Diazepam Inhibits Electrically Evoked and Tonic Dopamine Release in the Nucleus Accumbens and Reverses the Effect of Amphetamine

Abstract

Diazepam is a benzodiazepine receptor agonist with anxiolytic and addictive properties. Although most drugs of abuse increase the level of release of dopamine in the nucleus accumbens, here we show that diazepam not only causes the opposite effect but also prevents amphetamine from enhancing dopamine release. We used 20 min sampling in vivo microdialysis and subsecond fast-scan cyclic voltammetry recordings at carbon-fiber microelectrodes to show that diazepam caused a dose-dependent decrease in the level of tonic and electrically evoked dopamine release in the nucleus accumbens of urethane-anesthetized adult male Swiss mice. In fast-scan cyclic voltammetry assays, dopamine release was evoked by electrical stimulation of the ventral tegmental area. We observed that 2 and 3 mg of diazepam/kg reduced the level of electrically evoked dopamine release, and this effect was reversed by administration of the benzodiazepine receptor antagonist flumazenil in doses of 2.5 and 5 mg/kg, respectively. No significant effects on measures of dopamine re-uptake were observed. Cyclic voltammetry experiments further showed that amphetamine (5 mg/kg, intraperitoneally) caused a significant increase in the level of dopamine release and in the half-life for dopamine re-uptake. Diazepam (2 mg/kg) significantly weakened the effect of amphetamine on dopamine release without affecting dopamine re-uptake. These results suggest that the pharmacological effects of benzodiazepines have a dopaminergic component. In addition, our findings challenge the classic view that all drugs of abuse cause dopamine release in the nucleus accumbens and suggest that benzodiazepines could be useful in the treatment of addiction to other drugs that increase the level of dopamine release, such as cocaine, amphetamines, and nicotine.

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

“…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. Additionally, a recent FSCV study demonstrated that BZPs decrease electrically evoked DA release in the NAc of anesthetized rats (Gomez-A et al, 2017). Our study builds upon these data by demonstrating the effects of diazepam on naturally occurring accumbal transient release events in the awake and freely moving animal.…”

“…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).…”

“…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). In the current study, we predicted that a real-time analysis of BZP-induced accumbal DA release events would reveal an increase in their frequency, but also a decrease in their amplitude.…”

Effects of Diazepam on Reaction Times to Stop and Go

“…There are some reports of non-GABA A receptor occupancy (5HT, D2) by diazepam (Saner and Pletscher, 1979 ; Gomez et al, 2017 ; van der Kooij et al, 2018 ) raising the possibility that the effects we observed could be mediated via non-GABAergic mechanisms. However, this is unlikely to explain our results given that we observed effects at therapeutic doses of diazepam and that GABAergic networks are a crucial substrate of response inhibition (Nicholson et al, 2018 ).…”

Automatic Identification of Phasic Dopamine Release

“…FSCV is able to measure variations in dopamine concentration with high temporal and spatial resolution (Yorgason et al, 2011). Therefore, it provides information about how fast dopamine is released from and reuptaked to synaptic terminals, which is very important to study effects of drugs of abuse (Gomez-A et al, 2017;Fawaz et al, 2009).…”