Rapid induction of dopamine sensitization in the nucleus accumbens shell induced by a single injection of cocaine

Abstract

Repeated intermittent exposure to cocaine results in the neurochemical sensitization of dopamine (DA) transmission within the nucleus accumbens (NAc). Indeed, the excitability of DA neurons in the ventral tegmental area (VTA) is enhanced within hours of initial psychostimulant exposure. However, it is not known if this is accompanied by a comparably rapid change in the ability of cocaine to increase extracellular DA concentrations in the ventral striatum. To address this question we used fast-scan cyclic voltammetry (FSCV) in awake-behaving rats to measure DA responses in the NAc shell following an initial intravenous cocaine injection, and then again 2-h later. Both injections quickly elevated DA levels in the NAc shell, but the second cocaine infusion produced a greater effect than the first, indicating sensitization. This suggests that a single injection of cocaine induces sensitization-related plasticity very rapidly within the mesolimbic DA system.

Keywords: Cocaine; Dopamine; Nucleus accumbens; Psychostimulant; Sensitization; Voltammetry.

Figure 1. Sensitization of NAc [DA]

(A) Average changes in [DA] are shown (n=8) following the first saline injection (saline 1, S1), the first cocaine injection (cocaine 1, C1), the second cocaine injection (cocaine 2, C2), and the final saline infusion (saline 2). According to linear mixed models regressions, both the first and second cocaine injection significantly increased [DA] in the NAc shell, relative to baseline (*, p<0.05). (B) The area under the curve (based on the data shown in A), a measure of total DA overflow in the NAc shell, was significantly increased following both the first (**, p<0.01) and second (*, p<0.05) cocaine infusion (relative to the first saline infusion). Also, compared to the first cocaine injection, the second cocaine infusion caused a significantly greater (i.e., sensitized) increase in [DA] within the NAc shell (+, p<0.05). (C) Coronal brain sections detailing locations of FSCV recordings in the NAc shell [12]. A cresyl violet stained hemisection of a brain slice is also displayed. As can be seen and detailed in the methods, when sacrificing rats the brain was purposely lesioned at the site of previous FSCV recordings to better visualize its location. Data are shown as mean ± SEM.

Figure 2. Individual Variation in Initial and Sensitized DA Response to Cocaine

Representative color plots and [DA] from 2 individual rats, (A) and (B). Data displayed from 90-second FSCV files, with the i.v. infusion of saline (ABi, iv) or cocaine (ABii, iii) occurring 5-seconds into the recording. The injection order was as follows: (i) “saline 1”, (ii) “cocaine 2,” 15-minutes after initial saline, (iii) “cocaine 3,” 2-hours after first cocaine injection, and finally (iv) “saline 2,” 1-hour after the second cocaine infusion. Color plots (i–iv) show current changes recorded on the carbon fiber electrode, plotted against the applied voltage (Eapp; −0.4 V to +1.3 V and back to −0.4 V, at 10Hz) and time. Calibrated [DA] traces are shown (ABv). ***, p<0.001, Wilcoxon Signed Rank Tests.