Dopamine signaling in the nucleus accumbens of animals self-administering drugs of abuse

Abstract

Abuse of psychoactive substances can lead to drug addiction. In animals, addiction is best modeled by drug self-administration paradigms. It has been proposed that the crucial common denominator for the development of drug addiction is the ability of drugs of abuse to increase extracellular concentrations of dopamine in the nucleus accumbens (NAcc). Studies using in vivo microdialysis and chronoamperometry in the behaving animal have demonstrated that drugs of abuse increase tonic dopamine concentrations in the NAcc. However, it is known that dopamine neurons respond to reward-related stimuli on a subsecond timescale. Thus, it is necessary to collect neurochemical information with this level of temporal resolution, as achieved with in vivo fast-scan cyclic voltammetry (FSCV), to fully understand the role of phasic dopamine release in normal behavior and drug addiction. We review studies that investigated the effects of drugs of abuse on NAcc dopamine levels in freely moving animals using in vivo microdialysis, chronoamperometry, and FSCV. After a brief introduction of dopamine signal transduction and anatomy and a section on current theories on the role of dopamine in natural goal-directed behavior, a discussion of techniques for the in vivo assessment of extracellular dopamine in behaving animals is presented. Then, we review studies using these techniques to investigate changes in phasic and tonic dopamine signaling in the NAcc during (1) response-dependent and -independent administration of abused drugs, (2) the presentation of drug-conditioned stimuli and operant behavior in self-administration paradigms, (3) drug withdrawal, and (4) cue-induced reinstatement of drug seeking. These results are then integrated with current ideas on the role of dopamine in addiction with an emphasis on a model illustrating phasic and tonic NAcc dopamine signaling during different stages of drug addiction. This model predicts that phasic dopamine release in response to drug-related stimuli will be enhanced over stimuli associated with natural reinforcers, which may result in aberrant goal-directed behaviors contributing to drug addiction.

Figure 1

Phasic dopamine signaling in the NAcc associated with drug seeking and taking (a) Phasic dopamine signaling consists of multiple phasic events (triangles). The first event is elicited by the animal’s approach of the operant lever (pre-response signal; 1), whereas a bigger second event is associated with the onset of the audiovisual cue (dark gray bar) that is presented in response to the lever press (post-response signal; 2). A set of peaks (3) that is observed with an onset of approximately 10 seconds after the lever press and the beginning of the drug infusion (light gray bar), is thought to be a direct consequence of the pharmacological effect of the drug. The latency of this pharmacological effect relative to the operant response appears to be more variable than for the post-response signal. (b) During extinction, the audiovisual stimulus presented after the lever press is not accompanied by a drug infusion. As a consequence, the post-response dopamine signal becomes smaller with repeated non-reinforced responding. In contrast, the pre-response signal remains relatively stable during extinction. This suggests that the pre-response signal reflects the motivation to obtain drug, whereas the post-response encodes the expectation of the drug infusion.

Figure 2

Drug-induced changes in phasic and tonic dopamine transmission in the NAcc (a) In the drug-naïve state, phasic (triangles) and tonic (solid horizontal line) dopamine signaling in the NAcc is normal. Few spontaneous phasic dopamine events (no cue) are observed. Salient stimuli (non-drug cues) can elicit phasic dopamine release and goal-directed behavior. (b) Drugs of abuse enhance tonic (dashed line) and phasic (triangles) dopamine signaling. Stimuli not associated with drug (non-drug cues) and drug-related cues both elicit phasic dopamine events, but the latter cause more robust release due to the temporal proximity to the drug administration. Furthermore, the number of spontaneous phasic dopamine events is increased. This may lead to aberrant learning of drug-cue associations and thus abnormal goal-directed behavior such as compulsive drug taking. (c) Effects of drug withdrawal on dopamine signaling are variable. For example, dampened tonic dopamine concentrations during withdrawal can be returned to and above basal concentrations by exposure to drug cues and drug context (left to right). Such drug cues may also elicit more phasic dopamine release (dashed triangle) compared to non-drug cues because 1) drugs represent a higher reward magnitude than natural reinforcers and/or 2) extended withdrawal results in incubation of drug craving. As a consequence, independent of tonic dopamine levels, seeking for drugs is more prevalent than seeking for natural reinforcers, which may promote relapse to drug taking.