Abstract
Gamma frequency oscillations (γ, 30–100 Hz) have been suggested to underlie various cognitive and motor functions. The psychotomimetic drug methamphetamine (MA) enhances brain γ oscillations associated with changes in psychomotor state. Little is known about the cellular mechanisms of MA modulation on γ oscillations. We explored the effects of multiple intracellular kinases on MA modulation of γ induced by kainate in area CA3 of rat ventral hippocampal slices. We found that dopamine receptor type 1 and 2 (DR1 and DR2) antagonists, the serine/threonine kinase PKB/Akt inhibitor and N-methyl-D-aspartate receptor (NMDAR) antagonists prevented the enhancing effect of MA on γ oscillations, whereas none of them affected baseline γ strength. Protein kinase A, phosphoinositide 3-kinase and extracellular signal-related kinases inhibitors had no effect on MA. We propose that the DR1/DR2-Akt-NMDAR pathway plays a critical role for the MA enhancement of γ oscillations. Our study provides an new insight into the mechanisms of acute MA on MA-induced psychosis.
Highlights
Neuronal synchronization at γ frequency band (30–100 Hz, γ oscillations) emerges from activated neuronal networks, consisting of mutually connected principal cells and inhibitory cells (Fisahn et al, 1998). γ oscillations provide a millisecond-precision timing matrix that facilitates interneuronal communication and information transfer (Akam and Kullmann, 2014)
We found that MA caused a robust enhancement of hippocampal γ oscillations, through the activation of DR-Akt-N-methyl-D-aspartate receptor (NMDAR) signaling pathways
Our results demonstrate that MA increases hippocampal γ oscillation strength in vitro, is dependent on both DR1 and DR2 activation, Akt activity and NMDAR activity, but not on extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K) or protein kinase A (PKA) activity
Summary
Neuronal synchronization at γ frequency band (30–100 Hz, γ oscillations) emerges from activated neuronal networks, consisting of mutually connected principal cells and inhibitory cells (Fisahn et al, 1998). γ oscillations provide a millisecond-precision timing matrix that facilitates interneuronal communication and information transfer (Akam and Kullmann, 2014). Aberrant γ oscillations have been considered as a biomarker of a variety of neurological and psychiatric disorders, including Alzheimer’s disease (Mably and Colgin, 2018), ADHD (Barry and Clarke, 2013), schizophrenia and major depression Enhanced γ oscillation power has been associated with psychosis. Γ oscillation abnormalities in schizophrenia include abnormal increases in baseline power as well as deficits in evoked oscillations (Hirano et al, 2015). MA enhances γ oscillations in the nucleus accumbens and causes psychosis-like repetitive behaviors in rodents (Morra et al, 2012). Amphetamine, a metabolite of MA, enhances γ oscillations in the neocortex (Pinault, 2008; Qi et al, 2018) and hippocampus (Leung and Ma, 2018). Whereas hippocampal γ oscillations are crucially involved in a triangular relation with the nucleus accumbens and prefrontal cortex (Ma and Leung, 2010), the effect of MA on hippocampal γ oscillations is yet unknown
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