Optogenetic stimulation of accumbens shell or shell projections to lateral hypothalamus produce differential effects on the motivation for cocaine.

Previous studies suggest that pharmacological or molecular activation of the nucleus accumbens shell (AcbSh) facilitates extinction of cocaine-seeking behavior. However, overexpression of CREB, which increases excitability of AcbSh neurons, enhances cocaine-seeking behavior while producing depression-like behavior in tests of mood. These discrepancies may reflect activity in differential AcbSh outputs, including those to the lateral hypothalamus (LH), a target region known to influence addictive behavior and mood. Presently, it is unknown whether there is a causal link between altered activity in the AcbSh-LH pathway and changes in the motivation for cocaine. In this study, we used an optogenetics approach to either globally stimulate AcbSh neurons or to selectively stimulate AcbSh terminal projections in the LH, in rats self-administering cocaine. We found that stimulation of the AcbSh-LH pathway enhanced the motivation to self-administer cocaine in progressive ratio testing, and led to long-lasting facilitation of cocaine-seeking behavior during extinction tests conducted after withdrawal from cocaine self-administration. In contrast, global AcbSh stimulation reduced extinction responding. We compared these opposing motivational effects with effects on mood using the forced swim test, where both global AcbSh neuron and selective AcbSh-LH terminal stimulation facilitated depression-like behavioral despair. Together, these findings suggest that the AcbSh neurons convey complex, pathway-specific modulation of addiction and depression-like behavior, and that these motivation and mood phenomenon are dissociable.

Nucleus accumbens responses differentiate execution and restraint in reward-directed behavior.

Our behavior is powerfully driven by environmental cues that signal the availability of rewarding stimuli. We frequently encounter stimuli-a bowl of candy or an alert from our smartphone-that trigger actions to obtain those rewards, even though there may be positive outcomes associated with not acting. The inability to restrain one's action in the presence of reward-associated cues is one type of impulsive behavior and a component of such maladaptive behaviors as overeating, gambling, and substance abuse. The nucleus accumbens (NAc) is ideally situated to integrate multiple cognitive and affective inputs to bias action via outputs through the basal ganglia. NAc neurons have been shown to respond to cues that predict reward availability, goal-directed behaviors aimed at obtaining them, and delivery of the reward itself. As these processes are typically associated, it is difficult to discern whether signals in the NAc are more closely related to processing reward-predictive aspects of goal-directed behavior or selection of behavioral response. To dissociate these possibilities, we recorded the activity of NAc neurons while rats performed a task in which two different cues both informed rats of reward availability but required them to either press a lever (Go) or withhold pressing (NoGo) to obtain the reward. Individual cue-responsive neurons showed either increases or decreases in activity at cue onset. Increases in activity were larger, and decreases smaller, when rats withheld lever pressing, whether correctly for NoGo trials or in error on Go trials. Thus NAc cue responses correlated with action, regardless of cue type or accuracy.

Reduction of cocaine self-administration and D3 receptor-mediated behavior by two novel dopamine D3 receptor-selective partial agonists, OS-3-106 and WW-III-55.

Dopamine D3 receptor (D3R)-selective compounds may be useful medications for cocaine dependence. In this study, we identified two novel arylamide phenylpiperazines, OS-3-106 and WW-III-55, as partial agonists at the D3R in the adenylyl cyclase inhibition assay. OS-3-106 and WW-III-55 have 115- and 862-fold D3R:D2 receptor (D2R) binding selectivity, respectively. We investigated their effects (0, 3, 5.6, or 10 mg/kg) on operant responding by using a multiple variable-interval (VI) 60-second schedule that alternated components with sucrose reinforcement and components with intravenous cocaine reinforcement (0.375 mg/kg). Additionally, we evaluated the effect of OS-3-106 (10 mg/kg) on the dose-response function of cocaine self-administration and the effect of WW-III-55 (0-5.6 mg/kg) on a progressive ratio schedule with either cocaine or sucrose reinforcement. Both compounds were also examined for effects on locomotion and yawning induced by a D3R agonist. OS-3-106 decreased cocaine and sucrose reinforcement rates, increased latency to first response for cocaine but not sucrose, and downshifted the cocaine self-administration dose-response function. WW-III-55 did not affect cocaine self-administration on the multiple-variable interval schedule, but it reduced cocaine and sucrose intake on the progressive ratio schedule. Both compounds reduced locomotion at doses that reduced responding, and both compounds attenuated yawning induced by low doses of 7-OH-DPAT (a D3R-mediated behavior), but neither affected yawning on the descending limb of the 7-OH-DPAT dose-response function (a D2R-mediated behavior). Therefore, both compounds blocked a D3R-mediated behavior. However, OS-3-106 was more effective in reducing cocaine self-administration. These findings support D3Rs, and possibly D2Rs, as targets for medications aimed at reducing the motivation to seek cocaine.

Nucleus accumbens shell, but not core, tracks motivational value of salt.

To appropriately respond to an affective stimulus, we must be able to track its value across changes in both the external and internal environment. The nucleus accumbens (NAc) is a critical component of reward circuitry, but recent work suggests that the NAc encodes aversion as well as reward. It remains unknown whether differential NAc activity reflects flexible changes in stimulus value when it is altered due to a change in physiological state. We measured the activity of individual NAc neurons when rats were given intraoral infusions of a hypertonic salt solution (0.45 M NaCl) across multiple sessions in which motivational state was manipulated. This normally nonpreferred taste was made rewarding via sodium depletion, which resulted in a strong motivation to seek out and consume salt. Recordings were made in three conditions: while sodium replete (REP), during acute sodium depletion (DEP), and following replenishment of salt to normal sodium balance (POST). We found that NAc neurons in the shell and core subregions responded differently across the three conditions. In the shell, we observed overall increases in NAc activity when the salt solution was nonpreferred (REP) but decreases when the salt solution was preferred (DEP). In the core, overall activity was significantly altered only after sodium balance was restored (POST). The results lend further support to the selective encoding of affective stimuli by the NAc and suggest that NAc shell is particularly involved in flexibly encoding stimulus value based on motivational state.

Encoding of aversion by dopamine and the nucleus accumbens.

Adaptive motivated behavior requires rapid discrimination between beneficial and harmful stimuli. Such discrimination leads to the generation of either an approach or rejection response, as appropriate, and enables organisms to maximize reward and minimize punishment. Classically, the nucleus accumbens (NAc) and the dopamine projection to it are considered an integral part of the brain's reward circuit, i.e., they direct approach and consumption behaviors and underlie positive reinforcement. This reward-centered framing ignores important evidence about the role of this system in encoding aversive events. One reason for bias toward reward is the difficulty in designing experiments in which animals repeatedly experience punishments; another is the challenge in dissociating the response to an aversive stimulus itself from the reward/relief experienced when an aversive stimulus is terminated. Here, we review studies that employ techniques with sufficient time resolution to measure responses in ventral tegmental area and NAc to aversive stimuli as they are delivered. We also present novel findings showing that the same stimulus - intra-oral infusion of sucrose - has differing effects on NAc shell dopamine release depending on the prior experience. Here, for some rats, sucrose was rendered aversive by explicitly pairing it with malaise in a conditioned taste aversion paradigm. Thereafter, sucrose infusions led to a suppression of dopamine with a similar magnitude and time course to intra-oral infusions of a bitter quinine solution. The results are discussed in the context of regional differences in dopamine signaling and the implications of a pause in phasic dopamine release within the NAc shell. Together with our data, the emerging literature suggests an important role for differential phasic dopamine signaling in aversion vs. reward.

Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum.

Transient increases in nucleus accumbens (NAc) dopamine concentration are observed when animals are presented with motivationally salient stimuli and are theorized to energize reward seeking. They arise from high-frequency firing of dopamine neurons in the ventral tegmental area (VTA), which also results in the release of endocannabinoids from dopamine cell bodies. In this context, endocannabinoids are thought to regulate reward seeking by modulating dopamine signaling, although a direct link has never been demonstrated. To test this, we pharmacologically manipulated endocannabinoid neurotransmission in the VTA while measuring transient changes in dopamine concentration in the NAc during reward seeking. Disrupting endocannabinoid signaling dramatically reduced, whereas augmenting levels of the endocannabinoid 2-arachidonoylglycerol (2AG) increased, cue-evoked dopamine concentrations and reward seeking. These data suggest that 2AG in the VTA regulates reward seeking by sculpting ethologically relevant patterns of dopamine release during reward-directed behavior.