Abstract
For over 40 years, in vivo microdialysis techniques have been at the forefront in measuring the effects of illicit substances on brain tonic extracellular levels of dopamine that underlie many aspects of drug addiction. However, the size of microdialysis probes and sampling rate may limit this technique’s ability to provide an accurate assessment of drug effects in microneural environments. A novel electrochemical method known as multiple-cyclic square wave voltammetry (M-CSWV), was recently developed to measure second-to-second changes in tonic dopamine levels at microelectrodes, providing spatiotemporal resolution superior to microdialysis. Here, we utilized M-CSWV and fast-scan cyclic voltammetry (FSCV) to measure changes in tonic or phasic dopamine release in the nucleus accumbens core (NAcc) after acute cocaine administration. Carbon-fiber microelectrodes (CFM) and stimulating electrodes were implanted into the NAcc and medial forebrain bundle (MFB) of urethane anesthetized (1.5 g/kg i.p.) Sprague-Dawley rats, respectively. Using FSCV, depths of each electrode were optimized by determining maximal MFB electrical stimulation-evoked phasic dopamine release. Changes in phasic responses were measured after a single dose of intravenous saline or cocaine hydrochloride (3 mg/kg; n = 4). In a separate group, changes in tonic dopamine levels were measured using M-CSWV after intravenous saline and after cocaine hydrochloride (3 mg/kg; n = 5). Both the phasic and tonic dopamine responses in the NAcc were augmented by the injection of cocaine compared to saline control. The phasic and tonic levels changed by approximately x2.4 and x1.9, respectively. These increases were largely consistent with previous studies using FSCV and microdialysis. However, the minimal disruption/disturbance of neuronal tissue by the CFM may explain why the baseline tonic dopamine values (134 ± 32 nM) measured by M-CSWV were found to be 10-fold higher when compared to conventional microdialysis. In this study, we demonstrated phasic dopamine dynamics in the NAcc with acute cocaine administration. M-CSWV was able to record rapid changes in tonic levels of dopamine, which cannot be achieved with other current voltammetric techniques. Taken together, M-CSWV has the potential to provide an unprecedented level of physiologic insight into dopamine signaling, both in vitro and in vivo, which will significantly enhance our understanding of neurochemical mechanisms underlying psychiatric conditions.
Highlights
Substance dependence is a global public health problem
Previous studies have demonstrated that dopamine release in the nucleus accumbens, dorsal striatum, and the prefrontal cortex is a cardinal feature in models of addiction, with dopamine receptor blockade in these areas disrupting drug-seeking behaviors (Berke and Hyman, 2000; Ito et al, 2002; Vanderschuren et al, 2005; Murray et al, 2012; Zbukvic et al, 2016; Hodebourg et al, 2019)
Cocaine administration consistently led to enhancement of stimulation-evoked dopamine responses (Figure 2)
Summary
A 2019 survey revealed 20.4 million people aged 12 or older in the United States suffered from substance use disorder (Substance Abuse and Mental Health Services Administration, 2020). Around 40–60% of patients experience relapse within one year of treatment discharge (McLellan et al, 2000), which is hypothesized to be a result of long-term neuroplastic changes after chronic drug use (Kalivas and O’Brien, 2008). Previous studies have demonstrated that dopamine release in the nucleus accumbens, dorsal striatum, and the prefrontal cortex is a cardinal feature in models of addiction, with dopamine receptor blockade in these areas disrupting drug-seeking behaviors (Berke and Hyman, 2000; Ito et al, 2002; Vanderschuren et al, 2005; Murray et al, 2012; Zbukvic et al, 2016; Hodebourg et al, 2019). Measuring dopamine with high temporal and spatial resolution in vivo is a major challenge
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