Highlights d PVT-NAc neurons develop inhibitory responses to rewardpredictive cues d Glutamatergic PFC axons to PVT show reductions in activity to cues d GABAergic LHA axons to PVT show increases in activity during licking d Optogenetic stimulation of PFC axons disrupts PVT-NAc cue encoding and behavior

Dopaminergic neurons contribute to intracranial self-stimulation (ICSS) and other reward-seeking behaviors, but itis not yet known where dopaminergic neurons intervene in the neural circuitry underlying reward pursuit or which psychological processes are involved. In rats working for electrical stimulation of the medial forebrain bundle, we assessed the effect of GBR-12909 (1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-[3-phenylpropyl]piperazine), a specific blocker of the dopamine transporter. Operant performance was measured as a function of the strength and cost of electrical stimulation. GBR-12909 increased the opportunity cost most subjects were willing to pay for a reward of a given intensity. However, this effect was smaller than that produced by a regimen of cocaine administration that drove similar increases in nucleus accumbens (NAc) dopamine levels in unstimulated rats. Delivery of rewarding stimulation to drug-treated rats caused an additional increase in dopamine concentration in the NAc shell in cocaine-treated, but not GBR-12909-treated, rats. These behavioral and neurochemical differences may reflect blockade of the norepinephrine transporter by cocaine but not by GBR-12909. Whereas the effect of psychomotor stimulants on ICSS has long been attributed to dopaminergic action at early stages of the reward pathway, the results reported here imply that increased dopamine tone boosts reward pursuit by acting at or beyond the output of the circuitry that temporally and spatially summates the output of the directly stimulated neurons underlying ICSS. The observed enhancement of reward seeking could be attributable to a decrease in the value of competing behaviors, a decrease in subjective effort costs, or an increase in reward-system gain.

The neurobiological study of reward was launched by the discovery of intracranial selfstimulation (ICSS). Subsequent investigation of this phenomenon provided the initial link between reward-seeking behavior and dopaminergic neurotransmission. We re-evaluated this relationship by psychophysical, pharmacological, optogenetic, and computational means. In rats working for direct, optical activation of midbrain dopamine neurons, we varied the strength and opportunity cost of the stimulation and measured time allocation, the proportion of trial time devoted to reward pursuit. We found that the dependence of time allocation on the strength and cost of stimulation was similar formally to that observed when electrical stimulation of the medial forebrain bundle served as the reward. When the stimulation is strong and cheap, the rats devote almost all their time to reward pursuit; time allocation falls off as stimulation strength is decreased and/or its opportunity cost is increased. A 3D plot of time allocation versus stimulation strength and cost produces a surface resembling the corner of a plateau (the "reward mountain"). We show that dopamine-transporter blockade shifts the mountain along both the strength and cost axes in rats working for optical activation of midbrain dopamine neurons. In contrast, the same drug shifted the mountain uniquely along the opportunity-cost axis when rats worked for electrical MFB stimulation in a prior study. Dopamine neurons are an obligatory stage in the dominant model of ICSS, which positions them at a key nexus in the final common path for reward seeking. This model fails to provide a cogent account for the differential effect of dopamine transporter blockade on the reward mountain. Instead, we propose that midbrain dopamine neurons and neurons with non-dopaminergic, MFB axons constitute parallel limbs of brain-reward circuitry that ultimately converge on the final-common path for the evaluation and pursuit of rewards.

Like indirect dopamine agonists, pimozide does not alter the sensitivity of brain reward circuity but changes reward-system gain, subjective effort costs, and/or the value of activities that compete with ICSS. The 3D method is more sensitive and informative than the 2D methods employed previously.

There is ample evidence that blockade of CB1 receptors reduces reward seeking. However, the reported effects of CB1 blockade on performance for rewarding electrical brain stimulation stand out as an exception. By applying a novel method for conceptualizing and measuring reward seeking, we show that AM-251, a CB1 receptor antagonist, does indeed decrease performance for rewarding electrical stimulation of the medial forebrain bundle in rats. Reward seeking depends on multiple sets of variables, including the intensity of the reward, its cost, and the value of competing rewards. In turn, reward intensity depends both on the sensitivity and gain of brain reward circuitry. We show that drug-induced changes in sensitivity cannot account for the suppressive effect of AM-251 on reward seeking. Therefore, the role of CB1 receptors must be sought among the remaining determinants of performance. Our analysis provides an explanation of the inconsistencies between prior reports, which likely arose from the following: (1) the averaging of data across subjects showing heterogeneous effects and (2) the use of methods that cannot distinguish between the different determinants of reward pursuit. By means of microdialysis, we demonstrate that blockade of CB1 receptors attenuates nucleus accumbens dopamine release in response to rewarding medial forebrain bundle stimulation, and we propose that this action is responsible for the ability of the drug to decrease performance for the electrical reward.