Are glutamate receptors specifically implicated in some forms of memory processes?

Convergent data indicate that certain substances that interact with N-methyl-d-aspartate (NMDA) receptors or metabotropic glutamate receptors (mGluRs) do not affect acquisition processes per se, or retrieval, but interfere specifically with the formation of memory traces. This action differs widely in its amplitude and time-course according to the learning task used. We showed that systemic injection of the competitive NMDA receptor antagonists, γ-l-glutamyl-l-aspartate (γ-LGLA) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), or intracerebroventricular infusion of d-2-amino-5-phosphonovalerate (D-AP5), immediately following acquisition of a Y-maze avoidance learning task in mice, deeply impaired retention of the temporal component of the task (leaving the start alley within the first 5 s of a trial), which significantly improved in controls during the hours following acquisition. In contrast the same substances had no or only slight effects on retention of the discrimination component (choice of the correct alley), which did not improve over time in control animals. This retention deficit did not appear to be due to an action on acquisition, retrieval and/or forgetting processes, or to state-dependent effects. Moreover, γ-LGLA, CPP or AP5, when administered immediately after partial acquisition of a food-reinforced bar-press task, suppressed the spontaneous improvement in post-training performance observed in control mice 24 h after the training session. (R,S)-α-methyl-4-carboxyphenylglycine (MCPG), an antagonist of mGluRs, also suppressed the post-training performance increment and its effects were antagonized by the co-administration of trans-ACPD, an agonist of mGluRs. Post-training improvement of performance over time is thought to reflect an active and dynamic process, leading to the organization of memory traces. According to this hypothesis, our results suggest that synaptic plasticity mediated by NMDA receptors and/or mGluRs activation is involved in mechanisms underlying long-term consolidation of memory traces.     

Reduced plastic brain responses to repetitive transcranial magnetic stimulation in severe obstructive sleep apnea syndrome

ObjectivesAbnormalities in cortical excitability have been proposed to underlie the pathophysiology of various neurocognitive manifestations of obstructive sleep apnea syndrome (OSAS). Transcranial magnetic stimulation (TMS) provides a noninvasive method for study and modulation of cortical excitability in the human brain, and repetitive TMS (rTMS) has been proven useful for neurophysiologic investigation in various neurologic conditions. We aimed to investigate cortical excitability in patients with OSAS during wakefulness and to determine if rTMS would change the abnormal excitability patterns.MethodsMeasures of motor cortical and corticospinal excitability (resting motor threshold [RMT], motor-evoked potential [MEP] amplitude, and cortical silent period [CSP]) were taken before and after a session of 10-Hz rTMS applied to the motor cortex in 13 individuals with untreated severe OSAS (apnea–hypopnea index [AHI] > 30) and 12 age- and sex-matched healthy controls (HC).ResultsOSAS subjects had a significantly higher RMT (P < .003) and a longer CSP duration (P < .002) compared to HC. No difference was observed between MEP values of OSAS subjects and HC (P > .05). In response to rTMS, the HC group had a significant increase in CSP and MEP values from baseline, which were absent in OSAS subjects.ConclusionsIndividuals with OSAS demonstrated increased motor cortex inhibition, which did not respond to 10-Hz rTMS. As rTMS-induced changes in MEP and CSP involve a separate neurotransmitter system (N-methyl-d-aspartate [NMDA] and gamma-aminobutyric acid [GABA], respectively), these findings suggest a widespread alteration in cortical neurophysiology in severe OSAS subjects that requires clarification with further exploration.     

Stochastic dynamics as a principle of brain function

The relatively random spiking times of individual neurons are a source of noise in the brain. We show that in a finite-sized cortical attractor network, this can be an advantage, for it leads to probabilistic behavior that is advantageous in decision-making, by preventing deadlock, and is important in signal detectability. We show how computations can be performed through stochastic dynamical effects, including the role of noise in enabling probabilistic jumping across barriers in the energy landscape describing the flow of the dynamics in attractor networks. The results obtained in neurophysiological studies of decision-making and signal detectability are modelled by the stochastical neurodynamics of integrate-and-fire networks of neurons with probabilistic neuronal spiking. We describe how these stochastic neurodynamical effects can be analyzed, and their importance in many aspects of brain function, including decision-making, memory recall, short-term memory, and attention.     

Comparison of the effects of calmidazolium, morphine and bupivacaine on N-methyl-d-aspartate- and septide-induced nociceptive behaviour

We have recently shown that spinal calmodulin inhibitors (W-7 and calmidazolium) dose-dependently inhibit the nociceptive reaction (biting, scratching, licking, BSL) evoked by intrathecal N-methyl-d-aspartate (NMDA) and septide, an agonist of the neurokinin (NK) NK₁ receptor. To compare this effect with that induced by standard analgesics, we now report a study of the effects of calmidazolium (14–420 nmol), bupivacaine (29–582 nmol) and morphine (26–260 nmol) when coadministered intrathecally with either NMDA (4 μg) or septide (0.5 μg). Calmidazolium had the highest potency for inhibiting septide-induced nociceptive behaviour, acting over a dose range of 34–130 nmol (dose eliciting a half-maximal response, ED₅₀, 67 nmol) lower than that of bupivacaine [ED₅₀ 234 (115–475) nmol]. Only the highest dose of morphine (260 nmol) inhibited septide-evoked BSL [ED₅₀=133 (69–255) nmol]. Higher doses of morphine could not be tested due to the appearance of an excitatory aversive reaction. Both calmidazolium [ED₅₀=232 (138–388) nmol] and bupivacaine [ED₅₀=123 (59–256) nmol] dose-dependently reduced NMDA-induced BSL reaching an almost maximal inhibition at the highest doses assayed (420 and 291 nmol, respectively). In contrast, morphine had less effect on NMDA-induced behaviour, inducing only a partial reduction of BSL even with the highest dose assayed (260 nmol). Overall, it can be concluded that the calmodulin inhibitor calmidazolium inhibits septide- and NMDA-evoked nociceptive behaviour with a potency and efficacy at least as high as those of morphine and bupivacaine. Received: 1 April 1998 / Accepted: 4 September 1998     

Blockade of inhibition in a pathway with dual excitatory and inhibitory action unmasks a capability for LTP that is otherwise not expressed

Long-term potentiation (LTP) can be readily elicited in a number of hippocampal pathways, but has not been seen in the dentate commissural pathway. The dentate commissural pathway is similar to the commissural/Schaffer collateral projection to CA1 except that it produces powerful inhibition that occurs nearly concurrently with the excitation. The present study evaluates whether this inhibition prevents the pathway from expressing LTP. Acute neurophysiological experiments were carried out in urethane anesthetized rats. To locally block inhibition in the dentate gyrus, a recording micropipette filled with 8 mM bicuculline was positioned in the dentate gyrus. A control saline-filled micropipette was positioned nearby. The commissural pathway was activated by stimulating electrodes in the contralateral CA3/CA4 region. Brief high-frequency stimulation of the commissural pathway reliably elicited LTP at the bicuculline electrode but not at the control electrode. This LTP required a threshold level of stimulation for its initiation, suggesting that like most other examples of LTP, the LTP in the commissural system depended upon activation of a voltage-dependent receptor. The high-frequency stimuli used to induce LTP produced an extracellular negativity at the bicuculline electrode that was not present at the control electrode. This negative potential was selectively blocked by ketamine and MK801, suggesting that the negative potential reflects N-methyl-D-aspartate (NMDA) receptor activation. Taken together, these results suggest that LTP is not normally expressed by the dentate commissural pathway because the simultaneous inhibition prevents the depolarization-related relief of Mg2+ blockade of the NMDA receptor.     

Density and distribution of NMDA receptors in the human hippocampus in Alzheimer''s disease

We examined the distribution and density of N-methyl-D-aspartate (NMDA) displaceable L-[3H]glutamate binding sites in human hippocampal samples obtained postmortem from Alzheimer's disease (AD) patients and from age-matched controls. Binding to NMDA receptors was stable for at least 72 h postmortem, and the pharmacological profile corresponded to that described using electrophysiology. NMDA receptors were concentrated in the terminal fields of major hippocampal pathways including the perforant path, Schaffer collaterals and the hippocampal output to the subiculum, all of which are proposed to use an excitatory amino acid transmitter. Little if any change in hippocampal receptor density was observed in AD patients compared to age-matched controls except in one case where major hippocampal cell loss occurred. The distribution of NMDA receptors did, however, correspond to the predilection for neuritic plaques and neurofibrillary tangles in hippocampal subfields.     

Late effects of a perinatal exposure to a 16 PAH mixture: Increase of anxiety-related behaviours and decrease of regional brain metabolism in adult male rats

Polycyclic Aromatic Hydrocarbons (PAHs) are ubiquitous pollutants originated from incomplete combustion processes. Ingestion of contaminated food is the main route of exposure for humans. These molecules are able to cross the placental barrier and are also found in breast milk. Since PAHs are neurotoxic agents, the potential adverse effects of a perinatal exposure of the developing brain is a key issue for public health especially concerning PAH mixture. In this study, female rats were exposed trough diet to a mixture of 16 PAHs, at doses of 2 μg/kg/day or 200 μg/kg/day during gestation and 1.5 μg/kg/day or 150 μg/kg/day during breast-feeding period. To assess late neurotoxic effects in male offsprings, behavioural and cognitive tests were carried out and histochemical analyses using cytochrome oxidase as a cerebral metabolism marker were performed on adult animals. Results showed that anxiety-related behaviours significantly increased in exposed animals, but there was no significant alteration of motor activity and learning and memory abilities. Several brain areas of the limbic system showed a neuronal hypometabolism in exposed animals. This work highlights that exposure to PAHs at early stages of brain development can cause later troubles on behaviour and that PAHs are able to partly alter the central nervous system metabolism on adulthood.     

SAT-1 -1415T/C polymorphism and susceptibility to schizophrenia

Patients suffering from psychosis show increased blood and fibroblast total polyamine levels. Spermidine/spermine N1-acetyltransferase (SSAT-1) and its coding gene (SAT-1) are the main factors regulating polyamine catabolism. The aim of the present study was to examine the association between the SAT-1 -1415T/C single nucleotide polymorphism (SNP) and schizophrenia. A case-control design was used in order to compare the genotypes for the SNP between schizophrenia patients (n = 180, 83 females and 97 males), other non-psychotic psychiatric patients (n = 413, 256 females and 157 males), and healthy controls (n = 251, 101 females and 150 males).     

Studies with ketamine and alfentanil following Freund's complete adjuvant-induced inflammation in rats

1. N-Methyl-D-aspartate (NMDA) receptor antagonists suppress inflammatory hyperalgesia and the development of acute opioid tolerance. They may also enhance opioid-induced antinociception, while suppressing postopioid-induced hyperalgesia and opioid-enhanced inflammatory hyperalgesia. 2. The non-competitive NMDA receptor antagonist, ketamine, is a racemic chiral drug; its individual enantiomers have differing affinities for the NMDA receptor. The anaesthetic and antinociceptive potencies of (S)-ketamine are 1.5- and threefold higher, respectively, than those of (R)-ketamine in laboratory rodents. 3. The present study investigated the effects of racemic ketamine and enantiopure (S)-ketamine on inflammatory hyperalgesia in rats, 5 days after intraplantar injection of Freund's complete adjuvant (FCA) into one hind paw. First, racemic or (S)-ketamine was administered alone; second, racemic or (S)-ketamine was administered 30 min after initiation of i.v. infusions of the micro-opioid agonist, alfentanil. 4. Area under the curve (AUC) values for Von Frey paw withdrawal threshold (PWT) versus time curves were significantly increased (P < 0.05) for both inflamed and non-inflamed hind paws by racemic and (S)-ketamine (5 & 10 mg/kg, s.c.). Similarly, AUC values for reduction of hind paw volume versus time were significantly increased (P < 0.05) by racemic and (S)-ketamine (10 mg/kg, s.c.). 5. Alfentanil infusions significantly increased PWT in both hind paws, but neither racemic nor (S)-ketamine (5 mg/kg, s.c.) administered 30 min after initiation of alfentanil infusion produced further increases in PWT. 6. Racemic and (S)-ketamine produced antinociceptive effects in both hind paws, but an antihyperalgesic effect per se was not apparent. Additionally, there was a possible anti-inflammatory effect of both drugs in the inflamed hind paw. These findings complement previous studies in which non-competitive NMDA receptor antagonists suppressed behavioural hyperalgesia. 7. However, racemic and (S)-ketamine did not further enhance alfentanil's antinociceptive effects, although they appeared to prolong alfentanil's antinociceptive effects in the non-inflamed hind paw. These findings suggest that factors such as time-course, frequency and the mode of administration of NMDA receptor antagonists, in addition to the type of antinociceptive model (i.e. inflammatory compared with acute) and the nociceptive testing procedure (i.e. noxious mechanical compared with low threshold stimuli) may influence their effects on opioid-induced antinociception.