Acetazolamide potentiates the afferent drive to prefrontal cortex in vivo

Abstract

The knowledge on real‐time neurophysiological effects of acetazolamide is still far behind the wide clinical use of this drug. Acetazolamide – a carbonic anhydrase inhibitor – has been shown to affect the neuromuscular transmission, implying a pH‐mediated influence on the central synaptic transmission. To start filling such a gap, we chose a central substrate: hippocampal‐prefrontal cortical projections; and a synaptic phenomenon: paired‐pulse facilitation (a form of synaptic plasticity) to probe this drug's effects on interareal brain communication in chronically implanted rats. We observed that systemic acetazolamide potentiates the hippocampal‐prefrontal paired‐pulse facilitation. In addition to this field electrophysiology data, we found that acetazolamide exerts a net inhibitory effect on prefrontal cortical single‐unit firing. We propose that systemic acetazolamide reduces the basal neuronal activity of the prefrontal cortex, whereas increasing the afferent drive it receives from the hippocampus. In addition to being relevant to the clinical and side effects of acetazolamide, these results suggest that exogenous pH regulation can have diverse impacts on afferent signaling across the neocortex.

A New Kid on the Block? Carbonic Anhydrases as Possible New Targets in Alzheimer’s Disease

“…The mechanisms underpinning CAs actions on cognition remain largely unidentified. Modulation of CAs activity alters the buffering capacity, thus influencing intracellular and extracellular pH value, therefore affecting protein NMDA and GABA receptors function [58]. Early studies demonstrated that the associated activation of multi-synaptic inputs on pyramidal neurons in the hippocampal CA1 region transiently transform GABAergic IPSPs to EPSPs; this transformation depends on CA activation as it busts HCO 3 − intracellular concentrations favouring its efflux through the GABA A receptor channel [39,59].…”

The role of carbonic anhydrases in extinction of contextual fear memory

“…In particular, brief stimulation of the infralimbic cortex (a subregion of the vmPFC) was found to reduce fear memory and strengthened extinction (12,49). More recently, systemic administration of ACTZ was found to inhibit prefrontal cortical single-unit firing in vivo, leading to reduced basal neuronal activity of the prefrontal cortex (50). Taken together, these findings suggest that ACTZ impairs fear extinction memory through inhibition of vmPFC firing.…”

Carbonic anhydrase inhibitor acetazolamide shifts synaptic vesicle recycling to a fast mode at the mouse neuromuscular junction

“…CA is present in many tissues of the body, including the brain, where catalyzes a reversible reaction between CO 2 hydration and HCO 2 3 dehydration. However, the mechanisms of how this therapeutic effect is achieved are not known (Bueno-Junior et al, 2017;Ruusuvuori and Kaila, 2014). Zhang et al (2010) used the pH-sensitive fluorescence of Yellow Fluorescent Protein transgenically expressed in mouse motor nerve terminals to report pH changes due to presynaptic stimulation.…”

“…CA is present in many tissues of the body, including the brain, where catalyzes a reversible reaction between CO 2 hydration and dehydration. However, the mechanisms of how this therapeutic effect is achieved are not known (Bueno‐Junior et al, ; Ruusuvuori and Kaila, ).…”