High frequency deep brain stimulation can mitigate the acute effects of cocaine administration on tonic dopamine levels in the rat nucleus accumbens

Abstract

Cocaine's addictive properties stem from its capacity to increase tonic extracellular dopamine levels in the nucleus accumbens (NAc). The ventral tegmental area (VTA) is a principal source of NAc dopamine. To investigate how high frequency stimulation (HFS) of the rodent VTA or nucleus accumbens core (NAcc) modulates the acute effects of cocaine administration on NAcc tonic dopamine levels multiple-cyclic square wave voltammetry (M-CSWV) was used. VTA HFS alone decreased NAcc tonic dopamine levels by 42%. NAcc HFS alone resulted in an initial decrease in tonic dopamine levels followed by a return to baseline. VTA or NAcc HFS following cocaine administration prevented the cocaine-induced increase in NAcc tonic dopamine. The present results suggest a possible underlying mechanism of NAc deep brain stimulation (DBS) in the treatment of substance use disorders (SUDs) and the possibility of treating SUD by abolishing dopamine release elicited by cocaine and other drugs of abuse by DBS in VTA, although further studies with chronic addiction models are required to confirm that. Furthermore, we demonstrated the use of M-CSWV can reliably measure tonic dopamine levels in vivo with both drug administration and DBS with minimal artifacts.

Keywords: cocaine; deep brain stimulation; nucleus accumbens; substance use disorder; tonic dopamine; ventral tegmental area.

FIGURE 1

(A) Simplified diagram demonstrating some of the major dopaminergic projections from the VTA. (B) The optimal depths of electrodes in the VTA and nucleus accumbens core (NAcc) were first identified using FSCV (maximum dopamine evoked release; 60 Hz, 2 ms, 0.2 mA, 2 s duration; Supplementary Figure A1). The system was then switched to M-CSWV to record tonic dopamine levels in the NAcc. (C) Experimental set-up of tonic dopamine measurements. With the control and AMPT groups, no stimulation was given. Waiting time for AMPT group (250 mg/kg) was increased compared to the control group due to the different route of administration, with the expectation that i.p. injections would result in a slower onset of action than i.v. injections. The stimulation group consisted of the continuous high-frequency stimulation (130 Hz, 200 micro-sec, 0.2 mA), while saline (1 ml/kg) and cocaine (2 mg/kg) were given intravenously. Partly created with BioRender.com. N = 5/group (20 in total). AMPT, alpha-methyl-p-tyrosine; CFM, carbon fiber microelectrode; DA, dopamine; FSCV, fast-scan cyclic voltammetry; i.p., intraperitoneal; i.v., intravenous; stim., stimulation; M-CSWV, multiple-cyclic square wave voltammetry; MFB, medial forebrain bundle; NAc, nucleus accumbens; VTA, ventral tegmental area.

FIGURE 2

Changes in nucleus accumbens core (NAcc) tonic dopamine concentrations after saline and cocaine. (A) Rapid increase in dopamine was seen after i.v. cocaine administration (2 mg/kg) compared to i.v. saline (1 ml/kg). Arrow denotes time of drug administration. (B) Saline did not significantly alter tonic dopamine levels (–8.0 ± 3.4 nM, N = 7 rats, p = 0.054), whereas cocaine rapidly increased dopamine levels (+62.9 ± 14.9 nM, +62%, N = 7 rats, p = 0.006). Two out of seven of the sample had a stimulating electrode (turned off) adjacent to the recording electrode; both showed brisk increase in tonic dopamine levels with cocaine administration. *Denotes p < 0.025 (0.05/2, with Bonferroni correction, given there are two t-tests here). (C,D) Representative color plots and voltammograms after saline and cocaine administration, respectively.

FIGURE 3

Changes in nucleus accumbens core (NAcc) tonic dopamine concentrations after saline and alpha-methyl-p-tyrosine (AMPT). (A) Gradual reduction in dopamine tonic levels was seen after i.p. AMPT administration (250 mg/kg) compared to i.v. saline (1 ml/kg). Arrow denotes time of drug administration. (B) Saline did not significantly alter tonic dopamine levels (–2.2 ± 3.1 nM, N = 5 rats, p = 0.513), whereas AMPT reduced dopamine levels (–34.5 ± 5.7 nM, –27%, N = 5 rats; p = 0.004). *Denotes p < 0.025 (0.05/2, with Bonferroni correction, given there are two t-tests here). (C,D) Representative color plots and voltammograms, after saline and AMPT administration, respectively.

FIGURE 4

Tonic dopamine concentrations during nucleus accumbens core (NAcc) high frequency stimulation (HFS) and after cocaine administration. (A,C) Stimulation suppressed tonic dopamine levels (–28.3 ± 6.3 nM, –20%; N = 5 rats, p = 0.011). (B,F) Cocaine-induced increases in tonic dopamine levels were attenuated by stimulation to non-significant levels (new baseline vs. saline, –4.9 ± 2.6 nM, N = 5 rats, p = 0.131; saline vs. cocaine peak, 1.3 ± 3.5 nM, p = 0.739). Black bars represent stimulation period. Arrow denotes drug administration. *Denotes p < 0.017 (0.05/3, with Bonferroni correction, given there are three t-tests here); ns, non-statistically significant. (D,E) Representative color plots and voltammograms, corresponding to the time points marked by black and red dotted lines in panel (A), respectively. Further trend in tonic dopamine levels after local HFS was stopped demonstrated no marked changes in levels (Supplementary Figure A2).

FIGURE 5

Tonic dopamine concentrations during ventral tegmental area (VTA) high frequency stimulation (HFS) and after cocaine administration. (A,C) Stimulation suppressed tonic dopamine levels (–47.3 ± 7.0 nM, –42%; p = 0.002). (B,F) Cocaine-induced increases in tonic dopamine levels were attenuated by stimulation to non-significant levels compared to the new baseline (+11.2 ± 5.0 nM, +17%; p = 0.091). Black bars represent stimulation period. Arrow denotes drug administration. *Denotes p < 0.017 (0.05/3, with Bonferroni correction, given there are three t-tests here); ns, non-statistically significant. (D,E) Representative color plots and voltammograms, corresponding to the time points marked by black and red dotted lines in panel (A), respectively. Further trend in tonic dopamine levels after local HFS was stopped demonstrated no continued suppression in levels (Supplementary Figure A5). Representative color plot and voltammogram of new baseline after i.v. cocaine administration (2 mg/kg) during VTA stimulation is shown in Supplementary Figure A6.