Disruption of the mouse dopamine transporter gene results in spontaneous hyperlocomotion despite major adaptive changes, such as decreases in neurotransmitter and receptor levels. In homozygote mice, dopamine persists at least 100 times longer in the extracellular space, explaining the biochemical basis of the hyperdopaminergic phenotype and demonstrating the critical role of the transporter in regulating neurotransmission. The dopamine transporter is an obligatory target of cocaine and amphetamine, as these psychostimulants have no effect on locomotor activity or dopamine release and uptake in mice lacking the transporter.

The dopamine transporter (DAT) plays an important role in calibrating the duration and intensity of dopamine neurotransmission in the central nervous system. We have used a strain of mice in which the gene for the DAT has been genetically deleted to identify the DAT's homeostatic role. We find that removal of the DAT dramatically prolongs the lifetime (300 times) of extracellular dopamine. Within the time frame of neurotransmission, no other processes besides diffusion can compensate for the lack of the DAT, and the absence of the DAT produces extensive adaptive changes to control dopamine neurotransmission. Despite the absence of a clearance mechanism, dopamine extracellular levels were only 5 times greater than control animals due to a 95% reduction in content and a 75% reduction in release. Paradoxically, dopamine synthesis rates are doubled despite a decrease of 90% in the levels of tyrosine hydroxylase and degradation is markedly enhanced. Thus, the DAT not only controls the duration of extracellular dopamine signals but also plays a critical role in regulating presynaptic dopamine homeostasis. It is interesting to consider that the switch to a dopamine-deficient, but functionally hyperactive, mode of neurotransmission observed in mice lacking the DAT may represent an extreme example of neuronal plasticity resulting from long-term psychostimulant abuse.Dopamine is an important regulator of many physiological functions, including control of locomotion, cognition, affect, and neuroendocrine hormone secretion (1, 2). In the central nervous system, dopamine signaling is governed by a balance between the amount released, the duration of effects, and the responsiveness of receptors. The dopamine transporter is thought to play a central role in determining the duration of action of dopamine by rapidly taking up extracellular dopamine into presynaptic terminals after release (3). Differences in the number of uptake sites (4) in different brain regions provides dopamine with different extracellular lifetimes (5), which allows its diffusion to remote receptor sites (6). Furthermore, dopamine uptake rates are lowered by drugs of abuse such as cocaine and amphetamines, and this action is responsible for their stimulatory effects on behavior (7-9). In addition to the dynamic processes that govern dopamine neurotransmission, in the long term, dopamine is eventually inactivated by the degradative enzymes monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) (10).The physiological importance of the DAT has been mostly inferred from the behavioral and psychosocial effects of pharmacological agents that interfere with dopamine transport, such as psychostimulants and antidepressants. To examine the importance of the DAT, we created a strain of mice lacking the dopamine tranporter protein using homologous recombination (11). The most obvious phenotype of these genetically modified animals is their marked spontaneous hyperlocomotion, which is similar to animals on high doses of psychostimulants. In this work, ...

The ability to predict favorable outcomes using environmental cues is an essential part of learned behavior. Dopamine neurons in the midbrain encode such stimulus-reward relationships in a manner consistent with contemporary learning models, but it is unclear how encoding this translates into actual dopamine release in target regions. Here, we sampled dopamine levels in the rat nucleus accumbens on a rapid (100 ms) timescale using electrochemical technology during a classical conditioning procedure. Early in conditioning, transient dopamine-release events signaled a primary reward, but not predictive cues. After repeated cue-reward pairings, dopamine signals shifted in time to predictive cue onset and were no longer observed at reward delivery. In the absence of stimulus-reward conditioning, there was no shift in the dopamine signal. Consistent with proposed roles in reward prediction and incentive salience, these results indicate that rapid dopamine release provides a reward signal that is dynamically modified by associative learning.