Phasic dopamine release in appetitive behaviors and drug addiction

Abstract

Although dopamine is implicated in the development of addiction, it is unclear how specific dopamine release patterns are involved with drug seeking. Addictive drugs increase tonic dopamine levels on the order of minutes, as well as phasic dopamine release events that occur on a subsecond time scale. Phasic dopamine release is associated with the initiation of goal-directed behaviors, and has been shown to promote drug seeking. Prior experience with addictive drugs modulates the synaptic and intrinsic properties of dopamine neurons, affects the pattern of dopamine neuron firing and release, and alters dopamine-dependent behaviors related to drug addiction. In this review, we synthesize the known drug-dependent changes to the dopamine system along with the established functions of phasic dopamine release in order to provide a framework for conceptualizing the role of phasic dopamine release in drug addiction. Because drug addiction is commonly thought to involve changes in brain circuits important for natural reinforcement, we first present the role of phasic dopamine release in appetitive and goal-directed behaviors in the context of contemporary theories regarding the function of dopamine. Next, we discuss the known drug-induced changes to dopamine neurons and phasic release in both in vitro and in vivo preparations. Finally, we offer a simple model that chronic drug experience increases the contrast, or 'signal to noise', of phasic dopamine release to basal dopamine levels in response to drug-related stimuli, which could result in aberrant associations between cues and reinforcers that contribute to the development of addiction.

Figure 1

Schematic representation of changes to the dopamine system after chronic drug experience. (Left) Illustration of the firing patterns of three hypothetical dopamine neurons from a drug-naïve individual where each vertical line represents an action potential. For clarity, there is no distinction between transient increases in firing rate and burst firing, as both are represented by a cluster of action potentials. The specific firing patterns responsible for phasic dopamine release are unknown, but phasic release likely results from coordinated activity of dopamine neurons firing in single-spikes and/or bursts. Notice that behaviorally relevant salient stimuli elicits coordinated activity of dopamine neurons that translates into a phasic increase in dopamine release that could occur in brain regions receiving VTA input, such as the NAcc. However, presentation of drug-related stimuli are without effect on dopamine neuron firing and release in the drug-naïve condition. (Right) After withdrawal from chronic drug treatment, dopamine neuron firing rate and population activity can be reduced, which is represented by fewer spontaneous action potentials and the lack of activity in Neuron 3. While the effect on basal dopamine levels remains controversial, many studies demonstrate instrinsic and synaptic changes on dopamine neurons that could promote the efficacy of glutamatergic inputs on dopamine neurons. We hypothesize that these intrinsic and synaptic changes will increase dopamine neuron firing and phasic release in response to drug-related stimuli. We propose that this increased ‘signal to noise’ of phasic dopamine release to basal dopamine levels contributes to the aberrent processing of drug-related stimuli, which in turn can promote drug seeking.