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Midazolam inhibits long-term potentiation through modulation of GABAA receptors
1Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
Abstract:
Benzodiazepine drugs (BZ) are used for anxiety, insomnia, and seizures. They worsen memory, especially in large doses, but the mechanism of this action is uncertain. In micromolar concentrations, benzodiazepines have been shown to reduce long-term potentiation (LTP), which could be a cellular basis for their amnesic action. We have found that the LTP-inhibiting effects of BZ occur in the nanomolar concentrations attained in humans, and that this effect occurs through modulation of GABAA receptor function. We recorded extracellular synaptic input/output (I/O) curves for population spikes (PS) and EPSPs in rat hippocampal slices before and after induction of LTP. LTP increased maximal PS and EPSPs and shifted I/O curves for PS and EPSPs to the left, reflecting increased synaptic responsiveness after LTP. Curves relating EPSPs to PS were also shifted, so that after LTP larger PS were elicited for the same size EPSP (E-S potentiation). Midazolam (0.5 microM) markedly inhibited the left-shift in PS I/O curves due to E-S potentiation but did not significantly affect other parameters. 8-Phenyltheophylline (10 microM), an adenosine receptor antagonist, did not prevent midazolam inhibition of LTP. Bicuculline, a GABAA receptor antagonist, caused a dose-dependent antagonism of midazolam's LTP inhibition. Our results suggest that benzodiazepines reduce LTP primarily through reduction of E-S potentiation, and that this effect occurs through modulation of GABAA receptor function. This could in part account for the ability of benzodiazepines to disturb new memory formation.
Insights
Benzodiazepines impair memory by reducing long-term potentiation (LTP) at concentrations found in humans. This effect is mediated by GABAA receptor modulation, specifically by reducing evoked synaptic potentiation.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Benzodiazepines (BZ) are widely prescribed for anxiety, insomnia, and seizures.
- BZ are known to impair memory, particularly at higher doses, but the underlying mechanisms remain unclear.
- Previous studies indicated BZ reduce long-term potentiation (LTP) in micromolar concentrations, suggesting a cellular basis for amnesia.
Purpose of the Study:
- To investigate the mechanism by which benzodiazepines inhibit LTP.
- To determine if BZ-induced LTP inhibition occurs at clinically relevant nanomolar concentrations.
- To elucidate the role of GABAA receptor function in BZ's effects on synaptic plasticity and memory.
Main Methods:
- Extracellular synaptic input/output (I/O) curves for population spikes (PS) and excitatory postsynaptic potentials (EPSPs) were recorded in rat hippocampal slices.
- LTP was induced, and its effects on synaptic responsiveness and E-S potentiation were analyzed.
- The impact of midazolam (a BZ) and bicuculline (a GABAA antagonist) on LTP and E-S potentiation was assessed.
Main Results:
- LTP enhanced synaptic responsiveness, indicated by left-shifts in PS and EPSP I/O curves and E-S potentiation.
- Midazolam (0.5 microM) significantly inhibited the E-S potentiation component of LTP but did not affect other parameters.
- GABAA receptor antagonist bicuculline dose-dependently blocked midazolam's inhibitory effect on LTP.
Conclusions:
- Benzodiazepines reduce LTP primarily by inhibiting E-S potentiation, a key aspect of synaptic plasticity.
- This amnesic effect is mediated through the modulation of GABAA receptor function.
- The findings suggest that GABAA receptor-mediated inhibition of E-S potentiation contributes to benzodiazepine-induced memory impairment in humans.