In vivo microdialysis evidence that midazolam facilitates propofol-induced reduction in rat accumbal dopamine release

Abstract

The aim of this study was to determine whether propofol reduces extracellular concentrations of dopamine in the rat nucleus accumbens and, if so, whether this effect is potentiated by midazolam. Propofol and midazolam were administered intravenously, via the external jugular vein, to freely‐moving rats. The extracellular concentrations of dopamine in the nucleus accumbens were measured consecutively every 25 min by using in vivo brain microdialysis with electrochemical detection. Propofol (2.5, 5.0 and 10.0 mg/kg) decreased the accumbal dopamine concentrations in a dose‐dependent manner. The largest dose (10.0 mg/kg) decreased dopamine concentration by a maximum of 34% (P < 0.01) at its peak effect. The smallest dose of propofol (2.5 mg/kg) did not affect dopamine concentrations when given alone, but decreased concentrations by 23% (P < 0.05) when combined with a dose of midazolam (0.075 mg/kg) having only a minimal effect on dopamine concentrations. The present study demonstrates that propofol dose‐dependently reduces dopamine release in rat nucleus accumbens, and that the effect is facilitated by midazolam; a similar interaction is also seen clinically, on preoperative anxiety and on anaesthesia.

Diazepam Concurrently Increases the Frequency and Decreases the Amplitude of Transient Dopamine Release Events in the Nucleus Accumbens

“…It is possible that the electrophysiological results represent a disinhibition of DA neural activity in the VTA (O'Brien and White, 1987;Tan et al, 2010), which increases both the frequency and amplitude of accumbal transient release events. By contrast, the microdialysis results (Zetterström and Fillenz, 1990;Invernizzi et al, 1991;Finlay et al, 1992Finlay et al, , 1995Takada et al, 1993;Murai et al, 1994;Dazzi et al, 1995;Hegarty and Vogel, 1995;Motzo et al, 1997;Yoshida et al, 1999;Bentue-Ferrer et al, 2001;Rada and Hoebel, 2005;Gomez-A et al, 2017) and the recent anesthetized FSCV study (Gomez-A et al, 2017) might represent a localized suppression of accumbal DA release events. However, it should also be noted that the aforementioned electrophysiological studies identified dopamine neurons solely using electrophysiological criteria-which is now considered insufficient to determine whether a recorded unit is DAergic or GABAergic (Ungless et al, 2004;Ungless and Grace, 2012).…”

“…2011), it remains unclear how they alter DA release. All drugs of abuse are thought to increase brain DA levels (Di Chiara and Imperato, 1988), and the electrophysiology literature indicates that BZPs disinhibit VTA DA neurons (Tan et al, 2010(Tan et al, , 2011; however, the microdialysis literature generally reports that BZPs decrease accumbal DA concentration (Zetterström and Fillenz, 1990;Invernizzi et al, 1991;Finlay et al, 1992Finlay et al, , 1995Takada et al, 1993;Murai et al, 1994;Dazzi et al, 1995;Hegarty and Vogel, 1995;Motzo et al, 1997;Yoshida et al, 1999;Bentue-Ferrer et al, 2001;Rada and Hoebel, 2005; Gomez-A et al, 2017), but see Bentue-Ferrer et al (2001). Although microdialysis studies show a net reduction in extracellular DA concentration, the temporal resolution provided by this technique makes it difficult to discern whether a reduction in the amplitude of transient release events contributes to this effect.…”

“…A BZP-induced disinhibition of DA neural activity would also suggest that indices of NAc DA signaling should be enhanced. However, microdialysis studies generally report that BZPs decrease accumbal DA concentration (Zetterström and Fillenz, 1990;Invernizzi et al, 1991;Finlay et al, 1992Finlay et al, , 1995Takada et al, 1993;Murai et al, 1994;Dazzi et al, 1995;Hegarty and Vogel, 1995;Motzo et al, 1997;Yoshida et al, 1999;Bentue-Ferrer et al, 2001;Rada and Hoebel, 2005;Gomez-A et al, 2017), but see Bentue-Ferrer et al (2001). Furthermore, a recent fastscan cyclic voltammetry (FSCV) study reported that BZPs decrease the amplitude of electrically evoked accumbal DA concentrations (Gomez-A et al, 2017).…”

Diazepam attenuates the effects of cocaine on locomotion, 50‐kHz ultrasonic vocalizations and phasic dopamine in the nucleus accumbens of rats

“…Although the initial evidence that benzodiazepines decrease tonic dopamine date from the early 1990s, until recently it was generally accepted that all drugs of abuse, including benzodiazepines, cause an increase in the concentration of mesolimbic dopamine (Tan et al, 2010). However, this hypothesis was not supported by most microdialysis and PET studies, showing that benzodiazepines decrease dopamine concentrations in the dorsal and ventral striatum of several species (Dewey et al, 1992;Finlay et al, 1992;Gomez-A et al, 2017;Murai et al, 1994;Takada et al, 1993;Yoshida et al, 1999;Zetterström & Fillenz, 1990; but see Keller & Goeders, 2019). FSCV studies also showed that diazepam also diminished spontaneous and evoked phasic release of dopamine in the NAc and dorsal striatal of rodents (Brodnik et al, 2019;Gomez-A et al, 2017;Lopes et al, 2019;Schelp et al, 2018).…”

Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling

“…At the level of the VTA, benzodiazepines disinhibit DA neuron firing through action at local GABAergic interneurons [ 126 ], which in principle would result in increased DA levels in the NAc. However, at the level of the NAc, benzodiazepines are documented to reduce basal DA levels in studies employing in vivo microdialysis [ 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 ] and to attenuate evoked DA release in studies employing ex vivo and in vivo fast-scan cyclic voltammetry [ 37 , 47 , 136 ]. Direct recordings from DA axons in striatum have demonstrated that diazepam enhances the effects of striatal GABA tone at GABA A receptors on DA axons, further inhibiting DA release [ 47 ].…”