Preferential enhancement of dopamine transmission within the nucleus accumbens shell by cocaine is attributable to a direct increase in phasic dopamine release events

Abstract

Preferential enhancement of dopamine transmission within the nucleus accumbens (NAc) shell is a fundamental aspect of the neural regulation of cocaine reward. Despite its importance, the nature of this effect is poorly understood. Here, we used fast-scan cyclic voltammetry to examine specific transmission processes underlying cocaine-evoked increases in dopamine transmission within the NAc core and shell. Initially, we examined altered terminal dopamine concentrations after global autoreceptor blockade. This was the first examination of autoreceptor regulation of naturally occurring phasic dopamine transmission and provided a novel characterization of specific components of dopamine neurotransmission. Comparison of increased dopamine signaling evoked by autoreceptor blockade and cocaine administration allowed robust resolution between increased frequency, concentration, and duration of phasic dopamine release events after cocaine delivery. Cocaine increased dopamine transmission by slowed uptake and increased concentration of dopamine released in the core and shell. However, an additional increase in the number phasic release events occurred only within the NAc shell, and this increase was eliminated by inactivation of midbrain dopaminergic neurons. This represents the first evidence that cocaine directly increases the frequency of dopamine release events and reveals that this is responsible for preferentially increased dopamine transmission within the NAc shell after cocaine administration. Additionally, cocaine administration resulted in a synergistic increase in dopamine concentration, and subregion differences were abolished when cocaine was administered in the absence of autoregulation. Together, these results demonstrate that cocaine administration results in a temporally and regionally specific increase in phasic dopamine release that is significantly regulated by dopamine autoreceptors.

Figure 1.

Experimental design and histology. A, B, Recording sessions (indicated by arrows) were followed by electrical stimulation of dopaminergic cell bodies (indicated by boxes after the arrows). Subsequent recording sessions began 5 min after stimulation offset. Specific manipulations are color coded throughout the study, with baseline (no manipulation) recordings coded as white and saline control sessions as black. A, rac/coc subjects received raclopride infusions (1 mg/kg; 6 s) (green) followed by cocaine (3 mg/kg; 6 s) (gray). B, coc/rac subjects received cocaine (orange) followed by raclopride (blue). C, For rac/coc subjects, dopamine measurements were conducted in either the NAc core (n = 7) or shell (n = 6). D, Measurements for coc/rac subjects were also conducted in either the core (n = 7) or shell (n = 5).

Figure 2.

Analysis of dopamine transients. A, The holding potential applied to the carbon-fiber electrode (−0.4 V) was ramped to 1.3 V and back 10 times per second. Oxidation and reduction reactions at the carbon surface result in changes in current that are plotted in false color. Dopamine release evoked by electrical stimulation (white dashed line) and naturally occurring dopamine transients (inverted white triangles) appear as brief green events at the potential of peak dopamine oxidation (∼0.65 V). B, Current was converted into [DA] and amplitudes for stimulated release (boxes on the trace indicate stimulation onset and offset), and transients are displayed above each event (indicated by orange circles). The point at which half-width was calculated is shown by the orange dashed lines, and the half-width values are given below.

Figure 3.

Representative examples of increases in dopamine concentration during drug delivery. A–D, Individual examples of 90 s [DA] traces across intravenous drug infusion (indicated by yellow boxes; 6 s; 0.2 ml). Insets provide increased resolution of naturally occurring transient events. A, B, Raclopride-evoked changes in [DA] within the NAc core (A) and NAc shell (B). C, Cocaine-evoked changes in [DA] within the NAc core (C) and NAc shell (D).

Figure 4.

Average drug-evoked increases in dopamine concentration and core–shell comparisons: rac/coc subjects. A, B, Mean concentration traces (solid lines) and mean plus SE (dashed lines) for saline (black), raclopride (rac; green), and cocaine in the presence of raclopride (rac-coc; gray) are superimposed on one another. Yellow boxes indicate the time of drug infusion. A, B, Drug-evoked [DA] changes within the NAc core (A) and NAc shell (B). C, D, [DA] was binned every 2.5 s for comparisons between the core and shell after raclopride (rac) administration C and cocaine administration in the presence of raclopride (rac-coc; D). Data from the NAc shell are displayed by open circles, and data from the core are shown as filled circles. Error bars indicate SEM. > signs indicate statistical significance (p < 0.01) between groups identified by their appropriate color-coded symbol. An asterisk inside the symbol indicates when drug-evoked [DA] is significantly greater compared with [DA] before drug infusion.

Figure 5.

Average drug-evoked increases in dopamine concentration and core–shell comparisons: coc/rac subjects. Mean concentration traces (solid lines) and mean plus SE (dashed lines) for saline (black), cocaine (coc; orange), and raclopride in the presence of cocaine (coc-rac; blue) are superimposed on one another. Yellow boxes indicate the time of drug infusion. A, B, Drug-evoked [DA] changes within the NAc core (A) and NAc shell (B). C, D, [DA] was binned every 2.5 s for comparisons between the core and shell after cocaine (coc) administration (C) and raclopride administration in the presence of cocaine (coc-rac; D). Data from the NAc shell are displayed by open circles, and data from the core are shown as filled circles. Error bars indicate SEM. > signs indicate statistical significance (p < 0.01) between groups identified by their appropriate color-coded symbol. An asterisk inside the symbol indicates when drug-evoked [DA] is significantly greater compared with [DA] before drug infusion.

Figure 6.

Transient frequency. A, Transients per minute after saline (black), raclopride (rac; green), and cocaine administration in the presence of raclopride (rac-coc; gray). B, Transients per minute after saline (black), cocaine (coc; orange), and raclopride administration in the presence of cocaine (coc-rac; blue). A, B, Data from the NAc shell are displayed by open circles, and data from the core are shown as filled circles. > signs indicate statistical significance (p < 0.01) between groups identified by their appropriate color-coded symbol. Error bars indicate SEM. C, Illustration of the approximate spread of microinfusions (based on dye infusion) into the VTA and location of carbon-fiber placements within the NAc shell. D, Mean baseline and cocaine-evoked (obtained from the first 3 min after cocaine infusion) transient frequency after either vehicle infusion (0.5 μl of saline) or vehicle containing the GABA agonists baclofen and muscimol (Bac/Mus) into the VTA. Error bars indicate SEM. *p < 0.05.

Figure 7.

Transient amplitude distributions. A, B, A color plot and corresponding [DA] trace from a baseline condition demonstrate the variability of transient amplitudes. Symbols are described in Figure 2. C–H, All dopamine transients within the 15 min recording sessions were grouped in 10 nm bins beginning with transients between 30 and 39 nm (30) and ending with transients between 150 and 159 nm (150). C–E, Core–shell comparisons of amplitude histograms for saline (from rac/coc subjects; C), raclopride (rac; D), and cocaine administration in the presence of raclopride (rac-coc; E). F–H, Core–shell comparisons for saline (from coc/rac subjects; F), cocaine (coc; G), and raclopride administration in the presence of cocaine (coc-rac; H). C–H, Data from the NAc core are presented as filled circles, and data from the NAc shell are presented as open circles. > signs indicate statistical significance (p < 0.01) between groups identified by their appropriate color-coded symbol. Error bars indicate SEM.

Figure 8.

Transient half-width. A, B, Representative color plot and corresponding [DA] trace after raclopride (A) and cocaine (B) administration. A, B, Examples are representative of ongoing transients between 5 and 15 min after drug delivery (i.e., after the initial drug effects described in Figs. 3–5). C–F, Half-width data were taken from all dopamine transients within the 15 min recording sessions; solid bars represent data from the NAc core, and striped bars represent data from the shell. C, D, Mean transient half-width after saline (sal; black), raclopride (rac; green), and cocaine administration in the presence of raclopride (rac-coc; gray) within the core (C) and within the shell (D). E, F, Mean transient half-width after saline (black), cocaine (coc; orange), and raclopride administration in the presence of cocaine (coc-rac; blue). C–F, Error bars indicate SEM. *p < 0.05.