentration) in the olfactory bulbs (24%); (c) diminished neuronal uptake of [3H]GABA in the frontal cerebral cortex (65%), hypothalamus (86%) and olfactory bulbs (82%). (4) Chronic stress: (a) reduced the endogenous levels of GABA in the frontal cerebral cortex (51%), hypothalamus (26%) and olfactory bulbs (15%); (b) decreased GAD activity in the corpus striatum (32%) and olfactory bulbs (34%); (c) decreased neuronal uptake of [3H]GABA in the hypothalamus (83%). (5) These findings suggest that compensatory changes may develop in the GABAergic system after chronic stress.
Neurochemical Research, 2009
The naturally occurring toxin rottlerin has been used by other laboratories as a specific inhibit... more The naturally occurring toxin rottlerin has been used by other laboratories as a specific inhibitor of protein kinase C-delta (PKC-d) to obtain evidence that the activitydependent distribution of glutamate transporter GLAST is regulated by PKC-d mediated phosphorylation. Using immunofluorescence labelling for GLAST and deconvolution microscopy we have observed that D-aspartate-
Neurochemical Research, 2010
It is well known that animals exposed to stressful stimuli during their early life develop differ... more It is well known that animals exposed to stressful stimuli during their early life develop different neurological disorders when they become adults. In this study, we evaluated the effect of acute cold stress on gamma-aminobutyric acid (GABA) and L-Serine (L-Ser) transporters in vitro, using the uptake of [(3)H]-GABA and [(3)H]L-Ser by synaptosomes-enriched fractions isolated from rat cerebral cortex during postnatal development. GABA and L-Ser uptake studies in vitro will be used in this investigation as a colateral evidence of changes in the expression of transporters of GABA and L-Ser. We observed that the maximum velocity (V (max)) in L-Ser and GABA uptake after stress session increased in all stages studied. In contrast, K (m) values of L-Ser uptake enhancent in almost age calculated, excluding at PD21 after cold stress during development, at the same time as K (m) (uptake affinity) values of GABA increased in just about age considered but not at PD5 compared with the control group. Finally we investigated the mechanism by which cells regulate the substrate affinity of L-Ser and GABA transporters. We demonstrated a significantly increase in total PKC activity to PD5 from PD21. Pretreatment with PKC inhibitor: staurosporine (SP) led to a restoration of control uptake in several postnatal-days suggesting a relationship between amino acids system and PKC activation. These findings suggest that a single exposure to postnatal cold stress at different periods after birth modifies both GABA and L-Ser transporters and the related increase in total PKC activity could be intracellular events that participate in neuronal plasticity by early life stress, which could be relevant to function of transporters in the adult rat brain.
Neurobiology of Learning and Memory, 2008
It is accepted that once consolidation is completed memory becomes permanent. However, it has als... more It is accepted that once consolidation is completed memory becomes permanent. However, it has also been suggested that reactivation (retrieval) of the original memory, again, makes it sensitive to the same treatments that affect memory consolidation when given after training. Previous results demonstrated that the immediate post-training intraperitoneal administration of N x -nitro-L-arginine methyl ester (L-NAME), a non-specific inhibitor of nitric oxide synthase (NOS), impairs retention test performance of a one-trial step-through inhibitory avoidance response in adult mice. The effect of L-NAME on retention was attributed to an action on memory consolidation of the original learning. For the first time, we report that the administration of L-NAME after the first retention test (memory reactivation) of the inhibitory avoidance response impairs retention performance over six consecutive days. This impairment effect is dose-and-time dependent and could not be attributed to a retrieval deficit since a mild footshock did not reinstate the original avoidance response and no spontaneous recovery was observed at least 21 days after training. Further support for a storage deficit interpretation as opposed to a retrieval deficit was obtained from the fact that L-NAME's effects after retrieval were not due to state-dependency. The impairment effect of L-NAME was dependent on the age of the original memory. That is, there was an inverse correlation between the susceptibility of the memory trace when reactivated and the time elapsed between training and the first retrieval session. We suggest an action of L-NAME on memory reactivation-induced processes that are different from memory extinction of the original learning extending the biological significance of nitric oxide on memory.
European Journal of Neuroscience, 2005
Although it is generally accepted that memory consolidation requires regulation of gene expressio... more Although it is generally accepted that memory consolidation requires regulation of gene expression, only a few transcription factors (TFs) have been clearly demonstrated to be specifically involved in this process. Increasing research data point to the participation of the Rel/nuclear factor-kappaB (NF-kappaB) family of TFs in memory and neural plasticity. Here we found that two independent inhibitors of NF-kappaB induced memory impairment in the one-trial step-through inhibitory avoidance paradigm in mice: post-training administration of the drug sulfasalazine and 2 h pretraining administration of a double-stranded DNA oligonucleotide containing the NF-kappaB consensus sequence (kappaB decoy). Conversely, one base mutation of the kappaB decoy (mut-kappaB decoy) injection did not affect long-term memory. Accordingly, the kappaB decoy inhibited NF-kappaB in hippocampus 2 h after injection but no inhibition was found with mut-kappaB decoy administration. A temporal course of hippocampal NF-kappaB activity after training was determined. Unexpectedly, an inhibition of NF-kappaB was found 15 min after training in shocked and unshocked groups when compared with the naïve group. Hippocampal NF-kappaB was activated 45 min after training in both shocked and unshocked groups, decreasing 1 h after training and returning to basal levels 2 and 4 h after training. On the basis of the latter results, we propose that activation of NF-kappaB in hippocampus is part of the molecular mechanism involved in the storage of contextual features that constitute the conditioned stimulus representation. The results presented here provide the first evidence to support NF-kappaB activity being regulated in hippocampus during consolidation, stressing the role of this TF as a conserved molecular mechanism for memory storage.
Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 2007
Postnatal development changes in mechanisms of synaptosomal amino acid transport have been studie... more Postnatal development changes in mechanisms of synaptosomal amino acid transport have been studied in rat cerebral cortex. Specific uptake of radiolabeled L-serine was examined and compared with that of radiolabeled GABA using synaptosomes-enriched fractions freshly prepared from cerebral cortex at different postnatal days from the birth to young adulthood. The preparations were incubated with 10 nM of [ 3 H]L-serine and 10 nM of [ 3 H]-GABA in either the presence or absence of NaCl, KCl or choline chloride, at 2 and 30°C, for different periods up to 30 min. The uptake of [ 3 H]L-serine was temperature dependent in synaptosomal fractions prepared from cerebral cortex of rats in postnatal days 5, 7, 13 and 21, but stronger dependence was observed in adult brain, irrespective of the presence of Na + , K + or choline ions. At all postnatal ages studied, [ 3 H]-GABA uptake showed a high activity in the presence of Na + ions and at 30°C. The values of K m were 90-489 μM in L-serine uptake. However, in the uptake of GABA the values of K m were 80-150 μM. The highest values of V max were obtained at 5 and 21 postnatal days for both transport systems. These results indicate that the uptake of L-serine and GABA are regulated differentially during postnatal development.