Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. During Pavlovian learning, previously neutral stimuli that predict rewards can acquire motivational properties, whereby they themselves become attractive and desirable incentive stimuli. But individuals differ in whether a cue acts solely as a predictor that evokes a conditional response, or also serves as an incentive stimulus, and this determines the degree to which a cue might bias choice or even promote maladaptive behavior. Here we use rats that differ in the incentive motivational properties they attribute to food cues to probe the role of the neurotransmitter dopamine in stimulus-reward learning. We show that intact dopamine transmission is not required for all forms of learning in which reward cues become effective predictors. Rather, dopamine acts selectively in a form of reward learning in which “incentive salience” is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behavior. This work provides insight into the neurobiology of a form of reward learning that confers increased susceptibility to disorders of impulse control.

Neurotransmission operates on a millisecond timescale, but is changed by normal experience or neuropathology over days, weeks or even months. Despite the great importance of long-term neurotransmitter dynamics, no technique exists to track these changes within a subject from day to day over extended periods of time. Here we describe and characterize a microsensor that can detect the neurotransmitter dopamine with subsecond temporal resolution over months in vivo in rats and mice.

Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that once drug use is well established, its control is dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to ascertain the spatiotemporal profile of striatal dopamine release and to investigate how it changes during the period from initial to established drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling i.v. catheters over the course of 3 wk of cocaine self-administration. We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks, a period during which VMS dopamine signaling declined. This emergent dopamine signaling in the DLS mediated discriminated behavior to obtain drug but did not promote escalated or compulsive drug use. We also demonstrate that this recruitment of dopamine signaling in the DLS is dependent on antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responses to obtain cocaine. D rug use often begins as a recreational behavior driven by the rewarding properties of the abused drug. However, addiction is characterized by habitual and compulsive drug use in which other factors, such as withdrawal symptoms, stress, and drug-associated conditioned stimuli (CS), also contribute to the motivation to consume drugs, and drug taking becomes increasingly prioritized over other behaviors (1). A wealth of evidence shows that the mesolimbic dopamine projection from the ventral tegmental area to the ventromedial striatum (VMS) is central to drug reinforcement (2). The ambient concentration of dopamine in the VMS is increased when animals self-administer drugs of abuse, including cocaine (3), and animals maintain this elevated dopamine level by regulating their rate of responding for drug (4). In addition, with repeated pairing of environmental stimuli with the drug, these CS also gain the propensity to elicit changes in dopamine concentration in the VMS (5-8); and even though these phasic neurochemical responses last only a few seconds, they are capable of controlling drug-seeking and -taking behavior (5). Together, these results implicate dopamine release in the VMS as a critical substrate in the control of drug use (2, 3, 9).However, the progression of drug taking beyond recreational use is thought to reflect the engagement of different psychological processes mediated within several neural loci (10, 11), with a particular emphasis on the incorporation of the sensorimotor (dorsolateral) striatum (DLS) in the c...

Drug addiction is a neuropsychiatric disorder marked by escalating drug use. Dopamine neurotransmission in the ventromedial striatum (VMS) mediates acute reinforcing effects of abused drugs, but with protracted use the dorsolateral striatum (DLS) is thought to assume control over drug seeking. We measured striatal dopamine release during a cocaine self-administration regimen that produced escalation of drug taking in rats. Surprisingly, we found that phasic dopamine decreased in both regions as the rate of cocaine intake increased; with the decrement in dopamine in the VMS significantly correlated with the rate of escalation. Administration of the dopamine precursor L-DOPA at a dose that replenished dopamine signaling in the VMS reversed escalation, thereby demonstrating the causal relationship between diminished dopamine transmission and excessive drug use. Thus, together these data provide mechanistic and therapeutic insight into the excessive drug intake that emerges following protracted use.