Cognitive, behavioral, and motor effects of the NMDA antagonist ketamine in Huntington's disease

Murman, Daniel L.; Giordani, Bruno; Mellow, Alan M.; Johanns, Jewel; Little, Roderick J. A.; Hariharan, M.; Foster, Norman L.

doi:10.1212/wnl.49.1.153

Cited by 41 publications

(15 citation statements)

References 18 publications

(5 reference statements)

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“…Moreover, subanesthetic doses of ketamine have been observed to induce psychotic symptoms (36), influence degree of alertness, and impair perception (37), as well as lower free recall, recognition, and semantic and working memory performance (38)(39)(40). We used a digit span test to ensure that our patients were alert, attentive, and cooperative when the ERP recording began.…”

Section: Discussionmentioning

confidence: 99%

Evidence relating human verbal memory to hippocampal N -methyl- d- aspartate receptors

Grünwald¹,

Beck²,

Lehnertz³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

132

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Studies in rodents and nonhuman primates have linked the activity of N-methyl-D-aspartate (NMDA) receptors within the hippocampus to animals' performance on memory-related tasks. However, whether these receptors are similarly essential for human memory is still an open question. Here we present evidence suggesting that hippocampal NMDA receptors, most likely within the CA1 region, do participate in human verbal memory processes. Words elicit a negative event-related potential (ERP) peaking around 400 ms within the anterior mesial temporal lobe (AMTL-N400). Ketamine, an NMDA-receptor antagonist, reduces the amplitude of the AMTL-N400 (in contrast to other hippocampal potentials) on initial presentation, eliminates the typical AMTL-N400 amplitude reduction with repetition, and leads to significant memory impairment. Of the various hippocampal subfields, only the density of CA1 neurons correlates with the word-related ERPs that are reduced by ketamine. Altogether, our behavioral, anatomical, and electrophysiological results indicate that hippocampal NMDA receptors are involved in human memory. L ong-term potentiation (LTP) is a long-lasting increase in synaptic efficacy after high-frequency stimulation of afferent fibers. It depends on high levels of postsynaptic calcium. The primary source of the calcium influx during the induction of hippocampal LTP occurs through an ion channel that is coupled to the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor (1, 2). NMDA receptors are thus hypothesized to play a crucial role in the induction of associative LTP within the hippocampal CA1-region (3); this is viewed as a putative mechanism for Hebbian learning. This form of synaptic plasticity has been offered as a cellular model of memory processes in hippocampal slice preparations (4). Numerous studies in rodents and primates have linked hippocampal LTP with spatial learning and memory (5) although there are some contradictory results (6).NMDA receptors are also abundant within the human hippocampus (14, 15). NMDA receptor antagonists block LTP induction in surgically resected specimens from the human temporal cortex (16). The human mesial temporal lobe system is considered essential for declarative memory (7, 8), contributing to both encoding and retrieval (9-13). Despite the suggestive findings of animal studies, however, the question of whether hippocampal NMDA receptors contribute to human memory processes remains unsettled.The occasional need to place depth electrodes within the mesial temporal lobes during the presurgical evaluation of patients with pharmacoresistant temporal lobe epilepsy affords us the opportunity to record depth potentials directly from the human hippocampal formation. Analyses of limbic event-related potentials (ERPs) can contribute to the presurgical workup with respect to both the lateralization of the epileptogenic focus (17-19) and the prediction of surgical outcome (20,21). Limbic ERPs also offer unique opportunities for investigating the relationship between hippocampal structures ...

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Section: Discussionmentioning

confidence: 99%

Evidence relating human verbal memory to hippocampal N -methyl- d- aspartate receptors

Grünwald¹,

Beck²,

Lehnertz³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

132

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“…Studies using glutamate antagonists, such as: ketamine [43], riluzole [5], remacemide [44] and lamotrigine [45], have demonstrated modest symptomatic benefits, but were insufficiently powered to demonstrate neuroprotective effects. A 30 month, Phase III trial of 347 symptomatic individuals, the 'coenzyme Q10 andremacemide evaluation in HD' (CARE-HD) trial was recently completed by the Huntington Study Group (HSG) and in retrospect was powered to detect too large of a slowing in progression (40%).…”

Section: Excitotoxicity Metabolic Insufficiency and Oxidative Injurymentioning

confidence: 99%

Neuroprotective therapy for Huntington’s disease: new prospects and challenges

Hersch¹,

Rosas²

2001

Expert Review of Neurotherapeutics

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Extraordinary advances in understanding of the molecular bases of neurodegeneration have occurred since the Huntington's disease genetic mutation was discovered. Many relevant routes to neuronal demise in Huntington's disease have been identified including: glutamatergic stress, metabolic insufficiency, oxidative stress, proapoptotic signaling, inflammatory signaling, altered proteolysis, protein aggregation, transcriptional dysregulation, abnormal protein folding and neurotrophin insufficiency. Each represents specific therapeutic opportunities, which are being tested in high-throughput screens as well as in genetic models of Huntington's disease, transgenic mouse models and human clinical trials. Challenges include the uncertain power of these preclinical studies to predict therapeutic efficacy in humans, prioritizing the many approaches for human clinical trials and learning how to perform neuroprotective trials in presymptomatic individuals while protecting them from unwanted genetic information.

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“…These results suggest that glutamate receptors may be good targets for drug development for the clinical treatment of opioid tolerance and dependence, and neuropathic pain. Although NMDA antagonists have been used clinically, their use is often associated with debilitating side effects such as memory, motor and cognitive impairments, and psychotomimetic effects (152)(153)(154)(155)(156). Either more selective NMDA antagonists, or perhaps other glutamate receptors, particularly mGluRs, are needed because they may be the best targets for future drug developments.…”

Section: Discussionmentioning

confidence: 99%

Common Mechanisms Underlying Opioid Tolerance and Dependence and Neuropathic Pain: Role of Metabotropic Glutamate Receptors

Fundytus

2000

Pain Research and Management

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It has been suggested that opioid tolerance and dependence share common mechanisms with neuropathic pain. This short review deals with the role of glutamate and glutamate receptors in opioid tolerance and dependence, and neuropathic pain. Particular attention is given to the role of metabotropic glutamate receptors (mGluRs). First, the different types of glutamate receptors, which include N-methyl-D-aspartate, alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid, kainate and mGluRs, are described. Following this, evidence suggesting that these receptors are involved in opioid tolerance and dependence are summarized. At the end of this section, a model that has been previously proposed to explain mechanisms by which mGluRs may be involved in opioid tolerance and dependence are described. Next is a discussion of the evidence suggesting that glutamate receptors are similarly involved in neuropathic pain, and also in opioid sensitivity associated with neuropathic pain. Again, a hypothetical model used to explain mechanisms by which mGluRs may be involved in neuropathic pain is briefly described. The relevance of the data is discussed in terms of some of the clinical implications of the material presented in the article. Mécanismes communs sous-jacents à la tolérance et à la dépendance aux substances opioïdes, ainsi qu'aux douleurs névropathiques : rôle des récepteurs du glutamate métabotropique RÉSUMÉ : La tolérance et la dépendance aux substances opioïdes partageraient des mécanismes communs aux douleurs névropathiques. Il sera question, dans le présent survol, du rôle du glutamate et des ré-cepteurs du glutamate dans la tolérance et la dépendance aux substances opioïdes, ainsi que dans les douleurs névropathiques. Une attention particulière est accordée au rôle des récepteurs du glutamate métabotropique (mGluR). Tout d'abord, on décrit les différents types de récepteur du glutamate, notamment le N-méthyl-D-aspartate, l'alpha-amino-3-hydroxyl-5-méthyl-isoxazole-4-acide proprionique, le kaïnate et les mGluR. Suit un résumé des données selon lesquelles ces récepteurs sont mis en cause dans la tolérance et la dépendance aux substances opioïdes. À la fin de cette partie, on décrit un modèle déjà proposé pour expliquer comment les mGluR pourraient participer à ce phénomène de tolérance et de dépendance. Ensuite, il y a une discussion sur les éléments qui donnent à penser que les récepteurs du glutamate sont également mis en cause dans les douleurs névropathiques ainsi que dans la sensibilité aux substances opioïdes, associée aux douleurs névropathiques. Encore une fois, on fait une brève description du modèle hypothétique utilisé pour expliquer comment les mGluR contribueraient aux douleurs névropathiques. La pertinence des données est ici discutée en fonction de certaines des incidences cliniques du matériel présenté dans l'article.

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Cognitive, behavioral, and motor effects of the NMDA antagonist ketamine in Huntington's disease

Abstract: These results describe the spectrum of clinical effects produced by increasing NMDA receptor blockade in HD patients. The clinical effects appearing with higher levels of NMDA receptor blockade can identify the range of doses used in clinical trials of NMDA receptor antagonists.

Cited by 41 publications

References 18 publications

Evidence relating human verbal memory to hippocampal N -methyl- d- aspartate receptors

Evidence relating human verbal memory to hippocampal N -methyl- d- aspartate receptors

Neuroprotective therapy for Huntington’s disease: new prospects and challenges

Common Mechanisms Underlying Opioid Tolerance and Dependence and Neuropathic Pain: Role of Metabotropic Glutamate Receptors

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