The striatum and its ventral extension, the nucleus accumbens, are involved in behaviors as diverse as motor planning, drug seeking, and learning. Invariably, these striatally mediated behaviors depend on intact dopaminergic innervation. However, the mechanisms by which dopamine modulates neuronal function in the striatum and nucleus accumbens have been difficult to elucidate. Recent electrophysiological studies have revealed that dopamine alters both voltage-dependent conductances and synaptic transmission, resulting in state-dependent modulation of target cells. These studies make clear predictions about how dopamine, particularly via D1 receptor activation, should alter the responsiveness of striatal neurons to extrinsic excitatory synaptic activity.

Ventral tegmental area (VTA) neuron firing precedes behaviors elicited by reward-predictive sensory cues and scales with the magnitude and unpredictability of received rewards. These patterns are consistent with roles in the performance of learned appetitive behaviors and in positive reinforcement, respectively. The VTA includes subpopulations of neurons with different afferent connections, neurotransmitter content, and projection targets. Because the VTA and substantia nigra pars compacta are the sole sources of striatal and limbic forebrain dopamine, measurements of dopamine release and manipulations of dopamine function have provided critical evidence supporting a VTA contribution to these functions. However, the VTA also sends GABAergic and glutamatergic projections to the nucleus accumbens and prefrontal cortex. Furthermore, VTA-mediated but dopamine-independent positive reinforcement has been demonstrated. Consequently, identifying the neurotransmitter content and projection target of VTA neurons recorded in vivo will be critical for determining their contribution to learned appetitive behaviors.

Both the nucleus accumbens (NAc) and basolateral amygdala (BLA) contribute to learned behavioral choice. Neurons in both structures that encode reward-predictive cues may underlie the decision to respond to such cues, but the neural circuits by which the BLA influences reward-seeking behavior have not been established. Here, we test the hypothesis that the BLA drives NAc neuronal responses to reward-predictive cues. First, using a disconnection experiment, we show that the BLA and dopamine projections to the NAc interact to promote the reward-seeking behavioral response. Next, we demonstrate that BLA neuronal responses to cues precede those of NAc neurons, and that cue-evoked excitation of NAc neurons depends on BLA input. These results indicate that BLA input is required for dopamine to enhance the cue-evoked firing of NAc neurons, and that this enhanced firing promotes reward-seeking behavior.

Three hypotheses concerning the role of dopamine in these structures are proposed: (1) that dopamine release in the dorsal striatum serves to facilitate the ability to respond appropriately to temporally predictable stimuli (that is, stimuli that are so predictable that animals engage in anticipatory behavior just prior to the stimulus); (2) that dopamine in the nucleus accumbens facilitates the ability to respond to temporally unpredictable stimuli (which require interruption of ongoing behavior); and (3) that accumbens neurons participate in action selection in response to such stimuli by virtue of their direct (monosynaptic inhibitory) and indirect (polysynaptic excitatory) projections to basal ganglia output nuclei.

Dopamine released in the nucleus accumbens is thought to contribute to the decision to exert effort to seek reward. This hypothesis is supported by findings that performance of tasks requiring higher levels of effort is more susceptible to disruption by manipulations that reduce accumbens dopamine function than tasks that require less effort. However, performance of some low-effort cue-responding tasks is highly dependent on accumbens dopamine. To reconcile these disparate results, we made detailed behavioral observations of rats performing various operant tasks and determined how injection of dopamine receptor antagonists into the accumbens influenced specific aspects of the animals' behavior. Strikingly, once animals began a chain of operant responses, the antagonists did not affect the ability to continue the chain until reward delivery. Instead, when rats left the operandum, the antagonists severely impaired the ability to return. We show that this impairment is specific to situations in which the animal must determine a new set of approach actions on each approach occasion; this behavior is called "flexible approach." Both high-effort operant tasks and some low-effort cue-responding tasks require dopamine receptor activation in the accumbens because animals pause their responding and explore the chamber, and accumbens dopamine is required to terminate these pauses with flexible approach to the operandum. The flexible approach hypothesis provides a unified framework for understanding the contribution of the accumbens and its dopamine projection to reward-seeking behavior.

The nucleus accumbens (NAc) has long been thought of as a limbic-motor interface. Despite behavioral and anatomical evidence in favor of this idea, little is known about how NAc neurons encode information about motivationally relevant environmental cues and use this information to affect motor action. We therefore investigated the firing of these neurons during the performance of a discriminative stimulus (DS) task using simultaneous multiple single-unit recordings in rats. In this task, two stimuli are randomly presented to the animal: a DS, which signals the availability of a sucrose reward contingent on an operant response, and a similar but nonrewarded stimulus (NS). Subpopulations of NAc neurons increased or decreased their firing in association with several distinct components of the task. In this paper, we investigate cue- and operant-responsive neurons. Neurons excited and inhibited by cues showed larger firing changes in response to the DS than the NS and larger changes when the animal made an operant response to the cue than when the animal failed to respond. Excitations during operant responding were not modulated by the information contained by the cue, whereas inhibitions during operant responding were somewhat larger if the operant response occurred during the DS and somewhat smaller if they occurred in the absence of a cue. These results are consistent with the hypothesis that the firing of subpopulations of NAc neurons encode both the predictive value of environmental stimuli and the specific motor behaviors required to respond to them.

Reward-predictive cues exert powerful control over behavioral choice and may be a critical factor in drug addiction. Reward-seeking elicited by predictive cues is facilitated by the release of dopamine in the nucleus accumbens (NAc), yet the contribution of dopamine to the specific NAc firing patterns that underlie goal-directed behavior has remained elusive. We present evidence that subpopulations of NAc neurons that respond to predictive cues require the dopaminergic projection from the ventral tegmental area (VTA) to promote reward-seeking behavior. Rats trained to perform an operant response to a cue to obtain a sucrose reward were implanted with both multiunit recording electrodes in the NAc and microinjection cannulas in the VTA. Both the behavioral response to cues and the cue-evoked firing of NAc neurons were blocked by injection of the GABA B agonist baclofen into the VTA. An additional group of rats was trained on the same task and then implanted with microinjection cannulas in the NAc. Like VTA baclofen injection, injection of dopamine receptor antagonists into the NAc profoundly reduced cue-elicited reward seeking. Together, these results support the conclusion that both the behavioral response to the cue and the specific NAc neuronal firing that promotes the response depend on dopamine release within the NAc. Our findings suggest a neural mechanism by which the dopamine-dependent firing of NAc neurons mediates goaldirected behavior.

The effects of dopamine (DA) and the psychostimulants cocaine and amphetamine on excitatory transmission in the nucleus accumbens (NAc) were examined in rat NAc slices using both extracellular-field and whole-cell patch-clamp recording. DA, cocaine, and amphetamine reversibly reduced the excitatory synaptic responses (EPSPs/EPSCs) elicited by stimulation of prelimbic cortical afferents. DA and amphetamine increased paired-pulse facilitation, reduced the frequency of spontaneous miniature EPSCs (mEPSCs), and had no effect on mEPSC amplitude, suggesting a presynaptic mechanism for the observed reduction in excitatory synaptic transmission. The effects of DA and amphetamine were attenuated by the D1 receptor antagonist SCH23390 but not by the D2 receptor antagonist sulpiride. The broad-spectrum DA receptor agonist 6,7-ADTN mimicked the effects of DA and the psychostimulants, but neither the D1 receptor agonists SKF38393 and SKF81297 nor the D2 receptor agonist quinpirole caused a significant reduction in EPSP magnitude. SKF38393 at a higher concentration (100 microM) was effective in reducing the EPSP, however, and this reduction was sensitive to SCH23390. There was no difference in the effects of DA in cells from mutant mice lacking D1a receptors and cells from wild-type control mice. Unilaterally lesioning the dopaminergic afferents to the NAc using 6-hydroxydopamine attenuated the amphetamine-induced reduction in EPSP magnitude in slices from the lesioned hemisphere but not the control (unlesioned) hemisphere. These results indicate that DA and psychostimulants (acting indirectly by increasing endogenous extracellular DA levels) reduce excitatory synaptic transmission in the NAc by activating presynaptic DA receptors with D1-like properties.