Cue-evoked dopamine release in the nucleus accumbens shell tracks reinforcer magnitude during intracranial self-stimulation

Abstract

The mesolimbic dopamine system is critically involved in modulating reward-seeking behavior and is transiently activated upon presentation of reward-predictive cues. It has previously been shown, using fast-scan cyclic voltammetry in behaving rats, that cues predicting a variety of reinforcers including food/water, cocaine or intracranial self-stimulation (ICSS) elicit time-locked transient fluctuations in dopamine concentration in the nucleus accumbens (NAc) shell. These dopamine transients have been found to correlate with reward-related learning and are believed to promote reward-seeking behavior. Here, we investigated the effects of varying reinforcer magnitude (intracranial stimulation parameters) on cue-evoked dopamine release in the NAc shell in rats performing ICSS. We found that the amplitude of cue-evoked dopamine is adaptable, tracks reinforcer magnitude and is significantly correlated with ICSS seeking behavior. Specifically, the concentration of cue-associated dopamine transients increased significantly with increasing reinforcer magnitude, while, at the same time, the latency to lever press decreased with reinforcer magnitude. These data support the proposed role of NAc dopamine in the facilitation of reward-seeking and provide unique insight into factors influencing the plasticity of dopaminergic signaling during behavior.

Figure 1. Reinforcer magnitude influences response rates for ICSS

The threshold curve shows the average number of presses in a 1 min interval for a range of stimulation currents (n = 6 animals). Based on these findings, the average currents chosen for the low, medium and high reinforcer magnitudes were 67 μA ± 8.71, 115 μA ± 11.4, and 186.67 μA ± 8.43, respectively (see methods for details).

Figure 2. Transient increases in dopamine release follow cue onset during ICSS

A) Top, A time line of the ICSS paradigm used during dopamine measurements. Each trial began with cue onset (2 s prior to lever extension) and ended with stimulation delivery. Trials were separated by a random interval of 5 s – 25 s (as indicated by the dashed line). Center, a color plot from a single trial in a single animal. It displays the transient dopamine activity observed in response to cue onset and stimulation. Changes in current due to dopamine oxidation are color-coded and occur at the oxidation potential for dopamine (~0.6 V vs. Ag/AgCl). Bottom, the dopamine concentration extracted from these data using principal component regression are shown. B) A color plot and corresponding concentration versus time trace averaged over 70 trials during responding for a high stimulation current in a single animal.

Figure 3. Cue-evoked dopamine release in the NAc shell varies as a function of reinforcer magnitude

A) Representative dopamine concentration traces are shown for the low, medium, and high reinforcer magnitude conditions. Cue onset is indicated by the first dashed line (gray) and lever presentation is indicated by the second dashed line (black). B) Average concentrations across each trial for cue-evoked (upper) and stimulated-evoked (lower) dopamine at different reinforcer magnitudes. Data points are the average (± SEM) across animals (n = 6).

Figure 4. Cue-evoked dopamine in the NAc shell significantly influences reward-seeking behavior and is a function of reinforcer value

A) The slopes of the average cue-evoked (gray line) and stimulated (black line) dopamine signals as a function of stimulation current were significantly different from one another (p < 0.001). The slopes were obtained from a linear regression analysis. B) Cue-evoked dopamine was significantly correlated with the latency to press in an inverse manner (r² = 0.337,*p < 0.05). Each data point is the average response to the trials with low, medium or high ICSS currents from each animal.