The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation.

Tianeptine is a clinically used antidepressant that has drawn much attention, because this compound challenges traditional monoaminergic hypotheses of depression. It is now acknowledged that the antidepressant actions of tianeptine, together with its remarkable clinical tolerance, can be attributed to its particular neurobiological properties. The involvement of glutamate in the mechanism of action of the antidepressant tianeptine is consistent with a well-developed preclinical literature demonstrating the key function of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression. This article reviews the latest evidence on tianeptine's mechanism of action with a focus on the glutamatergic system, which could provide a key pathway for its antidepressant action. Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders.

Exposing rats to a predator blocks primed burst potentiation in the hippocampus in vitro.

This study evaluated the effects of acute psychological stress (cat exposure) in adult male rats on electrophysiological plasticity subsequently assessed in the hippocampus in vitro. Two physiological models of memory were studied in CA1 in each recording session: (1) primed burst potentiation (PBP), a low-threshold form of plasticity produced by a total of five physiologically patterned pulses; and (2) long-term potentiation (LTP), a suprathreshold form of plasticity produced by a train of 100 pulses. Three groups of rats were studied: (1) undisturbed rats in their home cage (home cage); (2) rats placed in a chamber for 75 min (chamber); and (3) rats placed in a chamber for 75 min in close proximity to a cat (chamber/stress). At the end of the chamber exposure period, blood samples were obtained, and the hippocampus was prepared for in vitro recordings. Only the chamber/stress group had elevated (stress) levels of corticosterone. The major finding was that PBP, but not LTP, was blocked in the chamber/stress group. Thus, the psychological stress experienced by the rats in response to cat exposure resulted in an inhibition of plasticity, which was localized to the intrinsic circuitry of the hippocampus. This work provides novel observations on the effects of an ethologically relevant stressor on PBP in vitro and of the relative insensitivity of LTP to being modulated by psychological stress. We discuss the relevance of these electrophysiological findings to our behavioral work showing that predator stress impairs spatial memory.

Chronic psychosocial stress impairs learning and memory and increases sensitivity to yohimbine in adult rats.

BACKGROUND: It is well known that intense and prolonged stress can produce cognitive impairments and hippocampal damage and increase noradrenergic activity in humans. This study investigated the hypothesis that chronic psychosocial stress would affect behavior, drug sensitivity, and hippocampal-dependent learning and memory in rats. The work provides a novel connection between animal and human studies by evaluating the effects of stress on a rat's response to yohimbine, an alpha(2) adrenergic receptor antagonist. METHODS: Rats were exposed to a cat for 5 weeks and randomly housed with a different group of cohorts each day (psychosocial stress). The effects of the stress manipulations were then assessed on open field behavior, spatial learning and memory in the radial arm water maze and the behavioral response to a low dose of yohimbine (1.5 mg/kg). RESULTS: Stressed rats displayed impaired habituation to a novel environment, heightened anxiety, and increased sensitivity to yohimbine. In addition, the stressed rats exhibited impaired learning and memory. CONCLUSIONS: There are commonalities between the current findings on stressed rats and from studies on traumatized people. Thus, psychosocial stress manipulations in rats may yield insight into the basis of cognitive and neuroendocrine disturbances that commonly occur in people with anxiety disorders.

Correlation between cognitive deficits and Abeta deposits in transgenic APP+PS1 mice.

Doubly transgenic mAPP+mPS1 mice (15-16 months) had impaired cognitive function in a spatial learning and memory task that combined features of a water maze and a radial arm maze. Nontransgenic mice learned a new platform location each day during 4 consecutive acquisition trials, and exhibited memory for this location in a retention trial administered 30 min later. In contrast, transgenic mice were, on average, unable to improve their performance in finding the hidden platform over trials. The cognitive performance of individual mice within the transgenic group were inversely related to the amount of Abeta deposited in the frontal cortex and hippocampus. These findings imply that mAPP+mPS1 transgenic mice develop deficits in cognitive ability as Abeta deposits increase. These data argue that radial arm water maze testing of doubly transgenic mice may be a useful behavioral endpoint in evaluating the functional consequences of potential AD therapies, especially those designed to reduce Abeta load.

Simultaneous induction of long-term potentiation in the hippocampus and the amygdala by entorhinal cortex activation: mechanistic and temporal profiles.

The medial temporal lobe, including the entorhinal cortex, the amygdala and the hippocampus, has an important role in learning and memory, and its circuits exhibit synaptic plasticity (long-term potentiation [LTP]). The entorhinal cortex is positioned to exert a potent influence on the amygdala and the hippocampus given its extensive monosynaptic projections to both areas. We therefore studied the effects of activation of the entorhinal cortex with simultaneous recording of LTP in the hippocampus and amygdala in the anesthetized rat. theta Burst stimulation of the lateral entorhinal cortex induced LTP simultaneously in the basal amygdaloid nucleus and in the dentate gyrus. However, the mechanisms involved in the induction of LTP in the two areas differed. The N-methyl-D-aspartate receptor antagonist 3-[(+/-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid delivered 1 h before LTP induction (10 mg/kg, i.p.), blocked LTP in the dentate gyrus but not in the amygdala. In addition we found that the basal amygdala as well as the dentate gyrus sustained late-phase LTP (10 h) which may participate in memory encoding and/or modulation processes. Overall, the results suggest a coordinating role for the entorhinal cortex by simultaneously modulating activity and plasticity in these structures, albeit through different mechanisms. Interactive encoding of this sort is believed to endow memories with a different, more integrative, quality than when either pathway is activated alone.

Role of context in the expression of learning-induced plasticity of single neurons in auditory cortex.

Classical conditioning produces frequency-specific plasticity of receptive fields (RFs) of single neurons in cat auditory cortex (Diamond & Weinberger, 1986). In this article we show that although plasticity may be observed during both training trials and determination of RFs, it is usually expressed in a qualitatively different form (e.g., decreased response during conditioning vs. increased response to this same conditioned stimulus in the postconditioning RF). This differential expression of learning-induced plasticity provides evidence for a role of context in neurophysiological mechanisms of learning in auditory cortex. A model of cortical neurons functioning within a mosaic of influences is presented. The Functional Mosaic model views the induction and expression of plasticity as separate processes.

Physiological plasticity of single neurons in auditory cortex of the cat during acquisition of the pupillary conditioned response: II. Secondary field (AII).

The discharges of 22 single neurons were recorded in the secondary auditory cortical field (AII) during acquisition of the pupillary dilation conditioned defensive response in chronically prepared cats. All 22 neurons developed discharge plasticity in background activity, and 21/22 cells developed plasticity in their responses to the acoustic conditioned stimulus (CS). Nonassociative factors were ruled out by the use of a sensitization phase (CS and US [unconditioned stimulus] unpaired) preceding the conditioning phase and by ensuring stimulus constancy at the periphery by neuromuscular paralysis. Changes in background neuronal activity were related to measures of behavioral learning or to changes in the level of arousal. Specifically, decreases in background activity (17/22 cells) developed at the time that subjects began to display conditioned responses. Increases in background activity (5/22) developed in animals that became more tonically aroused during conditioning. However, both increases (11/22) and decreases (10/22) in evoked activity developed independently of the rate of pupillary learning, tonic arousal level, or changes in background activity. These findings indicate that changes in background activity are closely related to behavioral processes of learning and arousal whereas stimulus-evoked discharge plasticity develops solely as a consequence of stimulus pairing. A comparative analysis of the effects of conditioning on secondary and primary (AI) auditory cortex indicates that both regions develop neuronal discharge plasticity early in the conditioning phase and that increases in background activity in primary auditory cortex are also associated with elevated levels of tonic arousal. In addition, the overall incidence of single neurons developing learning-related discharge plasticity is significantly greater in AII than in AI. The relevance of these findings is discussed in terms of parallel processing in sensory systems and multiple sensory cortical fields.

Physiological plasticity of single neurons in auditory cortex of the cat during acquisition of the pupillary conditioned response: I. Primary field (AI).

The effects of conditioning on the discharges of single neurons in primary auditory cortex (AI) were determined during acquisition of the pupillary conditioned response in chronically prepared cats. Acoustic stimuli (1-s white noise or tone) were presented with electrodermal stimulation unpaired during a sensitization control phase followed by pairing during a subsequent conditioning phase. Stimulus constancy at the periphery was ensured by the use of neuromuscular blockade. Discharge plasticity developed rapidly for both evoked and background activity, the former attaining criterion faster than the latter. The pupillary dilation conditioned response was acquired at the same rate as were changes in evoked activity (i.e., 10-15 trials) and faster than background activity (i.e., 20-25 trials). Increases in background activity were correlated with increasing level of tonic arousal, as indexed by pretrial size of the pupil.

Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function.

Stress blocks hippocampal primed-burst potentiation, a low threshold form of long-term potentiation, thereby suggesting that stress should also impair hippocampal-dependent memory. Therefore, the effects of stress on working (hippocampal-dependent) and reference (hippocampal-independent) memory were evaluated. Rats foraged for food in seven arms of a 14-arm radial maze. After they ate the food in four of the seven baited arms, they were placed in an unfamiliar environment (stress) for a 4-hr delay. At the end of the delay they were returned to the maze to locate the food in the 3 remaining baited arms. Stress impaired only working memory. Stress interfered with the retrieval of previously stored information (retrograde amnesia), but did not produce anterograde amnesia. Stress appears to induce a transient disruption of hippocampal function, which is revealed behaviorally as retrograde amnesia and physiologically as a blockade of synaptic plasticity.

Short-term beta-amyloid vaccinations do not improve cognitive performance in cognitively impaired APP + PS1 mice.

Prior work demonstrated that beta-amyloid (A beta) immunotherapy for 8 months prevented cognitive impairment in 16-month-old APP + PS1 transgenic mice. In the present study, 4 immunizations administered biweekly to cognitively impaired 16-month-old transgenic mice could not reverse deficits in working memory or reference memory in the radial arm water maze or in visual platform recognition, possibly because of inadequate antibody exposure. Nontransgenic mice showed cognitive savings between the 16- and 18-month test periods, but the transgenic groups did not. These results suggest that a longer period of active immunotherapy, or passive immunization, may be required to provide sufficient antibody titers to improve cognition in older transgenic mice. A beta-based immunotherapy for Alzheimer's disease will likely be more successful prophylactically than therapeutically.

Behavioral assessment of Alzheimer's transgenic mice following long-term Abeta vaccination: task specificity and correlations between Abeta deposition and spatial memory.

Long-term vaccinations with human beta-amyloid peptide 1-42 (Abeta1-42) have recently been shown to prevent or markedly reduce Abeta deposition in the PDAPP transgenic model of Alzheimer's disease (AD). Using a similar protocol to vaccinate 7.5-month-old APP (Tg2576) and APP+PS1 transgenic mice over an 8-month period, we previously reported modest reductions in brain Abeta deposition at 16 months. In these same mice, Abeta vaccinations had no deleterious behavioral effects and, in fact, benefited the mice by providing partial protection from age-related deficits in spatial working memory in the radial arm water maze task (RAWM) at 15.5 months. By contrast, control-vaccinated transgenic mice exhibited impaired performance throughout the entire RAWM test period at 15.5 months. The present study expands on our initial report by presenting additional behavioral results following long-term Abeta vaccination, as well as correlational analyses between cognitive performance and Abeta deposition in vaccinated animals. We report that 8 months of Abeta vaccinations did not reverse an early-onset balance beam impairment in transgenic mice. Additionally, in Y-maze testing at 16 months, all mice showed comparable spontaneous alternation irrespective of genotype or vaccination status. Strong correlations were nonetheless present between RAWM performance and extent of "compact" Abeta deposition in both the hippocampus and the frontal cortex of vaccinated APP+PS1 mice. Our results suggest that the behavioral protection of long-term Abeta vaccinations is task specific, with preservation of hippocampal-associated working memory tasks most likely to occur. In view of the early short-term memory deficits exhibited by AD patients, Abeta vaccination of presymptomatic AD patients could be an effective therapeutic to protect against such cognitive impairments.

Development of an intact blood-brain barrier in brain tissue transplants is dependent on the site of transplantation.

Transplantation of fetal septal forebrain tissue was performed to the anterior chamber of the eye, or intracranially to the rostral hippocampal formation in rats, to evaluate the impact of transplantation site on the development of an intact blood-brain barrier (BBB). The tissue was studied at 1,2,3, and 4 wk following transplantation by means of intravenous injection of Trypan blue, which is a vital stain not normally penetrating the BBB, as well as with an antibody specifically directed against the rat BBB, SM171. In the intraocular septal transplants, there was a significant leakage of Trypan blue 1 wk postgrafting, associated with a few laminin-immunoreactive blood vessels that did not contain any SM17I-immunoreactivity. However, at 2 wk postgrafting, the intraocular grafts exhibited an extensive plexus of thin-walled blood vessels expressing SMI71 immunoreactivity and no Trypan blue leakage. Thus, it appeared that a BBB had developed to some degree by 2 wk postgrafting in oculo. In the intracranial grafts, on the other hand, Trypan blue leakage could be seen as long as 3 wk postgrafting, and a dense plexus of blood vessels with SMI71 immunoreactivity was first seen at 4 wk postgrafting. Thus, the development of Trypan blue impermeability was delayed with 1 to 2 wk in the intracranial versus the intraocular grafts. Control experiments using psychological stress in adult rats as a means to transiently disrupt the BBB revealed that an increase in Trypan blue leakage correlated well with the disappearance of SMI71 immunoreactivity. Taken together, these studies demonstrate that the site of transplantation can influence the development of an intact BBB in neural tissue grafts.

Psychological stress repeatedly blocks hippocampal primed burst potentiation in behaving rats.

Primed burst (PB) potentiation is a long-term increase in CA1 population spike amplitude produced by brief physiologically patterned electrical stimulation of the hippocampal commissure. Exposure of rats to a novel environment resulted in a blockade of short-term (Post-tetanic potentiation, PTP) and long-term (PB potentiation) plasticity in all cases (n = 6). When the animals had extensive exposure to the environment (14 consecutive days), PTP and PB potentiation occurred. With placement of the rats in a second novel environment, once again, neither PTP nor PB potentiation was observed. Placement of rats in each of the two novel environments produced a significant increase in serum corticosterone levels, while placement in the familiar environment produced no increase in response. These findings support the hypothesis that hippocampal plasticity is repeatedly susceptible to modulation by the stress of forced exposure to a novel environment.

Classical conditioning rapidly induces specific changes in frequency receptive fields of single neurons in secondary and ventral ectosylvian auditory cortical fields.

To determine if learning-induced changes in the response of auditory cortical neurons to a conditioned stimulus (CS) reflect general changes in cellular excitability or alterations in signal processing that are specific to that stimulus, we determined frequency receptive fields (FRFs) of single neurons in secondary and ventral ectosylvian auditory fields of the cat during classical conditioning. Associative changes in FRFs of most cells were specific to the frequency of the CS, established rapidly and reversed by extinction. Thus, learning causes specific changes in cortical processing of sounds whose significance is acquired.

Responses of single auditory cortical neurons to tone sequences.

The responses of single neurons in the primary and secondary auditory cortex of cat were recorded during the presentation of sequences consisting of five tones of different frequencies. Discharges to tones within these sequences usually (84%) exhibited a dependence on the 'direction' of the sequence (ascending, descending, or mixed frequencies). For sequences consisting of 5 tones of identical frequency (monotone) the response often depended on serial position, including cases in which the neuron only responded to later tones in the sequence. Comparison of responses to heterogeneous and monotone sequences showed that response dependence on serial position was a factor in response dependence on sequence direction. Auditory cortical neurons can exhibit stronger responses to a tone presented in a sequence than to the same tone presented alone. Hence, the responses to tones within sequences may not be highly predictable from the responses to isolated tones.

Adrenalectomy reduces the threshold for hippocampal primed burst potentiation in the anesthetized rat.

Previously we demonstrated that the threshold for inducing hippocampal long-term potentiation (LTP) was reduced when the pattern of electrical stimulation mimicked physiological activity. This form of LTP, termed primed burst (PB) potentiation, is blocked by stress. In the present study, we tested the possibility that adrenal hormones contribute to the stress-related inhibition of PB potentiation. Our primary finding is that the amount of stimulation current necessary to induce PB potentiation was lower in adrenalectomized rats than in controls. This finding indicates that adrenal hormones exert an inhibitory influence on the induction of physiological plasticity in the hippocampus.

Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes.

This study provides a comprehensive behavioral characterization during aging of transgenic mice bearing both presenilin-1 (PS1) and amyloid precursor protein (APP(670,671)) mutations. Doubly transgenic mice and non-transgenic controls were evaluated at ages wherein beta-amyloid (Abeta) neuropathology in APP+PS1 mice is low (5-7 months) or very extensive (15-17 months). Progressive cognitive impairment was observed in transgenic mice for both water maze acquisition and radial arm water maze working memory. However, transgenicity did not affect Y-maze alternations, circular platform performance, standard water maze retention, or visible platform recognition at either age, nor did transgenicity affect anxiety levels in elevated plus-maze testing. In sensorimotor tasks, transgenic mice showed a progressive increase in open field activity, a progressive impairment in string agility, and an early-onset impairment in balance beam. None of these sensorimotor changes appeared to be contributory to any cognitive impairments observed, however. Non-transgenic mice showed no progressive behavioral change in any measure evaluated. Given the age-related cognitive impairments presently observed in APP+PS1 transgenic mice and their progressive Abeta deposition/neuroinflammation, Abeta neuropathology could be involved in these progressive cognitive impairments. As such, the APP+PS1 transgenic mouse offers unique opportunities to develop therapeutics to treat or prevent Alzheimer's Disease through modulation of Abeta deposition/neuroinflammation.

Modulation of hippocampal primed burst potentiation by anesthesia.

This study demonstrates that the anesthetics urethane and pentobarbital differentially affect a low threshold form of long-lasting synaptic plasticity, termed primed burst (PB) potentiation, in the CA1 area of rat hippocampus. PB potentiation was generated by the delivery of a 5-pulse patterned stimulus train, consisting of one priming pulse followed 170 ms later by a burst of 4 pulses at 200 Hz. PB potentiation could not be reliably generated in urethane-anesthetized rats unless stimulus currents were raised to 150% of baseline levels during the stimulus train. In pentobarbital-anesthetized rats, PB potentiation could always be evoked at baseline stimulus intensities. Differences between the anesthetics which could contribute to their varying effects upon PB potentiation are discussed.

The neurosteroid dehydroepiandrosterone sulfate (DHEAS) enhances hippocampal primed burst, but not long-term, potentiation.

Dehydroepiandrosterone sulfate (DHEAS), which is synthesized in the brain and in the periphery, is known to affect the excitability of hippocampal neurons. However, its influence on electrophysiological plasticity has not been addressed. We have studied the effects of DHEAS on primed burst (PB) and long-term (LTP) potentiation, two electrophysiological models of memory. PB potentiation is a lasting increase in the amplitude of the CA1 population spike produced by minimal (threshold) electrical stimulation; LTP is produced by more extensive (supra-threshold) stimulation. Whereas intermediate doses (24 and 48 mg/kg, s.c.) of DHEAS given to rats enhanced PB potentiation, low (6 mg/kg) and high (96 mg/kg) doses were ineffective. LTP was not affected by any dose of DHEAS. The inverted-U relationship between DHEAS and PB potentiation is consistent with previous work demonstrating an inverted-U dose-dependent enhancement of memory by DHEAS. The present findings suggest that DHEAS could enhance memory by facilitating the induction of neural plasticity.

Corticosterone-attenuating and anxiolytic properties of mecamylamine in the rat.

1. The available evidence suggests that stress induced release of acetylcholine (ACh) in the brain has a significant role in mediating neuroendocrine, emotional, and physiological responses to stress. Recent findings also suggest that stress indirectly (via acetylcholine) and nicotine directly stimulates the HPA axis through activation of nAChRs. 2. Our working hypothesis is that under stressful conditions, nicotinic receptor antagonists, such as mecamylamine, should act to attenuate the activation of the HPA axis and exhibit anxiolytic behavioral effects. The purpose of this study was to determine whether or not mecamylamine would: a) produce anxiolytic effects in rats on the elevated plus maze and b) blunt the plasma corticosterone response to predator stress in rats. 3. Results suggested that mecamylamine has anxiolytic properties under stressful conditions. In the EPM experiment, mecamylamine (0.3 mg/kg) produced increased time spent in the open arms. Similarly, in the predator stressor experiment, mecamylamine blunted the stress-induced plasma corticosterone response, with the lowest dose of mecamylamine (0.1 mg/kg). 4. These findings may have important therapeutic implications since clinical observations have shown that low doses of mecamylamine reduce tension and anxiety in patients with Tourette syndrome.