Neuroscience & Biobehavioral Reviews, Год журнала: 2025, Номер 172, С. 106132 - 106132
Опубликована: Апрель 4, 2025
Язык: Английский
Pharmacological Reviews, Год журнала: 2021, Номер 73(2), С. 763 - 791
Опубликована: Март 5, 2021
Hydroxynorketamines (HNKs) are formed in vivo after (R,S)-ketamine (ketamine) administration. The 12 HNK stereoisomers distinguished by the position of cyclohexyl ring hydroxylation (at 4, 5, or 6 position) and their unique stereochemistry at two stereocenters. Although HNKs were initially classified as inactive metabolites because lack anesthetic effects, more recent studies have begun to reveal biologic activities. In particular, (2R,6R)- (2S6)-HNK exert antidepressant-relevant behavioral physiologic effects preclinical models, which led a rapid increase seeking clarify mechanisms pharmacological effects. To date, majority research has focused on actions (2R,6R)-HNK its robust tests antidepressant effectiveness limited adverse This review describes pharmacokinetics pharmacodynamics, well putative cellular, molecular, synaptic thought underlie both following metabolism from ketamine direct administration studies. Converging evidence indicates that modulate glutamatergic neurotransmission downstream signaling pathways several brain regions, including hippocampus prefrontal cortex. Effects other neurotransmitter systems, possible neurotrophic inflammatory processes, energy metabolism, also discussed. Additionally, therapeutic applications described, treatment unipolar bipolar depression, post-traumatic stress disorder, chronic pain, neuroinflammation, anti-inflammatory analgesic uses. SIGNIFICANCE STATEMENT: Preclinical indicate hydroxynorketamines may analgesic, anti-inflammatory, physiological relevant for variety human diseases. details pharmacodynamics HNKs, actions, action, potential applications.
Язык: Английский
Процитировано
77
Cell Reports, Год журнала: 2021, Номер 36(7), С. 109513 - 109513
Опубликована: Авг. 1, 2021
Ketamine produces rapid antidepressant action in patients with major depression or treatment-resistant depression. Studies have identified brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), as necessary for the effects underlying ketamine-induced synaptic potentiation hippocampus. Here, we delete BDNF TrkB presynaptic CA3 postsynaptic CA1 regions of Schaffer collateral pathway to investigate ketamine. The deletion Bdnf blocks potentiation. In contrast, ablation only eliminates We confirm BDNF-TrkB signaling is required ketamine's behavioral action. Moreover, ketamine application elicits dynamin1-dependent activation downstream trigger effects. Taken together, these data demonstrate a requirement neurons identify specific locus eliciting
Язык: Английский
Процитировано
67
Annual Review of Clinical Psychology, Год журнала: 2021, Номер 17(1), С. 207 - 231
Опубликована: Фев. 9, 2021
The therapeutic onset of traditional antidepressants is delayed by several weeks and many depressed patients fail to respond treatment altogether. In contrast, subanesthetic ketamine can rapidly alleviate symptoms depression within hours a single administration, even in who are considered treatment-resistant. Ketamine thought exert these effects restoring the integrity neural circuits that compromised depression. This hypothesis stems part from preclinical observations strengthen synaptic connections increasing glutamate-mediated neurotransmission promoting rapid neurotrophic factor release. An improved understanding how ketamine, other novel rapid-acting antidepressants, give rise processes will help foster future innovation. Here, we review history antidepressant advances preceded discovery, critically examine mechanistic hypotheses for may its effects, discuss impact this knowledge has had on ongoing drug discovery efforts.
Язык: Английский
Процитировано
65
Annual Review of Neuroscience, Год журнала: 2022, Номер 45(1), С. 581 - 601
Опубликована: Май 4, 2022
Depression is an episodic form of mental illness characterized by mood state transitions with poorly understood neurobiological mechanisms. Antidepressants reverse the effects stress and depression on synapse function, enhancing neurotransmission, increasing plasticity, generating new synapses in stress-sensitive brain regions. These properties are shared to varying degrees all known antidepressants, suggesting that synaptic remodeling could play a key role pathophysiology antidepressant function. Still, it unclear whether precisely how synaptogenesis contributes transitions. Here, we review evidence supporting emerging model which defined distinct distributed across multiple circuits, neurons assuming altered functional properties, configurations, and, importantly, reduced capacity for plasticity adaptation. act initially facilitating enabling reconfiguration this state. Subsequently, plays specific sustaining these changes over time.
Язык: Английский
Процитировано
65
Current Opinion in Behavioral Sciences, Год журнала: 2021, Номер 40, С. 130 - 136
Опубликована: Май 12, 2021
The human brain is a complex organ with multiple competing imperatives. It must perceive and interpret the world, incorporate new information, maintain its functional integrity over lifespan. Neural activity associated all of these processes. Spontaneous BOLD signals have been invoked as representing neural However, their exact role in processes remains controversial. Here, we review learning machine theory, molecular mechanisms synaptic plasticity homeostasis, recent experimental evidence to suggest that spontaneous may be more closely aligned off-line homeostatic than on-line fluctuations cognitive content.
Язык: Английский
Процитировано
61
Neuron, Год журнала: 2022, Номер 110(7), С. 1116 - 1138
Опубликована: Фев. 18, 2022
Язык: Английский
Процитировано
50
Frontiers in Molecular Neuroscience, Год журнала: 2022, Номер 14
Опубликована: Янв. 6, 2022
Fragile X Syndrome (FXS) is a leading inherited cause of autism and intellectual disability, resulting from mutation in the FMR1 gene subsequent loss its protein product FMRP. Despite this simple genetic origin, FXS phenotypically complex disorder with range physical neurocognitive disruptions. While numerous molecular cellular pathways are affected by FMRP loss, there growing evidence that circuit hyperexcitability may be common convergence point can account for many wide-ranging phenotypes seen FXS. The mechanisms include alterations to excitatory synaptic function connectivity, reduced inhibitory neuron activity, as well changes ion channel expression conductance. However, understanding impact on complicated inherent plasticity neural circuits, which display an array homeostatic maintain activity near set levels. also important regulator activity-dependent brain, meaning dysregulated both consequence hyperexcitable networks This makes it difficult separate direct effects myriad pleiotropic compensatory associated it, likely contribute pathophysiology. Here we will: (1) review models, focusing similarities/differences across brain regions, cell-types, developmental time points; (2) examine how excitability disruptions interact each other ultimately dysfunction FXS; (3) discuss these deficits disease-relevant behavioral like epilepsy sensory hypersensitivity. Through discussion where current field stands, aim introduce perspectives moving forward research.
Язык: Английский
Процитировано
41
Frontiers in Synaptic Neuroscience, Год журнала: 2022, Номер 14
Опубликована: Май 19, 2022
Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response changes activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones functional integration within dendritic regions, concurrent has historically been underassessed. Growing evidence for pathological disruptions excitation inhibition (E/I) balance neurological neurodevelopmental disorders indicates need an improved, more "holistic" understanding interplay. There continues be long-standing focus on persistent strengthening (excitatory long-term potentiation; eLTP) its role learning memory, although importance potentiation (iLTP) depression (iLTD) become increasingly apparent. Emerging further points dynamic dialogue between synapses, but much remains understood regarding mechanisms extent this exchange. In mini-review, we explore calcium signaling crosstalk play regulating excitability. We examine current knowledge synapse responses perturbances activity, with induced short-term pharmacological treatments which act either enhance or reduce excitability via ionotropic receptor regulation culture. To delve deeper into potential crosstalk, discuss influence key regulatory proteins, including kinases, phosphatases, structural/scaffolding proteins. Finally, briefly suggest avenues future research better understand synapses.
Язык: Английский
Процитировано
41
Neuromodulation Technology at the Neural Interface, Год журнала: 2022, Номер 25(8), С. 1289 - 1298
Опубликована: Янв. 3, 2022
Язык: Английский
Процитировано
40
Trends in Molecular Medicine, Год журнала: 2023, Номер 29(5), С. 364 - 375
Опубликована: Март 10, 2023
Acute administration of (R,S)-ketamine (ketamine) produces rapid antidepressant effects that in some patients can be sustained for several days to more than a week. Ketamine blocks N-methyl-d-asparate (NMDA) receptors (NMDARs) elicit specific downstream signaling induces novel form synaptic plasticity the hippocampus has been linked action. These events lead subsequent transcriptional changes are involved effects. Here we review how ketamine triggers this intracellular pathway mediate which underlies and links it
Язык: Английский
Процитировано
37