Antidepressant mechanisms: functional and molecular ... - Nature

Molecular Psychiatry (2002) 7, S15–S22  2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp

ORIGINAL RESEARCH ARTICLE

Antidepressant mechanisms: functional and molecular correlates of excitatory amino acid neurotransmission CA Stewart and IC Reid University of Dundee, Department of Psychiatry, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK Specific targeting of the serotonergic and noradrenergic systems for the development of antidepressant compounds has resulted in drugs with more favourable side-effect profiles but essentially no greater efficacy than those compounds discovered more than 40 years ago. Alternative targets are now being considered in the hope that they will have a faster onset of action and be useful for those patients currently unresponsive to conventional treatments. Excitatory amino acid neurotransmission has been attributed various roles in both normal and abnormal brain function. The N-methyl-D-aspartate receptor in particular has long been postulated to play a role in the formation of memories. Major depressive disorder is characterised by alterations in cognitive function, as well as affect. Although there is evidence that early adverse events and stress can have a causal influence on depression, the underlying neurobiology of the disorder is poorly understood. This review will document current evidence for the involvement of excitatory amino acid neurotransmission in the pathophysiology of the affective disorders. The preclinical literature suggests that both electroconvulsive stimulation and antidepressant drugs can affect hippocampal long-term potentiation and the expression of excitatory amino acid receptor subtypes. Exposing animals to stress, including the kind that produces learned helplessness, can also affect synaptic plasticity in the hippocampus. There is clinical evidence that patients with chronic depression have structural brain abnormalities, including hippocampal atrophy, and a preliminary study has shown that an N-methylD-aspartate receptor antagonist may have antidepressant efficacy. Molecular Psychiatry (2002) 7, S15–S22. DOI: 10.1038/sj/mp/4001014 Keywords: depressive disorder; hippocampus; synaptic plasticity; long-term potentiation; AMPA; NMDA; electroconvulsive

Introduction Although the monoamine hypothesis has long driven etiological studies and drug development, it differs little, at least in broad principle, from ancient Greek ‘humoral’ explanations of melancholia. The Ancients’ excess of ‘black bile’ is now our ‘serotonin imbalance’, or even ‘corticosteroid-mediated 5HT1a receptor dysregulation’. Clearly, this sort of neurohumoral conceptualisation—chemistry equals disorder—fails to capture important relationships between brain function and the clinical construct that is depressive disorder. In this sense, the often-expressed notion that the development of newer antidepressants represents the ‘rational application’ of psychopharmacology is only partly true. The latest antidepressants represent a welcome refinement of the original, core antidepressant pharmacology, but the therapeutic principles remain the same. In consequence, researchers have directed their attention to neural systems beyond monoamine receptor regulation, charting not only molecular events Correspondence: Dr CA Stewart, University of Dundee, Department of Psychiatry, Ninewells Hospital & Medical School, Dundee DDI 9SY, UK. E-mail: c.a.stewart얀dundee.ac.uk

within individual cells (see this issue), but also exploring the structure and function of networks of neurones in an effort to develop a more integrated and enriched neurobiology of depressive disorder. Although they do not always yield consistent results (see review by Soares, this issue), modern neuroimaging techniques have, for example, revealed both structural and functional abnormalities in the prefrontal cortex1 and the hippocampal formation2–4 in patients with depression. A post-mortem study on sufferers of manic depression also found a specific reduction in non-pyramidal neurones in the CA2 hippocampal region.5 Here, treading the middle ground between intracellular biology and the relationships between brain function and neuropsychology, we concentrate on the effects of stress and antidepressant agents on synaptic connectivity within the hippocampus.

The hippocampus and synaptic plasticity Much contemporary research into the function of the hippocampus has focused on its putative role in learning and memory. In the early 1970s, Bliss et al6 discovered a mechanism for the regulation of connectivity within the neural machinery of the hippocampus, which may explain why the hippocampus is able to

Excitatory amino acids and antidepressant action CA Stewart and IC Reid

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play a part in information storage. They called the mechanism ‘long-term potentiation’ (LTP).6 LTP represents an increase in the extra-cellular response of a neuronal population in the hippocampus brought about by applying trains of high-frequency stimulation to the afferent pathway. This ‘plastic’ phenomenon has been demonstrated in the human dentate gyrus,7 and is now known to occur in many other areas of the mammalian brain. Excitatory amino acids are the neurotransmitters responsible for transmission at most of the synapses that exhibit LTP. The most widely studied, and probably most abundant, form of LTP requires activation of a specific subclass of excitatory amino acid receptor, the N-methyl-D-aspartate (NMDA) receptor, for its induction.8 LTP is an activity-dependent form of synaptic plasticity that is rapidly established, durable and specific only to the inputs stimulated. These are characteristics considered essential for any neural mechanism proposed to underlie memory formation.9,10 Though much discussed as a possible memory mechanism, LTP is perhaps most usefully considered as a more generic process that confers specific computational properties on networks of neurones. The nature of these computational properties—and their neuropsychological counterparts—will be determined by the precise arrangement of neurones within any given brain region. Though beyond the scope of present technologies, this perspective begins to make tractable, at least in theory, the analysis of relationships between neuropsychology and the activities of networks of neurones in mental disorder, in a way that ‘monoamine receptorology’ could never achieve. Given the impact of antidepressant agents and psychological stressors on excitatory amino acid systems and LTP (reviewed below), it seems likely that modulation of this form of plasticity plays a significant role in affective processing. While the focus of this article is on hippocampal biology, the general principles may be extended to other key brain regions known to support this form of synaptic plasticity, such as the frontal cortex and amygdala.

Electroconvulsive stimulation and hippocampal synaptic plasticity Electroconvulsive therapy is a safe and highly effective treatment for severe depression that has been used for more than 60 years. One of the major side effects limiting its acceptability as a treatment has been a transient impairment to memory function. This amnesia comprises both retrograde (the recall of events occurring prior to treatment) and anterograde (learning and remembering new material) effects. The difficulty in learning new material can persist for anywhere from 1–12 weeks after a course of treatment.11 In animal models, impairment to avoidance learning has been shown to last up to 21 days.12 Early studies suggested that the memory impairments could be due to alterations in hippocampal synMolecular Psychiatry

aptic plasticity. Hesse and Teyler13 found that locally generated seizure activity could reverse previously induced long-term potentiation in the hippocampus. Subsequently, Anwyl et al14 gave rats a course of 10 electroconvulsive stimulation (ECS) treatments and then found that the induction of LTP by high-frequency stimulation to the Schaffer collateral/commissural fibres was impaired in the CA1 field of hippocampal slices. Experiments in our laboratory found that, as well as impairing high-frequencyinduced LTP in the dentate gyrus, a course of 10 ECS treatments spaced at 48-h intervals enhanced baseline responses, as represented by the slope of the excitatory postsynaptic potential (EPSP), when recordings were done in vivo.15 This suggested that ECS treatments might have impaired LTP because an LTP-occluding process had already been induced: a partial ‘saturation’ of plasticity. Later experiments suggested that this impairment to LTP lasted for 10–40 days after the final treatment.16 Daily recordings in conscious rats that had electrodes implanted under recoverable anaesthesia revealed an incremental increase in the synaptic response (EPSP slope) that reached a maximum after approximately five of the 10 ECS treatments.16 Experiments carried out in an independent laboratory found that a course of eight ECS treatments, spaced at 48-h intervals, produced an increase in the population spike measure of the synaptic response that was still present 91 days following the last treatment.17

Molecular mechanisms underlying the ECS effect The fact that ECS treatment causes an increase in baseline measures of the evoked response in the dentate does not necessarily mean that it is inducing the same long-term potentiation that discrete, non-convulsive, high-frequency stimulation would produce. In the dentate gyrus, LTP is dependent on the activation of NMDA receptors and can be blocked by the NMDA receptor antagonist AP5.18 We therefore substituted halothane for the non-competitive NMDA receptor antagonist ketamine as the anaesthetic during ECS application. This drug can be conveniently administered by intraperitoneal injection as it crosses the blood–brain barrier in significant amounts and is available for clinical use. Ketamine anaesthesia prevented both the increase in the pre-LTP levels of EPSP slope and the impairment to high-frequency-induced LTP seen with halothane anesthesia.19 This suggests that, like LTP, the ECS-induced changes to synaptic function required the activation of NMDA receptors. Gombos et al20 suggested that the increase in the population spike measure of the dentate response was not prevented by the same dose of ketamine. However, in this study there were no significant effects of ECS treatment on the dentate EPSP slope when it was given either without anaesthesia or in the presence of pentobarbitone. The relationship between the change in EPSP slope and the increase in the population spike is complex. The size of the population spike reflects the number of discharging granule cells, whereas the slope


of the evoked potential reflects the depolarisation at synapses on the granule cell dendrites that generates the EPSP.21 The population spike can increase disproportionately to the change in EPSP, and this form of plasticity has been termed ‘ES potentiation’.22 Thus, changes in population spike size may not always be linked to NMDA-mediated LTP. There is still some controversy over the exact postsynaptic mechanisms responsible for the expression of long-term potentiation.9 Whereas NMDA receptors are required for the induction of LTP in certain areas, they are probably not involved in its maintenance. The calcium current through the NMDA-receptor-related ion channel activates further intracellular pathways.23 Several potential transduction mechanisms could lead to the long-term expression of LTP, including the protease calpain, phosphatases and protein kinases (protein kinase C, calcium/calmodulindependent protein kinase II and 3⬘, 5⬘-cyclic monophosphate- [cAMP] dependent protein kinase A). LTP could be expressed as an increase in neurotransmitter release from the presynaptic terminal, an increase in the number or sensitivity of postsynaptic receptors or morphological changes at the postsynaptic site. Electrophysiological studies found a specific increase in ␣amino-2-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated current following LTP,24–26 which supported an increase in AMPA receptor function as the mechanism of LTP expression. This was further supported by Tocco et al,27 who found enhanced binding of [3H] AMPA following high-frequency stimulation of the perforant path. We used in situ hybridisation to measure the expression of mRNA selective for the AMPA receptor subunit (GluR1) and the NMDA receptor subunit (NR1A-G) in rat hippocampus following a course of ECS. Twenty-four hours after the last in a series of 10 ECS treatments, levels of mRNA for the AMPA receptor subunit were increased throughout the hippocampal formation. Expression of mRNA for the NR1A-G subunit was unchanged relative to anaesthetised controls.28 Wong et al29 also found an increase in GluR1 expression following ECS treatment. This increase in mRNA levels is suggestive of an up-regulation in postsynaptic AMPA receptors that may be responsible for the long-lasting electrophysiological changes seen in the dentate gyrus.16,17 A series of spaced ECS treatments was also shown to enhance the expression of Narp protein, an immediate early gene product that probably plays a regulatory role in the clustering of AMPA receptors at synaptic sites.30 Although the expression of mRNA for the NR1 subunit was unchanged in our study,28 ECS treatment has been shown to alter the expression of mRNA for other NMDA receptor subunits. Watkins et al31 found that chronic ECS treatment produced an acute increase in mRNA for both the NR2A and NR2B subunits of the NMDA receptor in the dentate gyrus, although only the NR2B increase was sustained 24 h later. The NR2 subunits appear to be important in determining the ion channel selectivity of the NMDA receptor and its cal-

cium-dependent inactivation. Mutant mice lacking the NR2A equivalent subunit exhibited significantly reduced LTP at hippocampal CA1 synapses.32 ECS treatment has been shown to produce alterations in the ligand-binding properties of the NMDA receptor complex in the cerebral cortex.33 Described as ‘adaptation’ of the receptor complex, the essential change was a decrease in the ability of glycine to inhibit 5,7DCKA to the strychnine-insensitive glycine site. This adaptation was not seen in the hippocampus, and the functional significance is unclear, although Skolnick34 proposes that it is indicative of a region-specific ‘dampening’ of NMDA receptor function. However, rather than altering the characteristics of the glutamate receptors responsible for the induction and expression of LTP, antidepressant treatments may have effects on signal transduction factors involved in its maintenance. A single seizure induced by pentylenetetrazol increased the mRNA for tissue-plasminogen activator throughout the brain.35 This protease has been correlated with morphological differentiation and is selectively induced in the granule cells following high-frequency stimulation of the perforant path.35 Electroconvulsive seizures have also been found to increase the levels of cAMP response element binding protein (CREB) mRNA in the hippocampus.36 This may cause up-regulation of specific target genes, such as those for brain derived neurotrophic factor (BDNF) and its receptor trkB.37 These effects are discussed in more detail by Duman in this issue. Alterations to BDNF will have specific consequences for hippocampal synaptic plasticity. Application of exogenous BDNF to a hippocampal slice promoted the induction of LTP by subthreshold tetanus.38 Patch clamp recording techniques suggested that this was due to direct modulation of the NMDA-receptor-associated channels.39

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Chemical antidepressant treatments and synaptic plasticity ECS treatment has effects on both mood and memory function. Since the hippocampal formation and longterm potentiation have been implicated in learning and memory, ECS-induced treatment effects on synaptic plasticity may not be related to its clinical efficacy, but be responsible for the cognitive side-effects. The development and duration of the effects of ECS treatment on hippocampal synaptic plasticity correlate well with both the amnesia and the clinical response16 as there is a high rate of relapse for patients following a course of ECS. One approach is to examine pharmacological treatments for depression that do not produce overt effects on cognitive function. O’Connor et al40 examined the effects of chronic treatment with imipramine (monoamine reuptake inhibitor) or buspirone (5-HT receptor agonist) on the hippocampal CA1 synaptic response in conscious rats that had been previously implanted with stimulating and recording electrodes. Fourteen days of imipramine at a dose of 10 mg kg−1 reduced the size of the EPSP evoked by low-frequency stimulation. A study by Molecular Psychiatry


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Massicotte et al41 found that 7–9 days of 5 mg kg−1 trimipramine suppressed LTP measured in the CA1 region of rat hippocampal slices. Initial short-term potentiation to the theta-burst stimulation appeared to be relatively intact, but the response decayed back to baseline within 30 min. The authors suggested that these effects could be responsible for the cognitive impairments produced by chronic administration of some tricyclic antidepressants, including trimipramine.42 There is some evidence that mood-stabilising agents can also affect hippocampal synaptic plasticity. Acutely, carbamazepine can dose dependently block LTP in the conscious rabbit dentate gyrus.43 To circumvent the potential problem of cognitive deficits with tricyclic antidepressant drugs,44 we examined the effects of chronic fluoxetine, a selective serotonin reuptake inhibitor that does not impair cognitive function, on both hippocampal synaptic plasticity and spatial learning.45 Rats were given a course of eight ECS treatments spaced at 48-h intervals or 15 days of daily injections with fluoxetine (1 mg kg−1, IP). Control groups were given anaesthesia alone or vehicle injections. Both antidepressant treatments enhanced the baseline field potentials as measured under urethane anaesthesia by either EPSP slope or population spike. There was also a reduction in the amount of LTP obtained on stimulation of the perforant path for both ECS- and fluoxetine-treated groups compared with their appropriate controls. Although both treatments had similar effects on hippocampal synaptic plasticity, repeated ECS treatments impaired acquisition and retention of place learning in the watermaze task, but fluoxetine-treated rats were unimpaired. This result suggests the effects of antidepressant treatments on dentate connectivity may relate to affective (clinical efficacy), rather than cognitive (memory impairment), function. Depression itself is associated with considerable cognitive dysfunction. These impairments include deficits in tasks sensitive to hippocampal dysfunction: visual delayed match-to-sample46 and verbal learning.3 Interestingly, the verbal learning impairment found in patients with chronic depression was correlated with the degree of reduction of hippocampal grey matter found using magnetic resonance imaging.3 Successful treatment of depression is normally associated with an improvement in cognitive function, although not always to the same level as age-matched controls.46

Molecular mechanisms underlying the antidepressant drug effect There is some evidence that acute administration of tricyclic antidepressants can interact directly with the NMDA receptor complex. These effects have been reviewed in detail by Petrie et al,47 and suggest that tricyclic antidepressants may act as NMDA antagonists at the phencyclidine recognition site within the ion channel. O’Connor et al40 showed that chronic treatment with either imipramine or buspirone reduced the Molecular Psychiatry

EPSP amplitude during a burst of high frequency. This was interpreted as an antidepressant effect on afferent nerve conduction via a use-dependent block of voltagedependent sodium channels. Conversely, the tricyclic compound trimipramine did not affect the size of the burst response to theta frequency stimulation in vitro.41 Although trimipramine treatments resulted in rapidly decaying LTP, there was no reduction in the NMDAmediated synaptic response and, therefore, induction mechanisms were probably intact.41 Studies of antidepressant interaction with excitatory amino acid function are not always consistent. For example, binding studies using hippocampal membrane preparations failed to reveal differences in the binding of various tritiated ligands to the NMDA or AMPA receptor following trimipramine. A phospholipase A2-stimulated increase in 3H-AMPA binding was, however, reduced.48 On the other hand, cerebral cortical membranes from mice treated with desipramine—a tricyclic compound with greater selectivity for inhibiting the reuptake of noradrenaline—for 3 weeks displayed reduced [3H] MK-801 binding.49 Chronic and acute treatment with the imipramine and the monoamine oxidase inhibitor phenelzine was also found to reduce the potassium-induced overflow of glutamate in slices from the prefrontal cortex, but not the striatum.50 The authors suggested that this effect may be neuroprotective against the kind of glutamate excitotoxicity that could be induced by stress and could lead to neuronal loss and atrophy. The same ‘adaptation’ in the binding characteristics of the NMDA receptor complex that was described for repeated ECS treatments was also seen following chronic treatment with several different antidepressant drugs, including imipramine and citalopram,33 though this effect was seen in the cerebral cortex and not the hippocampus. Whole rat brain levels of mRNA for glutamate receptor subunits were unchanged following treatment with citalopram,51 but region-specific differences in the levels of mRNA for NMDA receptor subunits were found in mice following treatment with imipramine and citalopram.52 Both drugs decreased the level of the zeta subunit (NR1) in the cortex, cerebellum, thalamus and striatum, but had no substantial effect in the hippocampus. This is consistent with the effects of ECS treatment on the NR1 subunit described above.28 However, mRNA for the mouse epsilon 1 subunit (homologue of NR2A) was decreased in the CA2 of hippocampus by citalopram and the epsilon 2 subunit (homologue of NR2B) decreased in CA1–4 of the hippocampus. These changes are in the opposite direction to those caused by ECS treatment in the rat dentate gyrus.31 As with ECS treatment, antidepressant drugs produce an increase in the levels of mRNA for CREB and BDNF in the hippocampus.36,37 These changes in postsynaptic receptor signal transduction mechanisms may have arisen through the activation of a variety of different receptors, including serotonergic and adrenergic postsynaptic receptors.53


Synaptic plasticity in animal models Although there are no satisfactory animal models of either depressive illness or mania, attempts have been made to represent some of the clinical features of the affective disorders. Stressful life events have been implicated consistently in the onset of depressive episodes in humans.54 In addition, exposing animals to inescapable stress has been said to induce ‘learned helplessness’, a behaviour that has been likened to the helplessness and hopelessness that is sometimes a feature of human depression. Shors et al55 demonstrated that exposing rats to inescapable electric shock significantly impaired LTP, measured as the increase in the CA1 population spike in hippocampal slices, compared with non-shocked controls. Interestingly, if rats were exposed to an identical amount of ‘escapable’ electric shock, LTP was inhibited to a significantly lesser extent. Whether the rats had control over the aversive stimulation could be differentiated in terms of the plasticity of the hippocampus. Many studies have looked at the effects of various different types of acute stress exposure on hippocampal long-term potentiation, as well as long-term depression. Long-term depression is a use-dependent decrease in synaptic efficacy that is normally induced using slightly different stimulation protocols and is also subserved by the NMDA receptor.56 These studies have been reviewed in detail by Petrie et al.47 Generally, exposure to stressors such as electric shock, restraint or a novel environment decreased the amount of LTP obtained in the CA1 region of the hippocampus.57–60 In some cases, exposure to acute stress enhanced the probability of obtaining long-term depression.61,62 Certain types of stress exposure have also been shown to impair synaptic plasticity measured in the dentate gyrus. Shors and Dryver63 found that an acute stress exposure impaired LTP in the dentate gyrus if recordings were made under anaesthesia for 2 h, but not 24 h, later. There appeared to be no effect of stress on the baseline synaptic responses. Acute cold stress, sufficient to increase serum levels of corticosterone, had no effect on either baseline synaptic efficacy or dentate LTP in conscious rats.64 However, transfer of either control or stress-assigned rats to the environmental cages produced a significant decrease in the size of the population spike. Studies carried out by Henke65 did find stressinduced changes to the size of the field potential. Exposure to a series of inescapable electric shocks led to a subsequent impairment on a runway escape task (‘learned helplessness’ effect) and also produced a reduction in the size of the dentate population spike compared with non-shocked controls.65 Henke also demonstrated a different electrophysiological profile between rats that could cope with exposure to restraint stress compared with those that could not. A failure to cope was defined as the development of gastric ulceration. Rats that developed gastric ulceration also displayed a reduction in the size of dentate population

spikes, whereas those with no stomach pathology had increased dentate potentials.65 The work of Henke emphasised the fact that rats, like humans, exhibit differences in their susceptibilities to the same stressful experiences. One of the factors long associated with an increased vulnerability to depressive disorder is early adversity. Various types of manipulation to the early mother-infant relationship produced alterations to hippocampal synaptic plasticity in juvenile rats. On the whole, these experimental interventions increased the electrophysiological response to high frequency-stimulation, resulting in greater potentiation of granule-cell-evoked responses.66–68 A preliminary study looking at the effect of an early adverse event on the susceptibility to stress in adulthood found that rats that had experienced a single maternal separation on postnatal day 3 and repeated stress exposure in adulthood had significantly greater granule cell population spikes than either separated unstressed rats or non-separated stressed controls.69 This suggested that a discrete adverse event early in development had lasting repercussions for hippocampal synaptic efficacy that remained latent until challenged by later-life stressors.

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Molecular mechanisms underlying the stress effects The molecular mechanisms responsible for the stressinduced changes to hippocampal synaptic plasticity are not fully understood. Shors et al63 suggested that stress induced the same cellular processes as high-frequency stimulation for two main reasons: (1) stress or prior LTP induction produced a similar decrease in experimental LTP 2 h later;63 and (2) both stress70 and LTP induction27 increased AMPA binding throughout the hippocampus. However, there were no significant increases in basal synaptic responses in stressed rats compared with controls. It is possible that exposure to stress has altered the probability of obtaining LTP or long-term depression to a given stimulus train, without any apparent change in the baseline evoked response. This alteration in the capacity for synaptic plasticity has been termed ‘metaplasticity’.71 Levels of intracellular calcium, which in turn can be regulated by excitatory amino acid receptors, may be an important determinant of the direction of synaptic change.72 Both [3H]AMPA and [3H]CNQX binding in hippocampal subfields were significantly correlated with emergence behaviour in that neophobic rats exhibited greater binding than their more neophilic counterparts.73 Neophobic rats were previously found to have a lower threshold for, and magnitude of, dentate LTP than neophilic rats.74 It is unclear how these differences relate to the findings of Shors et al,63 who administered inescapable stressors to all of their sample population. Interestingly, neophobic animals had lower basal levels of corticosterone measured 3 weeks after the emergence testing.73 Corticosteroid hormones may mediate the effects of stress on hippocampal synaptic plasticity. High levels Molecular Psychiatry


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of corticosterone in the rat can block the induction of LTP and facilitate LTD, whereas low levels can facilitate LTP.75 Selective glucocorticoid (Type II) agonists can mimic the effects of high corticosterone levels, whereas antagonists at this receptor can prevent stressinduced changes in synaptic plasticity.62 Corticosterone administration to the hippocampal slice inhibited high-frequency-induced LTP in association with a reduction of mRNA for NGF-␤ and BDNF.76

Antidepressant action of NMDA-receptor-directed compounds Numerous preclinical studies using NMDA receptor antagonists are suggestive of an antidepressant effect.34,47 Both competitive and non-competitive NMDA receptor antagonists are active in the forced swimming test77–79 and the learned helplessness model.80 However, the relationship between NMDA blockade and antidepressant action is not clear-cut; in certain cases NMDA receptor antagonists can inhibit the action of clinically effective antidepressant treatments.80 A preliminary clinical study has now suggested that the non-competitive NMDA receptor antagonist, ketamine, produced a rapid but reversible improvement in depressive symptoms following a single infusion. There was a significant change in the Hamilton Depression Rating Scale within 72 h of intravenous ketamine hydrochloride that returned to baseline 1–2 weeks later.81 The authors suggest that future testing with NMDA receptor antagonists that are free from psychotomimetic properties would be more useful.

Conclusions The evidence discussed above has shown that both antidepressant treatments and depressogenic stressors can affect hippocampal synaptic plasticity. In some cases, the ‘pathology’ and ‘treatment’ appear to be acting in the same way. Stress, ECS treatment or antidepressant drugs all inhibit LTP in the hippocampus. The fact that both ECS treatment and fluoxetine increase dentate synaptic transmission appears to be entirely consistent with the work of Henke,82 who found that stress-susceptible rats displayed a decrease in granule cell potentials but that stress-resistant rats had increased responses. Henke was also able to reduce ulcer formation in stressed rats by artificially inducing LTP via high-frequency stimulation of afferent pathways.82 It is less clear why the maternally separated rats that were exposed to a repeated inescapable stressor also had elevated dentate population spikes.69 More studies are required to show that there is an amelioration of stress-induced synaptic plasticity changes with antidepressant or mood-stabilising treatments. A preliminary study by Rowan et al83 found that the 5HT uptake enhancer, tianeptine, prevented an acute stress-induced block of LTP in urethane anaesthetised rats. Different neuronal pathways may mediate the effects of stress paradigms and antidepressant treatments on Molecular Psychiatry

hippocampal plasticity. Excitatory amino acid receptors, corticosteroids levels, monoamine neurotransmitters, neurotrophic factors and other cellular messengers all have the potential to interact with a consequence for neuronal connectivity in the hippocampus. Both immobilisation stress and corticosterone can reduce the expression of mRNA for BDNF in the hippocampus,84 whereas antidepressant treatments can elevate BDNF levels, probably via noradrenaline and serotonin receptors.53 It is clear that antidepressant treatment and experimental stressors each have the potential to profoundly alter excitatory amino acid mediated synaptic plasticity—and the associated molecular machinery—in the brain. Coupled with recent observations showing that a range of antidepressants, mood stabilisers and NMDA receptor channel blockers enhance dentate gyrus neurogenesis (while stressors reduce neurogenesis), this implies that antidepressant agents may act by protecting relevant neural circuits from the ravages of stress-induced neurotoxicity. We propose that this protection extends beyond simply bolstering neuronal survival and proliferation to the maintenance of plastic neural connectivity mechanisms that may prove essential for healthy affective and cognitive function.

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