Evidence for a dynorphin-mediated inner ear immune/inflammatory response and glutamate-induced neural excitotoxicity: an updated analysis.

Acoustic overstimulation (AOS) is defined as the stressful overexposure to high-intensity sounds. AOS is a precipitating factor that leads to a glutamate (GLU)-induced Type I auditory neural excitotoxicity and an activation of an immune/inflammatory/oxidative stress response within the inner ear, often resulting in cochlear hearing loss. The dendrites of the Type I auditory neural neurons that innervate the inner hair cells (IHCs), and respond to the IHC release of the excitatory neurotransmitter GLU, are themselves directly innervated by the dynorphin (DYN)-bearing axon terminals of the descending brain stem lateral olivocochlear (LOC) system. DYNs are known to increase GLU availability, potentiate GLU excitotoxicity, and induce superoxide production. DYNs also increase the production of proinflammatory cytokines by modulating immune/inflammatory signal transduction pathways. Evidence is provided supporting the possibility that the GLU-mediated Type I auditory neural dendritic swelling, inflammation, excitotoxicity, and cochlear hearing loss that follow AOS may be part of a brain stem-activated, DYN-mediated cascade of inflammatory events subsequent to a LOC release of DYNs into the cochlea. In support of a DYN-mediated cascade of events are established investigations linking DYNs to the immune/inflammatory/excitotoxic response in other neural systems.

Endogenous dynorphins, glutamate and N-methyl-d-aspartate (NMDA) receptors may participate in a stress-mediated Type-I auditory neural exacerbation of tinnitus.

Tinnitus is the phantom perception of sounds occurring in the absence of an external auditory stimulus. Tinnitus: [1] effects 50 million individuals, [2] often results from acoustic trauma and, [3] is very often exacerbated under stressful conditions. Tinnitus may result from lesions occurring at any location in the auditory system, but its mechanisms are poorly understood. Evidence is provided supporting an endogenous dynorphin-mediated potentiation of glutamate excitotoxicity at cochlear Type-I auditory dendrites that may well exacerbate chronic subjective neural-generated tinnitus during periods of heightened stress. The proposed mechanism is based on the following: [1] lateral efferent olivocochlear (LEOC) axon terminals contain endogenous dynorphin neuromodulators and are presynaptic to cochlear Type-I auditory dendrites that bear both κ-opioid and N-methyl-d-aspartate (NMDA) receptors/binding sites; [2] the release of presynaptic LEOC dynorphins is likely to be triggered by sympathetic stress via the locus coeruleus; [3] sodium salicylate induces an acute excitotoxicity by potentiating glutamate neurotransmitter effects at cochlear NMDA receptors, resulting in a Type-I auditory neural-generated tinnitus; [4] dynorphins participate in central NMDA-receptor-mediated excitotoxic inflammation; and [5] κ-opioid receptor ligands also modulate Type-I auditory neural activity by potentiating glutamate at cochlear NMDA receptors. A stress-activated release of dynorphins into the cochlea could potentiate the already excitotoxic effects of glutamate, producing: [1] hyperacusis, together with an acute exacerbation of [2] chronic aberrant Type-I neural activity and [3] a worsening of the activity-dependent central auditory neural plasticity changes that must certainly generate the perception of tinnitus. Treatment options are discussed.

Four weeks lithium treatment alters neuronal dendrites in the rat hippocampus.

A large body of evidence from molecular, cellular and human studies suggests that lithium may enhance synaptic plasticity, which may be associated with its therapeutic efficacy. However, only a small number of studies have directly assessed this. To determine whether lithium treatment alters structural synaptic plasticity, this study examined the effect of 4 wk lithium treatment on the amount and distribution of dendrites in the dentate gyrus (DG) and hippocampal area CA1 of young adult rats. Following 4 wk lithium or control chow feeding, animals were decapitated, the hippocampi were prepared and stained using a rapid Golgi staining technique and the amount and distribution of the dendritic branching was evaluated using Sholl analyses (method of concentric circles). In the DG, lithium treatment increased the amount and distribution of dendritic branches in the proximal half of dendritic trees of the granule cells and reduced branching in the distal half. In area CA1, the same treatment also increased the number of dendritic branches in the proximal half of apical dendritic trees of CA1 pyramidal cells and reduced branching in the distal half of apical dendritic trees but had no effect on basilar dendritic trees. The lithium treatment altered the total density of dendritic trees in neither the DG nor area CA1. These findings suggest that, in the DG and apical CA1, chronic lithium treatment rearranges neuronal morphology to increase dendritic branching and distribution to where major afferent input is received.

Effects of 4-weeks of treatment with lithium and olanzapine on long-term potentiation in hippocampal area CA1.

Neuroplastic theories propose that lithium has robust neuroprotective and neurotrophic actions leading to the up-regulation of synaptic plasticity, and this action may be associated with the efficacy of lithium in the treatment of bipolar disorder. Olanzapine, an atypical antipsychotic drug, is efficacious in the treatment of bipolar disorder. It has been suggested that olanzapine may also up-regulate synaptic plasticity by its neuroprotective and neurotrophic actions, and this action may be related to antipsychotic and anti-manic effects of the drug. However, few studies have directly examined whether these drugs alter synaptic plasticity. In the present study, to examine the effects of lithium and olanzapine on synaptic plasticity, we examined the effects of chronic treatment with lithium and olanzapine on long-term potentiation (LTP) and input and output (I/O) responses of field excitatory postsynaptic potentials (fEPSP) of CA1 pyramidal cells in hippocampal slices prepared from rats administered the drugs for 4 weeks. Our results show that 4 weeks of lithium treatment magnified LTP of CA1 pyramidal cells. However, the same treatment with olanzapine did not magnify LTP of CA1 pyramidal cells. Four weeks of treatment with lithium did not alter I/O responses of CA1 pyramidal cells. However, the same treatment with olanzapine increased I/O responses of CA1 pyramidal cells. The results suggest that lithium up-regulates synaptic plasticity in the hippocampus, and olanzapine increases synaptic transmission without apparent changes in LTP in the hippocampus.

Effects of 4-week treatment with lithium and olanzapine on levels of brain-derived neurotrophic factor, B-cell CLL/lymphoma 2 and phosphorylated cyclic adenosine monophosphate response element-binding protein in the sub-regions of the hippocampus.

A large body of evidence indicates that lithium, the prototype mood stabilizer in the treatment of bipolar disorder, has diverse neuroprotective and neurotrophic actions, and the actions are associated with its efficacy in treating bipolar disorder. It has been suggested that up-regulation of neurotrophic and neuroprotective factors including brain-derived neurotrophic factor (BDNF) and B-cell CLL/lymphoma 2 (Bcl-2) may underlie these neuroplastic actions of the drug. Olanzapine, an atypical anti-psychotic drug, has been shown to be an effective mood stabilizer. Olanzapine also has neurotrophic and neuroprotective actions, and these actions may underlie the efficacy of the drug for bipolar disorder and schizophrenia. However, the molecular mechanism by which the drug produces the neuroplastic actions is poorly understood. To understand a common molecular mechanism underlying the neuroplastic actions of lithium and olanzapine, we assessed the effect of 4-week lithium and olanzapine treatment on the levels of BDNF, Bcl-2 and cyclic adenosine monophosphate response element-binding protein (CREB), a transcription factor involved in expression of BDNF and Bcl-2, in the dentate gyrus and hippocampal area CA1. Our results show that 4-week treatment with both olanzapine and lithium increases the levels of Bcl-2 and CREB in the dentate gyrus and hippocampal area CA1. Four-week lithium treatment up-regulates BDNF in the dentate gyrus, and 4-week olanzapine treatment marginally did so. Neither drug altered BDNF levels in area CA1. These results suggest that the up-regulation of Bcl-2 and CREB may underlie the neuroplastic actions of olanzapine and lithium.

Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site.

N-methyl-D-aspartate receptor (NMDAR) hypo-function theory of schizophrenia proposes that impairment in NMDAR function be associated with the pathophysiology of schizophrenia and suggests that enhancement of the receptor function may produce efficacy for schizophrenia. Consistent with this theory, for the last decade, clinical trials have demonstrated that the enhancement of NMDAR function by potentiating the glycine site of the receptor is efficacious in the treatment of schizophrenia. Full agonists of the glycine site, glycine and D-serine and a glycine transporter-1 inhibitor, sarcosine, added to antipsychotic drugs, have been shown to be effective in the treatment of negative symptoms and possibly cognitive symptoms without significantly affecting the positive symptoms of schizophrenia. A partial agonist of the glycine site, D-cycloserine, added to antipsychotic drugs, can be effective for the negative symptoms at the therapeutic doses. However, these drugs have not shown clinical efficacy when added to clozapine, suggesting that the interactions of clozapine and the glycine site potentiators may be different from those of other antipsychotic drugs and the potentiators. This article suggests that the glycine site potentiators may produce efficacy for negative and cognitive symptoms by blocking apoptosis-like neuropathological processes in patients with chronic schizophrenia and thereby can deter progressive deterioration of the disorder. This article proposes a polypharmacy of glycine site potentiators augmented with antipsychotic drugs to control positive and negative symptoms in a synergistic manner and block deterioration in schizophrenia. Since the NMDAR complex consists of multiple sites modulating receptor functions, the efficacy of glycine site potentiators for schizophrenia suggests the possibility that manipulation of other modulating sites of the NMDAR can also be efficacious in the treatment of schizophrenia.

Effects of subchronic lithium treatment on levels of BDNF, Bcl-2 and phospho-CREB in the rat hippocampus.

Although it has been proposed that exposure to lithium up-regulates brain-derived neurotrophic factor (BDNF), B-cell leukaemia/lymphoma 2 protein (Bcl-2) and cyclic AMP-response element-binding protein (CREB), and these molecules are involved in the neuroplastic actions and clinical efficacy of the drug, the several lines of evidence suggest that the lithium-induced up-regulation of these molecules has not been consistently confirmed. Few studies have examined the effects of lithium exposure on the regulation of these molecules in the dentate gyrus (DG) and area CA1 in the hippocampus. We examined the effects of subchronic lithium treatment on the levels of BDNF, Bcl-2 and phosphorylated CREB in the DG and area CA1. We administered LiCl intraperitoneally (1 mEq/kg per day) to adult rats for 14 days, killed animals in 24 hr after the last administration of the drug, and determined the tissue levels of BDNF, Bcl-2 and pCREB in the DG and area CA1. Subchronic lithium treatment for 14 days did not significantly alter the levels of BDNF, Bcl-2 or phosphorylated CREB in the DG and area CA1 in the hippocampus. This study indicates that the lithium-induced up-regulation of these molecules may be various depending on the duration of lithium exposure and particular brain regions exposed to the drug.