Neuronal activity regulated pentraxin (narp) and GluA4 subunit of AMPA receptor may be targets for fluoxetine modulation.

Fluoxetine is the foremost prescribed antidepressant. Drugs acting on monoaminergic system may also regulate glutamatergic system. Indeed, the investigation of proteins associated with this system, such as Narp (neuronal activity-dependent pentraxin) and GluA4 subunit of AMPA receptor may reveal poorly explored modulations triggered by conventional antidepressants. This study aimed to uncover neurochemical mechanisms underlying the chronic fluoxetine treatment, mainly by evaluating these protein targets in the prefrontal cortex and in the hippocampus. Mice received a daily administration of fluoxetine (0.1, 1 or 10 mg/kg, p.o.) or potable water (vehicle group) for 21 days. These animals were submitted to the forced swim test (FST) to verify antidepressant-like responses and the open-field test (OFT) to assess locomotor activity. Modulation of signaling proteins was analyzed by western blot. Chronic treatment with fluoxetine (1 and 10 mg/kg) was effective, since it reduced the immobility time in the FST, without altering locomotor activity. Fluoxetine 10 mg/kg increased CREB phosphorylation and BDNF expression in the prefrontal cortex and hippocampus. Noteworthy, in the hippocampus fluoxetine also promoted Akt activation and augmented Narp expression. In the prefrontal cortex, a significant decrease in the expression of the GluA4 subunit and Narp were observed following fluoxetine administration (10 mg/kg). The results provide evidence of novel molecular targets potentially involved in the antidepressant effects of fluoxetine, since in mature rodents Narp and GluA4 are mainly expressed in the GABAergic parvalbumin-positive (PV+) interneurons. This may bring new insights into the molecular elements involved in the mechanisms underlying the antidepressant effects of fluoxetine.

Molecular Mechanisms Associated with the Benefits of Variable Practice in Motor Learning.

Variable practice promotes a higher level of motor learning than constant practice. The glutamate receptors, n-methyl-d-aspartate (NMDA) and alfa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA), have been associated with the changes in motor cortex that occur throughout the process of motor learning. Considering that, it is possible that variable practice is more associated with the NMDA and AMPA receptors than constant practice. This study aimed ao investigating the association between the glutamate receptors, NMDA and AMPA, and constant and variable practice schedules. Seventy-eight male mice practiced the rotarod task in a constant or variable scheduling, in two consecutive days (acquisition phase). Learning tests were performed 24 h and 10 days after the end of the acquisition phase. Variable practice was more associated with the NMDA receptor and had a greater AMPA receptor expression than constant practice. The results suggest that the benefits of variable practice are result of both the greater dependency on the NMDA receptor and the greater AMPA receptor expression.

Role of calcium-permeable AMPA receptors in memory consolidation, retrieval and updating.

The role of the calcium-permeable AMPA receptor (CP-AMPAR) in synaptic plasticity is well established. CP-AMPAR is believed to be recruited to synapse when the memory trace is in a plastic state; however, the direct implications of its expression for memory processes is less known. Here, we investigated the contribution of CP-AMPAR expressed in the basolateral amygdala (BLA) and hippocampus (HPC) in consolidation of different types of memory, retrieval and memory update. We showed that CP-AMPAR blockade by NASPM in the BLA and HPC impaired fear memory consolidation. NASPM infusion in the HPC also impaired spatial memory consolidation in the water maze, whereas consolidation of object location memory was not affected. We found evidence of the CP-AMPAR involvement in the BLA and in the HPC upon memory retrieval. Furthermore, memory update was affected by NASPM infusion in the HPC in both immediate shock deficit and water maze reversal learning tasks. Our data indicate that the activity of CP-AMPAR in the BLA and HPC is required for the consolidation of emotional memories. Moreover, this receptor activity is required for memory retrieval in the BLA and HPC. These findings support that CP-AMPAR has a key function in memory states in which plastic changes are presumably higher, such as the beginning of memory consolidation, and retrieval-induced updating.

BDNF and AMPA receptors in the cNTS modulate the hyperglycemic reflex after local carotid body NaCN stimulation.

The application of sodium cyanide (NaCN) to the carotid body receptors (CBR) (CBR stimulation) induces rapid blood hyperglycemia and an increase in brain glucose retention. The commissural nucleus tractus solitarius (cNTS) is an essential relay nucleus in this hyperglycemic reflex; it receives glutamatergic afferents (that also release brain derived neurotrophic factor, BDNF) from the nodose-petrosal ganglia that relays CBR information. Previous work showed that AMPA in NTS blocks hyperglycemia and brain glucose retention after CBR stimulation. In contrast, BDNF, which attenuates glutamatergic AMPA currents in NTS, enhances these glycemic responses. Here we investigated the combined effects of BDNF and AMPA (and their antagonists) in NTS on the glycemic responses to CBR stimulation. Microinjections of BDNF plus AMPA into the cNTS before CBR stimulation in anesthetized rats, induced blood hyperglycemia and an increase in brain arteriovenous (a-v) of blood glucose concentration difference, which we infer is due to increased brain glucose retention. By contrast, the microinjection of the TrkB antagonist K252a plus AMPA abolished the glycemic responses to CBR stimulation similar to what is observed after AMPA pretreatments. In BDNF plus AMPA microinjections preceding CBR stimulation, the number of c-fos immunoreactive cNTS neurons increased. In contrast, in the rats microinjected with K252a plus AMPA in NTS, before CBR stimulation, c-fos expression in cNTS decreased. The expression of AMPA receptors GluR2/3 did not change in any of the studied groups. These results indicate that BDNF in cNTS plays a key role in the modulation of the hyperglycemic reflex initiated by CBR stimulation.

Retrieval is not necessary to trigger reconsolidation of object recognition memory in the perirhinal cortex.

Memory retrieval has been considered as requisite to initiate memory reconsolidation; however, some studies indicate that blocking retrieval does not prevent memory from undergoing reconsolidation. Since N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in the perirhinal cortex have been involved in object recognition memory formation, the present study evaluated whether retrieval and reconsolidation are independent processes by manipulating these glutamate receptors. The results showed that AMPA receptor antagonist infusions in the perirhinal cortex blocked retrieval, but did not affect memory reconsolidation, although NMDA receptor antagonist infusions disrupted reconsolidation even if retrieval was blocked. Importantly, neither of these antagonists disrupted short-term memory. These data suggest that memory underwent reconsolidation even in the absence of retrieval.

Cross-sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens.

Repeated administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. Here we explore the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioral pharmacology, microdialysis measures of extracellular dopamine and glutamate, and Western blotting for GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR). A single exposure to restraint stress 3 weeks before testing revealed that enduring locomotor sensitization to cocaine was paralleled by an increase in extracellular dopamine in the core, but not the shell subcompartment, of the NAc. Wistar rats pre-exposed to acute stress showed increased basal levels of glutamate in the core, but the increase in glutamate by acute cocaine was blunted. The alterations in extracellular glutamate seem to be relevant, as blocking AMPAR by 6-cyano-7-nitroquinoxaline-2,3-dione microinjection into the core prevented both the behavioral cross-sensitization and the augmented increase in cocaine-induced extracellular dopamine. Further implicating glutamate, the locomotor response to AMPAR stimulation in the core was potentiated, but not in the shell of pre-stressed animals, and this was accompanied by an increase in NAc GluR1 surface expression. This study provides evidence that the long-term expression of restraint stress-induced behavioral cross-sensitization to cocaine recapitulates some mechanisms thought to underpin the sensitization induced by daily cocaine administration, and shows that long-term neurobiological changes induced in the NAc by acute stress are consequential in the expression of cross-sensitization to cocaine.

Taste aversion memory reconsolidation is independent of its retrieval.

Reconsolidation refers to the destabilization/re-stabilization memory process upon its activation. However, the conditions needed to undergo reconsolidation, as well as its functional significance is quite unclear and a matter of intense investigation. Even so, memory retrieval is held as requisite to initiate reconsolidation. Therefore, in the present work we examined whether transient pharmacological disruption of memory retrieval impedes reconsolidation of stored memory in the widely used associative conditioning task, taste aversion. We found that AMPA receptors inhibition in the amygdala impaired retrieval of taste aversion memory. Furthermore, AMPA receptors blockade impeded retrieval regardless of memory strength. However, inhibition of retrieval did not affect anisomycin-mediated disruption of reconsolidation. These results indicate that retrieval is a dispensable condition to undergo reconsolidation and provide evidence of molecular dissociation between retrieval and activation of memory in the non-declarative memory model taste aversion.

AMPA glutamate receptors mediate the antidepressant-like effects of N-acetylcysteine in the mouse tail suspension test.

The aim of this study was to investigate the involvement of noradrenaline, serotonin, and subtypes of glutamate receptors in the antidepressant-like effects of N-acetylcysteine (NAC). The tail suspension test was used with male CF1 albino mice. D,L-α-methyl-ρ-tyrosine and ρ-chlorophenylalanine methyl ester hydrochloride were used as synthesis inhibitors of noradrenaline and serotonin, respectively. N-methyl-D-aspartate (NMDA) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione were used as an NMDA receptor agonist and an α-amino acid-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) receptor antagonist, respectively. NAC (10, 25, and 50 mg/kg intraperitoneally) significantly (P<0.05) decreased tail suspension test immobility time, whereas pretreatment with D,L-α-methyl-ρ-tyrosine, ρ-chlorophenylalanine methyl ester hydrochloride, and NMDA partially prevented (P<0.05) the effects of NAC (25 mg/kg), and pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione completely abolished (P<0.01) this effect. The study corroborates the antidepressant-like effects of NAC in the TST, a model with a well-established predictive value. The results point to the key role of AMPA receptors in the mechanism of the antidepressant-like action of NAC. Like other AMPA potentiators, NAC indirectly modulates noradrenaline and serotonin pathways. It is suggested that the value of NAC as an antidepressant arises from combined and intertwined effects on a variety of pathways.

Involvement of AMPA/kainate-excitotoxicity in MK801-induced neuronal death in the retrosplenial cortex.

MK801 is a prototypical non-competitive NMDA receptor-antagonist that induces behavioural changes and reversible toxicity at low doses, while at higher doses triggers neuronal death that mainly affects the retrosplenial cortex (RSC) and to a lesser extent other structures such as the posterolateral cortical amygdaloid nucleus (PLCo). The mechanism of MK801-induced neurodegeneration remains poorly understood. In this study we analysed the participation of GABA-ergic and glutamatergic neurotransmission in MK801-induced neuronal death. We used a single i.p. injection of MK801 (2.5 mg/kg) that induced moderate neuronal death in the RSC and PLCo of female rats, and combined this treatment with the i.p., i.c.v., or intra-RSC infusion of drugs that are selective agonists or antagonists of the GABA-ergic or glutamatergic neurotransmission. We found that neuronal death in the RSC, but not the PLCo, was significantly reduced by the i.p. injection of thiopental, and the i.c.v. application of muscimol, both GABA-A agonists. MK801-toxicity in RSC was abrogated by intra-RSC infusion of muscimol, but the GABA antagonist picrotoxin had no effect. HPLC-analysis showed that levels of glutamate, but not GABA, in the RSC decreased after i.p. treatment with MK801. Intra-RSC infusion of MK801 did not enhance toxicity triggered by the i.p. injection of MK801, indicating that toxicity is not due to direct blockade of NMDA receptors in RSC neurons. MK801-toxicity in the RSC was abrogated by i.c.v. and intra-RSC infusions of the AMPA/kainate antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). Interestingly, i.c.v. application of neither muscimol or DNQX inhibited MK801-toxicity in the PLCo, suggesting that the mechanism of neuronal death in the RSC and the PLCo might be different. 1-naphthylacetyl spermine trihydrochloride (NASPM), which blocks Ca2+ permeable AMPA/kainate receptors, also reduced MK801-induced toxicity in the RSC. Intra-RSC infusion of AMPA or kainic acid alone promoted death of RSC neurons and was reminiscent of the degeneration induced by the i.p. treatment with MK801. Collectively, these experiments provide evidence for an AMPA/kainate-dependent mechanism of excitotoxicity in the death of RSC neurons after i.p. treatment with MK801.

Glutamate receptor antagonism in inferior colliculus attenuates elevated startle response of high anxiety diazepam-withdrawn rats.

Rats segregated according to low (LA) or high (HA) anxiety levels have been used as an important tool in the study of fear and anxiety. Since the efficacy of an anxiolytic compound is a function of the animal's basal anxiety level, it is possible that chronic treatment with a benzodiazepine (Bzp) affects LA and HA animals differently. Based on these assumptions, this study aimed to provide some additional information on the influence of acute, chronic (18 days) and withdrawal effects (48 h) from diazepam (10 mg/kg), in rats with LA or HA levels, on startle response amplitude. For this purpose, the elevated plus-maze (EPM) test was used. In addition, the role of glutamate receptors of the central nucleus of the inferior colliculus (cIC), the most important mesencephalic tectum integrative structure of the auditory pathways and a brain region that is linked to the processing of auditory information of aversive nature, was also evaluated. Our results showed that, contrary to the results obtained in LA rats, long-term treatment with diazepam promoted anxiolytic and aversive effects in HA animals that were tested under chronic effects or withdrawal from this drug, respectively. In addition, since Bzp withdrawal may function as an unconditioned stressor, the negative affective states observed in HA rats could be a by-product of GABA-glutamate imbalance in brain systems that modulate unconditioned fear and anxiety behaviors, since the blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors in the cIC clearly reduced the aversion promoted by diazepam withdrawal.

Aniracetam and DNQX affect the acquisition of rapid tolerance to ethanol in mice.

Several studies have emphasized the role of learning in the development of rapid tolerance and have shown that glutamate-mediated neurotransmission plays an important role in this phenomenon. Since the AMPA/kainate receptor system is directly involved in plasticity mechanisms, the influence of this receptor system on rapid tolerance induced by ethanol was studied using the rotarod. In the first experiment, mice were pretreated with aniracetam, an agonist of AMPA/kainate receptors, 30 min before ethanol (2.75 g/kg; IP) treatment, and tested on the rotarod. After 24 h, the groups were tested on the rotarod under ethanol treatment. Aniracetam facilitated the acquisition of rapid tolerance to ethanol. In the second experiment, mice received DNQX, a competitive antagonist of the AMPA receptor, 30 min before ethanol treatment (3 g/kg) and submitted to the rotarod. This dose of ethanol produced tolerance per se. Groups were tested under ethanol treatment (1.75 g/kg) after 24 h. DNQX blocked rapid tolerance to ethanol. Using a similar protocol, the third experiment showed that DNQX blocked the aniracetam-induced facilitation of rapid tolerance to ethanol. Our results show that aniracetam facilitates whereas DNQX blocks ethanol tolerance, suggesting that the non-NMDA receptors are involved in this phenomenon.

The microinjection of AMPA receptor antagonist into the accumbens shell failed to change food intake, but reduced fear-motivated behaviour in free-feeding female rats.

This study investigated the effect of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 2.5 and 5.0 nmol/side) microinjected into the core and shell sub-regions of the accumbens (Acb) nucleus, on food intake and the level of anxiety in female rats. Bilateral microinjections of CNQX (5.0 nmol/side) into the Acb shell (AP, +1.08 to +2.04), but not into the Acb core, induced an anxiolytic-like effect in relation to rats microinjected with vehicle, since the animals exhibited low level of SAP in the feeding test. The anxiolytic-like effect induced by 5.0 nmol CNQX microinjection into the Acb shell may not be ascribed to changes in the motor activity of the animals, because the frequency of locomotion, rearing and grooming remained unchanged after the drug microinjection. However, neither Acb shell nor Acb core CNQX microinjections were able to change the animals food intake along 1h feeding behaviour evaluation. Food intake remained unchanged 24h after the drug microinjections either into the Acb shell or into the Acb core. The data suggest that AMPA receptor blockade in the Acb nucleus may differentially change the ingestive and defensive behaviours in female rats.

Modulation of defensive responses and anxiety-like behaviors by group I metabotropic glutamate receptors located in the dorsolateral periaqueductal gray.

Glutamatergic neurotransmission in the dorsolateral periaqueductal gray (dlPAG) is related to defensive responses. However, the role of group I glutamate metabotropic receptors (mGluR) in these responses has been poorly investigated. The objective of the present study, therefore, was to test the hypothesis that interference with group I mGluR-mediated neurotransmission in dlPAG could modulate defensive responses. Male Wistar rats with cannulae aimed at the dlPAG were submitted to the following experiments: 1. intra dlPAG injections of vehicle (veh, 0.2 microL) or (RS)1-aminoindan-1,5-dicarboxylic acid (AIDA, 30-100 nmol, an mGluR1 receptor competitive antagonist) followed, 5 min later, by veh or trans-(+)-1-amino-1,3-ciclopentanedicarboxylic acid (tACPD, a group I and II mGluR agonist, 30 nmol); 2. intra-dlPAG injections of veh, AIDA (30 nmol) or 2-methyl-6-(phenylethynyl)-pyridine (MPEP, an mGluR5 receptor non-competitive antagonist, 50 nmol) followed by trans-azetidine-2,4-dicarboxylic acid (tADA, a group I mGluR agonist, 10 nmol); 3. and 4. intra-dlPAG injections of vehicle, AIDA (10-30 nmol) or MPEP (10-50 nmol) before the elevated plus maze (EPM) test; 5. intra-dlPAG injections of vehicle, AIDA (30 nmol) or MPEP (50 nmol) before the Vogel punished licking test. tACPD induced defensive responses characterized by jumps and an increased number of crossings in the observation box. These responses were attenuated by AIDA (30 nmol). tADA produced similar responses, although of lower intensity. tADA effects were prevented by AIDA and MPEP. Both drugs also produced anxiolytic-like effects in the EPM and Vogel tests when injected alone. The results suggest that group I metabotropic glutamate receptors in the dlPAG facilitate defensive responses and may also be involved in regulating anxiety-like behavior.

The microinjection of AMPA receptor antagonist into the accumbens shell, but not into the accumbens core, induces anxiolysis in an animal model of anxiety.

This study investigated the effect of the AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) microinjected into the core and shell sub-regions of the accumbens nucleus (Acb), on the level of fear/anxiety and emotional learning, in female rats submitted to the elevated plus-maze (EPM), an animal model of anxiety. Bilateral microinjections of DNQX (330 and 660 ng) into the Acb shell (AP, +1.08 to +2.16) induced an anxiolytic-like effect in relation to rats microinjected with vehicle, since there was an increased percentage of entries in the open arms of the maze. The 660 ng DNQX microinjection into the Acb shell also increased the percentage of entries into the open arms in relation to 660 ng DNQX microinjection into the Acb core. Prior DNQX microinjections in both core and shell sub-regions of the Acb failed to impair the emotional learning, since the animals exhibited an increase of the open arm avoidance on EPM Trial 2 in relation to EPM trial 1. DNQX microinjections into both sub-regions of the Acb did not change the number of entries into the enclosed arms, either in the EPM Trial 1 or in the EPM Trial 2, which indicates an absence of drug-induced locomotor impairment. Similarly, DNQX microinjections into both sub-regions of the Acb failed to alter the total arm entries, rearing, grooming and head-dipping frequency. The anxiolytic-like effect induced by DNQX suggests that the AMPA receptor in the Acb shell, but not in the Acb core, may underlie anxiety regulation in the EPM.

The reinstatement of amphetamine-induced place preference is long-lasting and related to decreased expression of AMPA receptors in the nucleus accumbens.

A great deal of effort has been devoted to elucidating the psychopharmacology underlying addiction and relapse. Long-term neuroadaptations in glutamate transmission seem to be of great relevance for relapse to stimulant abuse. In this study, we investigated amphetamine-induced conditioned place preference during adolescence and the reinstatement of the conditioned behavior following a priming injection of the drug 1 day (adolescence), 30 days (early adulthood) and 60 days (adulthood) after the extinction test. The nucleus accumbens was dissected immediately after the reinstatement test to examine alterations in GluR1 and NR1 subunits of glutamatergic receptors. Our results showed that a priming injection of amphetamine was able to reinstate the CPP 1 and 30 days after extinction. However, it failed to reinstate the conditioned response after 60 days. GluR1 levels were decreased on days 1 and 30 but not on day 60 while NR1 levels were unaltered in the reinstatement test. Using a relapse model we found that reinstatement of amphetamine-induced conditioning place preference during adolescence is long lasting and persists through early adulthood. Decreased levels of GluR1 in the nucleus accumbens might be related to the reinstatement of amphetamine-induced conditioning place preference.

The blockade of AMPA-kainate and NMDA receptors in the dorsal periaqueductal gray reduces the effects of diazepam withdrawal in rats.

It is well established that the most persistent sign of withdrawal from chronic benzodiazepine use in humans is anxiety. In contrast to other types of drugs of abuse, the emergence of this anxiety does not seem to be linked directly to alterations in the levels of dopamine in the mesolimbic system. Some studies have proposed that fear-like behaviors elicited by benzodiazepine withdrawal could be the result either of alterations in the sensitivity of GABAA receptors or in the neuronal hyperexcitability that results from neuroadaptative responses to chronic treatment, probably mediated by glutamate. The increased fear-like behaviors induced by benzodiazepine withdrawal are similar to the defense reaction displayed by animals exposed to dangerous situations or submitted to electrical or chemical stimulation of the dorsal periaqueductal gray (dPAG), a key structure of the brain aversive system. However, the involvement of the dPAG in drug abuse has been investigated only in the context of the physical effects of drug dependence. Thus, in this study we investigated the effects of injections into the dPAG of the glutamic acid diethyl ester (GDEE) and 2-amino-7-phosphonoheptanoate (AP-7) (AMPA-kainate and NMDA receptors antagonists, respectively) on fear-like behaviors promoted by benzodiazepine withdrawal in rats submitted to aversive events (foot-shocks) immediately before chronic diazepam administration in a conditioning place-preference paradigm, using a light-dark box. Our results showed that inhibition of the glutamatergic neurotransmission in the dPAG reduces the consequence of the diazepam withdrawal in rats, implicating the excitatory amino acids of the dPAG in the modulation of the aversive state induced by benzodiazepine drugs withdrawal.

Ingestive effects of NMDA and AMPA-kainate receptor antagonists microinjections into the lateral hypothalamus of the pigeon (Columba livia).

This study examined the ingestive and behavioral effects of NMDA- and AMPA/kainate glutamatergic receptor blockade in the lateral hypothalamic area (LHy) of free-feeding pigeons (Columba livia). Injections of MK-801 (NMDA receptor antagonist; 6 nmol) or CNQX (AMPA/kainate receptor antagonist; 25.8 nmol) into the LHy of free-feeding pigeons induced significant increases in food intake and in feeding duration, as well as reductions in the latency to start feeding. Duration, latency and volume of water intake, as well as duration of sleep-like behavior, alert immobility, locomotion and preening were not changed by these treatments in the LHy. These results indicate that glutamatergic inputs to cells containing NMDA and/or AMPA receptors located in the LHy could modify both the beginning of a feeding bout (or the end of a period of satiety) and its duration (satiation). Our data also suggest that these inhibitory glutamatergic influences on feeding behavior are tonically active in the LHy.

Glutamate modulators as novel interventions for mood disorders.

UNLABELLED: Recent evidence suggests that critical molecules in neurotrophic signaling cascades are long-term targets for currently available monoaminergic antidepressants. As chronic and severe mood disorders are characterized by impairments in neuronal resilience, pharmacological strategies that subserve a neuroprotective function might alter disorder pathophysiology and modify disease progression. Several promising approaches involve modulation of the glutamate neurotransmitter system, via post-synaptic receptor blockade or potentiation and presynaptic vesicular release inhibition. A focused review of the extant scientific literature was conducted, with a discussion of 3 compounds or classes of drugs currently undergoing clinical investigation: ketamine, riluzole, and AMPA receptor potentiators. Recent investigations in mood disordered patients suggest that the NMDA receptor antagonist ketamine might demonstrate rapid antidepressant properties. Riluzole has been shown to reverse glutamate-mediated impairments in neuronal plasticity and to stimulate the synthesis of brain derived neurotrophic factor. Open-label trials in treatment-resistant depression have yielded promising results. Likewise, AMPA receptor potentiators favorably impact neurotrophic factors as well as enhance cognition. CONCLUSIONS: Pharmacological approaches that modulate components of the glutamate system offer novel targets for severe, recurrent mood disorders. Controlled studies are necessary.

Glutamate modulators as novel interventions for mood disorders

Recentes evidências sugerem que as moléculas críticas nas cascatas de sinalizacão neurotrófica são alvos de longo prazo dos antidepressivos monoaminérgicos disponíveis atualmente. Na medida em que transtornos graves e crônicos são caracterizados por deficiências na resiliência neuronal, estratégias farmacológicas que sejam úteis para uma funcão neuroprotetora talvez possam alterar a fisiopatologia e modificar a progressão da doenca. Vários enfoques promissores envolvem a modulacão do sistema neurotransmissor do glutamato, via bloqueio ou potencializacão do receptor pós-sináptico e inibicão da liberacão vesicular pré-sináptica. Foi realizada uma revisão focada da literatura científica existente, com a discussão de três compostos ou classes de drogas que estão atualmente sob investigacão clínica: a ketamina, o riluzol e os potencializadores de receptores de AMPA. DISCUSSAO: Estudos recentes com pacientes com transtornos de humor sugerem que a ketamina, um antagonista do receptor NMDA, poderia ter demonstrado propriedades antidepressivas rápidas. O riluzol demonstrou reverter deficiências mediadas pelo glutamato na plasticidade neuronal e estimular a síntese de fatores neurotróficos derivados do cérebro. Ensaios abertos com depressão resistente ao tratamento produziram resultados promissores. Da mesma forma, os potencializadores de receptores de AMPA impactam favoravelmente os fatores neurotróficos, assim como melhoram a cognicão. CONCLUSÕES: Enfoques farmacológicos que modulam os componentes do sistema de glutamato oferecem novos alvos para transtornos de humor recorrentes e graves. São necessários estudos controlados.

Oral administration of guanosine impairs inhibitory avoidance performance in rats and mice.

Extracellular guanine-based purines, mainly the nucleoside guanosine, have recently been shown to exert neuroprotective effects, which seem to be related to antagonism of the glutamatergic system. In this study, we investigated the effects of acute oral administration of guanosine on inhibitory avoidance task in rats and mice. We also studied its effects on locomotor activity, anxiety-related behaviors and mechanisms of action involving the purinergic system. Guanosine (2.0 and 7.5mg/kg, per os), administered 75min pretraining, dose-dependently impaired retention of the inhibitory avoidance task in rats and mice, an effect not prevented by the adenosine receptor antagonist caffeine. Guanosine presented no effects on locomotor activity and anxiety-related behaviors. This amnesic effect of guanosine may be compatible with inhibition of glutamatergic system and seems to be not mediated by adenosine.