Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity

Ingram, R.; Kang, Heather; Lightman, Stafford; Jane, David E.; Bortolotto, Zuner A.; Collingridge, Graham L.; Lodge, David; Volianskis, Arturas

doi:10.1016/j.neuropharm.2018.06.008

Cited by 29 publications

(30 citation statements)

References 140 publications

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“…In contrast, LTP requires mainly activation of GluN2A and GluN2B containing NMDAr. It has been shown that ketamine inhibits STP more potently than LTP 85 and it is possible that is the induction of STP that prevents ketamine effects. This hypothesis needs to be addressed in future studies since STP has been speculated as a physiological mechanism supporting working memory 86 .…”

Section: Discussionmentioning

confidence: 99%

Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

Lopes-Aguiar

Ruggiero

Rossignoli

et al. 2020

Sci Rep

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N-methyl-D-aspartate receptor (NMDAr) antagonists such as ketamine (KET) produce psychotic-like behavior in both humans and animal models. NMDAr hypofunction affects normal oscillatory dynamics and synaptic plasticity in key brain regions related to schizophrenia, particularly in the hippocampus and the prefrontal cortex. It has been shown that prior long-term potentiation (LTP) occluded the increase of synaptic efficacy in the hippocampus-prefrontal cortex pathway induced by MK-801, a noncompetitive NMDAr antagonist. However, it is not clear whether LTP could also modulate aberrant oscillations and short-term plasticity disruptions induced by NMDAr antagonists. Thus, we tested whether LTP could mitigate the electrophysiological changes promoted by KET. We recorded HPC-PFC local field potentials and evoked responses in urethane anesthetized rats, before and after KET administration, preceded or not by LTP induction. Our results show that KET promotes an aberrant delta-high-gamma cross-frequency coupling in the PFC and an enhancement in HPC-PFC evoked responses. LTP induction prior to KET attenuates changes in synaptic efficiency and prevents the increase in cortical gamma amplitude comodulation. These findings are consistent with evidence that increased efficiency of glutamatergic receptors attenuates cognitive impairment in animal models of psychosis. Therefore, high-frequency stimulation in HPC may be a useful tool to better understand how to prevent NMDAr hypofunction effects on synaptic plasticity and oscillatory coordination in corticolimbic circuits. The hippocampal-prefrontal cortex (HPC-PFC) monosynaptic pathway is implicated in cognitive functions, such as working memory, decision making, and spatial-temporal processing 1,2. Dysfunctional connectivity within HPC-PFC circuits is associated with the pathophysiology and genetic predisposition to schizophrenia 3-5. In schizophrenia, HPC-PFC connectivity is decreased during working memory tasks and increased in resting state 5-7. Such effects may be mediated, at least in part, by N-methyl-D-aspartate receptor (NMDAr). NMDAr binding is reduced in schizophrenic patients in both HPC and PFC, and administration of an NMDAr antagonist, such as ketamine, can induce psychotic symptoms in healthy patients and an increase in resting-state HPC-PFC connectivity 8-10. This NMDAr hypofunction also affects synaptic plasticity, inducing impairments in critical circuits, such as HPC-PFC, promoting cognitive symptoms by pathological neural activity 11-13. However, the relationship between synaptic plasticity in HPC-PFC circuits and schizophrenia is not fully understood.

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Section: Discussionmentioning

confidence: 99%

Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

Lopes-Aguiar

Ruggiero

Rossignoli

et al. 2020

Sci Rep

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“…31 The psychedelic effects of ketamine appear to stem from blockade of the NMDA-receptor channel and inhibition of short-and long-term potentiation (STP and LTP) at glutamate synapses. 32 Lysergic acid diethylamide (LSD) elicits a marked transformation in conscious experience with absence of insight via stimulation of serotonergic 5-HT 2A receptors. 33 Any enterprise that proposes a detailed, unifying theory for the various pro-psychotic drugs risks being outmoded, in a fairly short time frame, as our knowledge of the microanatomy and physiology of synaptic networks reaches new heights of complexity.…”

Section: Psychosis and Pro-psychotic Drugsmentioning

confidence: 99%

Cannabis points to the synaptic pathology of mental disorders: how aberrant synaptic components disrupt the highest psychological functions

Morrison

Murray

2020

Dialogues in Clinical Neuroscience

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Cannabis can elicit an acute psychotic reaction, and its long-term use is a risk factor for schizophrenia. The main active psychoactive ingredient ∆9-tetrahydrocannabinol (Δ9 -THC) activates cannabinoid 1 (CB1) receptors, which are localized to the terminals of glutamate and GABA neurons in the brain. The endogenous cannabinoids are involved in information processing and plasticity at synapses in the hippocampus, basal ganglia, and cerebral cortex. Exogenously applied CB1 receptor agonists disrupt neuronal dynamics and synaptic plasticity, resulting in cognitive deficits and impairment of the highest psychological functions. Various other pro-psychotic drugs, such as ketamine and methamphetamine, exert their effects in the same microdomain of synaptic spines as Δ9 -THC. Additionally, many of the most robust findings in psychiatric genetics include components that localize to dendritic spines and have important roles in information processing and plasticity.

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“…Some of this literature, concerning the effects of ketamine in synaptic plasticity, neuroprotection, epilepsy, pain and behaviour, is cited in previous reviews [198, 209]. …”

Section: Background To 1980 Discoveriesmentioning

confidence: 99%

The 1980s: d-AP5, LTP and a Decade of NMDA Receptor Discoveries

et al. 2018

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In the 1960s and 70s, biochemical and pharmacological evidence was pointing toward glutamate as a synaptic transmitter at a number of distinct receptor classes, known as NMDA and non-NMDA receptors. The field, however, lacked a potent and highly selective antagonist to block these putative postsynaptic receptors. So, the discoveries in the early 1980s of d-AP5 as a selective NMDA receptor antagonist and of its ability to block synaptic events and plasticity were a major breakthrough leading to an explosion of knowledge about this receptor subtype. During the next 10 years, the role of NMDA receptors was established in synaptic transmission, long-term potentiation, learning and memory, epilepsy, pain, among others. Hints at pharmacological heterogeneity among NMDA receptors were followed by the cloning of separate subunits. The purpose of this review is to recognize the important contributions made in the 1980s by Graham L. Collingridge and other key scientists to the advances in our understanding of the functions of NMDA receptors throughout the central nervous system.

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Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity

Cited by 29 publications

References 140 publications

Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

Cannabis points to the synaptic pathology of mental disorders: how aberrant synaptic components disrupt the highest psychological functions

The 1980s: d-AP5, LTP and a Decade of NMDA Receptor Discoveries

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