Unraveling Sex Differences in Affect Processing: Unique Oscillatory Signaling Dynamics in the Infralimbic Cortex and Nucleus Accumbens Shell.

Background: Negative affect is prevalent in psychiatric diseases such as depression and addiction. Projections from the infralimbic cortex (IL) to the nucleus accumbens shell (NAcSh) are causally linked to learned negative affect as 20 Hz optogenetic stimulation of this circuit reduces conditioned taste aversion (CTA) in male but not female rats. However, the prior study did not provide insight into how innate versus learned negative affect are processed in these areas across sex. Methods: To address this issue, local field potential activity was simultaneously recorded in the IL and NAcSh in response to intraoral infusion of rewarding (saccharin) and aversive (quinine) tastants and following induction of a CTA in male and female Sprague Dawley rats. Results: Local field potential oscillatory activity within each brain region to saccharin varied across sex. In males, CTA increased IL resting-state power, which was correlated with the strength of the learned aversion, and reduced beta power and IL-NAcSh coherence. In females, CTA increased gamma power in the NAcSh. Similar effects were observed in males and females after CTA in theta-low gamma phase-amplitude coupling. Finally, while quinine produced similar effects in oscillatory power across sex, females showed differences in phase-amplitude coupling within the NAcSh that may be linked to aversion resistance. Conclusions: We revealed sex-specific hedonic processing in the IL and NAcSh and how oscillatory signaling is disrupted in learned negative affect, revealing translationally relevant insight into potential treatment strategies that can help to reduce the deleterious effects of learned negative affect in psychiatric illnesses.

Intrinsic Functional Connectivity between the Anterior Insular and Retrosplenial Cortex as a Moderator and Consequence of Cocaine Self-Administration in Rats.

While functional brain imaging studies in humans suggest that chronic cocaine use alters functional connectivity (FC) within and between key large-scale brain networks, including the default mode network (DMN), the salience network (SN), and the central executive network (CEN), cross-sectional studies in humans are challenging to obtain brain FC prior to cocaine use. Such information is critical to reveal the relationship between individual's brain FC and the subsequent development of cocaine dependence and brain changes during abstinence. Here, we performed a longitudinal study examining functional magnetic resonance imaging (fMRI) data in male rats (n = 7), acquired before cocaine self-administration (baseline), on 1 d of abstinence following 10 d of cocaine self-administration, and again after 30 d of experimenter-imposed abstinence. Using repeated-measures analysis of variance (ANOVA) with network-based statistics (NBS), significant connectivity changes were found between anterior insular cortex (AI) of the SN, retrosplenial cortex (RSC) of the DMN, somatosensory cortex, and caudate-putamen (CPu), with AI-RSC FC showing the most robust changes between baseline and 1 d of abstinence. Additionally, the level of escalated cocaine intake is associated with AI-RSC and AI-CPu FC changes between 1 d and 30 d of abstinence; further, the subjects' AI-RSC FC prior to cocaine intake is a significant moderator for the AI-RSC changes during abstinence. These results provide novel insights into the roles of AI-RSC FC before and after cocaine intake and suggest this circuit to be a potential target to modulate large-scale network and associated behavioral changes in cocaine use disorders.

Neuronal Ensembles in the Infralimbic Cortex Dynamically Process Distinct Aspects of Hedonic Value.

Hedonic processing is critical for guiding appropriate behavior, and the infralimbic cortex (IL) is a key neural substrate associated with this function in rodents and humans. We used deep brain in vivo calcium imaging and taste reactivity in freely behaving male and female Sprague Dawley rats to examine whether the infralimbic cortex is involved in encoding innate versus conditioned hedonic states. In experiment 1, we examined the IL neuronal ensemble responsiveness to intraoral innately rewarding (sucrose) versus aversive (quinine) tastants. Most IL neurons responded to either sucrose only or both sucrose and quinine, with fewer neurons selectively processing quinine. Among neurons that responded to both stimuli, some appear to encode hedonic processing. In experiment 2, we examined how IL neurons process devalued sucrose using conditioned taste aversion (CTA). We found that neurons that responded exclusively to sucrose were disengaged while additional quinine-exclusive neurons were recruited. Moreover, tastant-specific neurons that did not change their neuronal activity after CTA appeared to encode objective hedonic value. However, other neuronal ensembles responded to both tastants and appear to encode distinct aspects of hedonic processing. Specifically, some neurons responded differently to quinine and sucrose and shifted from appetitive-like to aversive-like activity after CTA, thus encoding the subjective hedonic value of the stimulus. Conversely, neurons that responded similarly to both tastants were heightened after CTA. Our findings show dynamic shifts in IL ensembles encoding devalued sucrose and support a role for parallel processing of objective and subjective hedonic value.SIGNIFICANCE STATEMENT Disrupted affective processing contributes to psychiatric disorders including depression, substance use disorder, and schizophrenia. We assessed how the infralimbic cortex, a key neural substrate involved in affect generation and affect regulation, processes innate and learned hedonic states using deep brain in vivo calcium imaging in freely behaving rats. We report that unique infralimbic cortex ensembles encode stimulus subjective and objective hedonic value. Further, our findings support similarities and differences in innate versus learned negative affective states. This study provides insight into the neural mechanisms underlying affect generation and helps to establish a foundation for the development of novel treatment strategies to reduce negative affective states that arise in many psychiatric disorders.

Prelimbic cortex and nucleus accumbens core resting state signaling dynamics as a biomarker for cocaine seeking behaviors.

Substance use disorders (SUDs) are characterized by maladaptive signaling in the prefrontal cortex and associated regions, however precisely how these drug-induced abnormalities may be linked to drug seeking/taking behaviors is not well understood. Here, in vivo local field potential (LFP) electrophysiology was used in rats to examine the relationship between overall spontaneous (resting state) activity within the prelimbic cortex (PrL) and nucleus accumbens (NAc) core, and their functional connectivity, to cocaine taking and seeking behaviors. Adult, male Sprague-Dawley rats were trained to self-administer either intravenous cocaine (0.33 mg/inf) or water reinforcement during 6-hour daily sessions over 2 weeks; extinction sessions were completed immediately after self-administration training and following 30 days experimenter-imposed abstinence. Rest LFP recordings were completed during 3 recording periods (15 min each in a chamber different from the self-administration context) conducted (1) prior to self-administration training (rest LFP 1) (2) immediately after 2 weeks of self-administration training (rest LFP 2) and (3) following 1 month abstinence (rest LFP 3). Our findings show that resting state LFP power in the PrL recorded prior to training (Rest LFP 1) was positively correlated with total cocaine intake and escalation of cocaine seeking at the beta frequency range. Immediately after self-administration training (Rest LFP 2) power in the NAc core at gamma frequency was negatively correlated with incubation of cocaine craving. For rats trained to self-administer water, no significant correlations were observed. Together, these findings show that resting state LFP at specific timepoints in the addiction cycle can serve as unique predictors (biomarkers) of cocaine use disorders.

Prelimbic Cortex Activity during a Distress Tolerance Task Predicts Cocaine-Seeking Behavior in Male, But Not Female Rats.

Distress tolerance (DT) is defined as the ability to persist in challenging goal-directed behavior in the face of stress, and individuals with low DT exhibit heightened drug-seeking behavior. However, no preclinical studies have examined the neurobiology underlying this phenomenon. To assess this, in vivo electrophysiology was used in Long Evans male and female rats during a DT task to record neural activity in the prelimbic cortex (PrL), a brain region implicated in drug-seeking. Rats were first assessed for DT, defined as the amount of time elapsed before rats quit seeking reward in an increasingly difficult operant task. Subsequently, rats underwent 2 weeks of self-administration for either water/saline or cocaine for 6 h/day. Animals then began a 1 month period of experimenter-imposed abstinence to induce heightened drug-seeking behavior. On day 28 of abstinence, DT and neural activity were reassessed; and on day 30, cocaine-seeking behavior was examined under extinction. Males had significantly higher DT than females and exhibited significantly more phasic PrL activity during the DT task. Furthermore, in male rats with a history of cocaine, PrL activity shifted to track DT; and this change in activity significantly correlated with the change in DT. Additionally, male (but not female) rats with low DT after 28 d of abstinence had significantly heightened drug-seeking behavior. Finally, PrL activity during the DT task predicted cocaine-seeking behavior. Collectively, these data demonstrate an important role for the PrL in DT in males, and link this neural activity and behavior to drug-seeking, particularly in males.SIGNIFICANCE STATEMENT Distress tolerance (DT) is defined as the ability to persist in challenging goal-directed behavior in the face of stress, and individuals with low DT exhibit heightened drug-seeking. Here, we investigated the role of the prelimbic cortex (PrL) in DT and its relationship to cocaine-seeking in male and female rats. We found that males had significantly higher DT than females and exhibited significantly more PrL activity during the DT task. Furthermore, male (but not female) rats with low DT after 28 d of abstinence had significantly heightened drug-seeking behavior. Finally, PrL activity during the DT task predicted cocaine-seeking. These data demonstrate an important role for the PrL in DT and link this neural activity and behavior to drug-seeking in males.

An opposing role for prelimbic cortical projections to the nucleus accumbens core in incubation of craving for cocaine versus water.

BACKGROUND: Both drug and natural reward-seeking have been shown to increase following an extended period of abstinence, a phenomenon termed 'incubation of craving'. Although this phenomenon involves many brain regions, the projections from the prelimbic cortex (PrL) to the nucleus accumbens (NAc) core have been strongly implicated in incubation of cocaine-seeking. However, this circuit has not been investigated in the context of incubation of craving for natural rewards. METHODS: Male Long Evans rats were trained to self-administer cocaine or water/saline 6 h/d for 14 days and subsequently entered 1 month of experimenter-imposed abstinence. Rats then underwent an optogenetic stimulation protocol used to induce long term depression in the PrL terminals to the NAc core immediately before beginning an extinction test used to assess incubation of craving. RESULTS: Control cocaine rats showed heightened drug-seeking on day 30 when compared to day 1 of abstinence, demonstrating incubation of craving. Notably, optogenetic stimulation of the PrL to NAc core pathway blocked this behavior in cocaine rats. In contrast, optogenetic stimulation of the PrL to NAc core pathway induced incubation of craving in water/saline rats. CONCLUSIONS: These findings suggest that neuroadaptations in the PrL to NAc core pathway play opposing roles in the incubation of craving for cocaine versus water.

A sex-dependent role for the prelimbic cortex in impulsive action both before and following early cocaine abstinence.

Although impulsive action is strongly associated with addiction, the neural underpinnings of this relationship and how they are influenced by sex have not been well characterized. Here, we used a titrating reaction time task to assess differences in impulsive action in male and female Long Evans rats both before and after short (4-6 days) or long (25-27 days) abstinence from 2 weeks of cocaine or water/saline self-administration (6 h daily access). Neural activity in the prelimbic cortex (PrL) and nucleus accumbens (NAc) core was assessed at each time point. We found that a history of cocaine self-administration increased impulsivity in all rats following short, but not long, abstinence. Furthermore, male rats with an increased ratio of excited to inhibited neurons in the PrL at the start of each trial in the task exhibited higher impulsivity in the naïve state (before self-administration). Following short abstinence from cocaine, PrL activity in males became more inhibited, and this change in activity predicted the shift in impulsivity. However, PrL activity did not track impulsivity in female rats. Additionally, although the NAc core tracked several aspects of behavior in the task, it did not track impulsivity in either sex. Together, these findings demonstrate a sex-dependent role for the PrL in impulsivity both before and after a history of cocaine.

Noninvasive Brain Stimulation Rescues Cocaine-Induced Prefrontal Hypoactivity and Restores Flexible Behavior.

BACKGROUND: To obtain desirable goals, individuals must predict the outcome of specific choices, use that information to direct appropriate actions, and adjust behavior accordingly in changing environments (behavioral flexibility). Substance use disorders are marked by impairments in behavioral flexibility along with decreased prefrontal cortical function that limits the efficacy of treatment strategies. Restoring prefrontal hypoactivity, ideally in a noninvasive manner, is an intriguing target for improving flexible behavior and treatment outcomes. METHODS: A behavioral flexibility task was used in Long-Evans male rats (n = 97) in conjunction with electrophysiology, optogenetics, and a novel rat model of transcranial alternating current stimulation (tACS) to examine the prelimbic cortex (PrL) to nucleus accumbens (NAc) core circuit in behavioral flexibility and determine whether tACS can restore cocaine-induced neural and cognitive dysfunction. RESULTS: Optogenetic inactivation revealed that the PrL-NAc core circuit is necessary for the ability to learn strategies to flexibly shift behavior. Cocaine self-administration history caused aberrant PrL-NAc core neural encoding and deficits in flexibility. Optogenetics that selectively activated the PrL-NAc core pathway prior to learning rescued cocaine-induced cognitive flexibility deficits. Remarkably, tACS prior to learning the task reestablished adaptive signaling in the PrL-NAc circuit and restored flexible behavior in a relatively noninvasive and frequency-specific manner. CONCLUSIONS: We establish a role of NAc core-projecting PrL neurons in behavioral flexibility and provide a novel noninvasive brain stimulation method in rats to rescue cocaine-induced frontal hypofunction and restore flexible behavior, supporting a role of tACS as a therapeutic to treat cognitive deficits in substance use disorders.

Activation of Infralimbic to Nucleus Accumbens Shell Pathway Suppresses Conditioned Aversion in Male But Not Female Rats.

Hedonic processing plays an integral role in directing appropriate behavior, but disrupted hedonic processing is associated with psychiatric disorders such as depression. The infralimbic cortex (IL) is a key structure in affective processing in rodents and activation of its human homolog, the ventromedial prefrontal cortex, has been implicated in suppressing aversive states. Here, we tested whether optogenetic activation of glutamatergic projections from the IL to the nucleus accumbens shell (NAcSh) suppresses the aversive impact of sucrose devalued using the conditioned taste aversion paradigm in males and female rats. In naive rats, no significant differences in appetitive or aversive taste reactivity (TR) to sucrose was observed indicating that initial sucrose palatability was equivalent across sex. However, we found that optical activation of the IL-NAcSh pathway during intraoral infusion of devalued sucrose inhibited aversive TR in male but not female rats. Interestingly, when allowed to freely ingest water and sucrose in a two-bottle test both males and females with a history of IL-NAcSh stimulation exhibited greater preference for sucrose. Optical pathway activation failed to alter TR to innately bitter quinine in either sex. Finally, both sexes lever pressed to self-stimulate the IL-NAcSh pathway. These results indicate that the IL-NAcSh pathway plays an important role in suppressing learned aversive states selectively in males but spares hedonic processing of innately aversive tastants. Further, pathway activation is reinforcing in both sexes, indicating that suppression of conditioned aversive TR can be dissociable from the effects of unconditioned rewarding properties of IL-NAcSh pathway activation.SIGNIFICANCE STATEMENT Negative emotional states contribute to psychiatric disorders including depression and substance use disorders. In this study, we examined whether brain circuitry previously implicated in suppressing negative emotional states in humans can inhibit learned aversion in male and female rats. We found that optical activation of the infralimbic to nucleus accumbens shell pathway attenuates learned aversive responses in male but not female rats, indicating an important sex difference in the function of this brain pathway. Furthermore, we found that pathway stimulation was reinforcing in both sexes. Collectively, these findings support the role of the infralimbic cortex and its projection to the nucleus accumbens shell in suppressing learned negative emotional states and highlight an important sex-specific function of this pathway.

Alpha-tACS effect on inhibitory control and feasibility of administration in community outpatient substance use treatment.

BACKGROUND: Deficits in inhibitory control (IC) and distress tolerance (DT) are associated with substance use disorders (SUD) and post-treatment return to substance use. Transcranial alternating current stimulation (tACS) modulates the neural oscillations that are associated with the cognitive and affective mechanisms contributing to IC and DT. The aims of the current study were to examine the feasibility and acceptability of administering tACS in a community-based SUD treatment setting, and to test the effect of alpha-tACS on IC and DT. METHOD: A double-blind, randomized, active sham-controlled trial of treatment-seeking adults with a SUD (N = 30, Meanage = 43.2 years, 70.0% male). Participants attended two sessions and completed computerized inhibitory control and distress tolerance tasks while receiving tACS targeting the bilateral dorsolateral prefrontal cortex (DLPFC). Participants received sham-tACS and were then randomized to receive sham-, alpha-, or gamma-tACS within 2-3 days. RESULTS: Treatment retention was 87%. Participant self-reported belief of having received tACS and mean side effect intensity ratings did not differ across conditions, with all side effect ratings in the absent to mild range. There was a large (d = 0.83) and significant effect of alpha-tACS on inhibitory control compared to sham-tACS (ß = 1.78, SE = 0.65, 95 % CI: 0.41, 3.14, p<0.01). There were no significant effects of condition on distress tolerance. CONCLUSIONS: To our knowledge, this is the first study of tACS in adults with a SUD. Our findings provide preliminary evidence for recruitment, retention, and administration feasibility of tACS in a community-based substance use treatment program and a beneficial effect of alpha-tACS on inhibitory control.

Nucleus accumbens shell dopamine mediates outcome value, but not predicted value, in a magnitude decision-making task.

Effective decision-making depends on an animal's ability to predict and select the outcome of greatest value, and the nucleus accumbens (NAc) and its dopaminergic input play a key role in this process. We previously reported that rapid dopamine release in the NAc shell preferentially tracks the "preferred" (i.e., large reward) option during cues that predict the ability to respond for rewards of different sizes, as well as during reward delivery itself. The present study assessed whether shell dopamine release at these discrete times selectively mediated choice behavior for rewards of different magnitudes using optogenetics. Here, using Long Evans TH:Cre± rats we employed selective optogenetic stimulation of dopamine terminals in the NAc shell during either reward-predictive cues (experiment 1) or reward delivery (experiment 2) in a magnitude-based decision-making task. We found that in TH:Cre± rats, but not littermate controls, optical stimulation during low-magnitude reward delivery during forced choice trials was sufficient to bias preference for this option when given a choice. In contrast, optical stimulation of shell dopamine terminals during low-magnitude reward-predictive cues in forced choice trials did not shift free choice behavior in TH:Cre± rats or controls. The findings indicate that preferential dopamine signaling in the NAc shell during reward outcome (delivery), but not reward-predictive cues are sufficient to influence choice behavior in our task supporting a causal role of dopamine in the NAc shell in reward outcome value, but not value-based predictive strategies.

Prelimbic Cortical Neurons Track Preferred Reward Value and Reflect Impulsive Choice during Delay Discounting Behavior.

In delay discounting, individuals discount the value of a reward based on the delay to its receipt. The prelimbic cortex (PrL) is heavily interconnected with several brain regions implicated in delay discounting, but the specific contributions of the PrL to delay discounting are unknown. Here, we used multineuron electrophysiological recording methods in Long-Evans male (n = 10) and female (n = 9) rats to characterize the firing dynamics of PrL neurons during discrete cue and lever press events in a delay discounting task. Rats' initial preference for the large reward decreased as delays for that outcome increased across blocks, reflecting classic discounting behavior. Electrophysiological recordings revealed that subgroups of neurons exhibited phasic responses to cue presentations and lever presses. These phasic neurons were found to respond to either large/delay, small/immediate, or both trial types and the percentage of these neurons shifted across blocks as the expected value of the reward changed. Critically, this shift was only seen during trials in which animals could choose their preferred option (free choice trials) and not during trials where animals could choose only one option (forced choice trials). Further, this shift was dependent on rats' inherent impulsivity because high impulsive rats demonstrated a greater percentage of small/immediate-responsive neurons as the task progressed. Collectively, these findings suggest a unique role for the PrL in encoding reward value during delay discounting that is influenced by individual differences in impulsivity.SIGNIFICANCE STATEMENT In delay discounting, individuals discount the value of a reward based on the delay to its receipt. Here, we used electrophysiology to investigate the role of the prelimbic cortex (PrL) in this process. We found that subsets of neurons shifted activity as a function of the changing expected delay and reward magnitude, but this shift was only evident during trials in which animals could choose their preferred option. Further, this dynamic neural activity depended on rats' inherent impulsivity, with impulsive rats exhibiting a stronger neural shift toward the immediate reward as the task progressed. These findings suggest a role for the PrL in encoding reward value during delay discounting that is influenced by goal-directed context and individual differences in impulsivity.

Drug-induced dysphoria is enhanced following prolonged cocaine abstinence and dynamically tracked by nucleus accumbens neurons.

Negative reinforcement models postulate that addicts use drugs to alleviate negative affective states (e.g. dysphoria) associated with withdrawal. In a pre-clinical model, rats exhibit negative affect to a normally rewarding tastant when it predicts impending, but delayed cocaine, and nucleus accumbens (NAc) neurons dynamically track this state. Here, we examined the effects of short versus prolonged experimenter-imposed cocaine abstinence on negative affect, cocaine seeking and self-administration. Rats were given 14 saccharin-cocaine sessions; NAc activity and affective responses to the taste (i.e. taste reactivity) were measured during sessions 1 and 14. Next, following 1 or 30 days of abstinence, taste reactivity and cell firing were recorded in a three-phase test session: (1) intraoral saccharin infusions, (2) extinction and (3) cocaine self-administration. Results showed that 30 days of abstinence led to a significant enhancement of aversive responses to the cocaine-paired tastant, accompanied by a dramatic decline in NAc phasic activity during tastant infusion. While extinction behavior did not differ across groups, NAc phasic firing reemerged during drug seeking. Further, when drug was again readily available, greater aversion to the drug-paired tastant before and after abstinence was associated with increased self-administration following prolonged (30-day) abstinence in rats classified as high (not low) aversive. Collectively, these findings show that drug-induced dysphoria is enhanced following prolonged cocaine abstinence and that NAc neural signaling is dynamic, dampening when negative affect is at its highest (phase 1), but transitioning back 'online' during subsequent drug seeking and taking (phases 2 and 3).

A Neuronal Ensemble in the Rostral Agranular Insula Tracks Cocaine-Induced Devaluation of Natural Reward and Predicts Cocaine Seeking.

In substance use disorders, negative affect associated with drug withdrawal can elicit strong drug craving and promote relapse. One brain region implicated in those processes is the rostral agranular insular cortex (RAIC), although precisely how this region encodes negative affect associated with drug seeking is unknown. Here, a preclinical model was used where RAIC activity was examined in male Sprague Dawley rats during intraoral infusions of a sweet (saccharin) paired with impending but delayed access to cocaine self-administration, and for comparative purposes, during the sweet predicting saline self-administration or injection of lithium chloride (LiCl), or during intraoral infusions of a bitter taste (quinine). Consistent with previous work, cocaine-paired saccharin, LiCl-paired saccharin, and quinine all elicited aversive taste reactivity. However, the aversive taste reactivity elicited by the cocaine-paired tastant was qualitatively different from that evoked by the other two agents. Furthermore, differences in taste reactivity were reflected in RAIC cell firing, where distinct shifts in neural signaling were observed specifically after cocaine but not LiCl conditioning. Notably, low motivation for cocaine (indicated by low loading and slower latencies to lever press) was correlated with this shift in RAIC signaling, but aversive (gaping) responses were not. Collectively, these findings indicate that cocaine-paired tastants elicit unique aspects of aversive behaviors that differ from traditional conditioned taste aversion (LiCl) or quinine and that the RAIC plays a role in modulating drug-seeking behaviors driven by drug-induced dysphoria (craving), but not negative affect per se.SIGNIFICANCE STATEMENT In substance use disorders, negative affect associated with drug cues can elicit craving and promote relapse; however, the underlying neurocircuitry of this phenomenon is unknown. Here, we investigated the role of the rostral agranular insula cortex (RAIC) in these processes using a preclinical model wherein intraoral delivery of a sweet is paired with delayed access to cocaine self-administration. The taste comes to elicit negative affect that predicts heightened drug seeking. Here, we found that a population of RAIC neurons became inhibited during presentation of the cocaine-paired tastant (when negative affect is high) and that this inhibitory neural profile predicted lower drug seeking. These findings suggest that the RAIC may function to oppose cue-induced cocaine craving and help reduce motivation for the drug.

Low distress tolerance predicts heightened drug seeking and taking after extended abstinence from cocaine self-administration.

Distress tolerance (DT), defined as the ability to persist in goal-directed behavior while experiencing psychological distress, is associated with greater frequency of substance use and poor treatment outcomes. To examine a potential causal role substance use may play in DT, we developed a rodent model of DT in which rats had to press a lever within a continuously decreasing time window for reward while receiving negative feedback on failure trials. DT was defined as the time rats continued to seek reward before quitting the task. We assessed the relationship of DT with cocaine seeking/taking by measuring DT before cocaine self-administration (SA), and after 1 week and 1 month of drug abstinence. We found that DT prior to cocaine SA did not predict cocaine seeking/taking, yet DT measured after 1 month abstinence significantly predicted subsequent high levels of early session cocaine taking. Additionally, high DT measured after abstinence protected against high cocaine seeking, but this protective effect was blocked in rats with high impulsivity. Finally, while a decrease in 1 month-abstinent DT was observed following SA across treatment conditions, among cocaine-exposed rats, greater cocaine SA correlated with a steeper decrease in DT. These results show that low DT after drug abstinence is associated with heightened levels of cocaine seeking and taking behavior and that impulsivity influences this effect. Collectively, these results support the validity of our rodent DT model while extending the human literature and set the foundation for future animal studies designed to determine neural mechanisms underlying DT.

Opposing Roles of Rapid Dopamine Signaling Across the Rostral-Caudal Axis of the Nucleus Accumbens Shell in Drug-Induced Negative Affect.

BACKGROUND: Negative reinforcement theories of drug addiction posit that addicts use drugs to alleviate negative mood states. In a preclinical model developed in our laboratory, rats exhibit negative affect to a normally rewarding taste cue when it predicts impending but delayed cocaine. The emergence of this state is accompanied by a reduction in dopamine concentration in the rostral nucleus accumbens shell. However, the rostral and caudal regions of the shell have been implicated in promoting opposing appetitive and aversive states, respectively. Here, we tested whether dopamine transmission along the rostral-caudal axis of the shell plays differential roles in the emergence of drug-induced negative affect. METHODS: In TH::Cre rats, the dopaminergic pathways from the ventral tegmental area to the rostral and caudal regions of the shell were optogenetically stimulated during intraoral delivery of a taste cue signaling delayed cocaine. Affective responses to the taste cue were measured using taste reactivity, and optical self-stimulation of the rostral and caudal shells was also examined. RESULTS: Optical stimulation of the rostral shell during tastant infusion prevented the emergence of negative affect, but activation of the caudal shell exacerbated aversive responses. These effects endured in the absence of optical stimulation, and the degree of negative affect in our model predicted self-stimulation responding. CONCLUSIONS: These findings reveal unprecedented, pronounced, and opposing roles of rapid dopamine signaling across the rostral-caudal axis of the nucleus accumbens in the control of drug-induced negative affect, a hallmark of continued drug seeking and use in human addicts.

Nucleus Accumbens Shell Dopamine Preferentially Tracks Information Related to Outcome Value of Reward.

Effective decision-making requires organisms to predict reward values and bias behavior toward the best available option. The mesolimbic dopamine system, including the nucleus accumbens (NAc) shell and core, is involved in this process. Although studies support a role of the shell and core in specific aspects of decision-making (e.g., risk, effort, delay), no studies have directly compared dopamine release dynamics in these subregions to cues exclusively signaling the availability of different reward magnitudes. Here, fast-scan cyclic voltammetry was used to compare rapid dopamine release dynamics in the NAc subregions during a magnitude-based decision-making task. Rats learned that distinct cues signaled the availability of either a small or large reward (one or two sugar pellets), and then were given an opportunity to choose their preferred option. We found that peak dopamine release tracked the more preferred (higher-magnitude) option in both core and shell subregions. Critically, however, overall (i.e., global) dopamine release was significantly higher and longer lasting in the shell and tracked the preferred magnitude during the entire cue period. Further, in the shell (not core), dopamine signaling significantly declined immediately at the lever press for reward but increased during the period of reward consumption. Collectively, the results indicate that although dopamine release in both the core and shell are activated by cues signaling the opportunity to respond for rewards of different magnitudes, dopamine release in the shell plays a differential and unique role in tracking information related to the outcome value of reward.

Impulsive Rats Exhibit Blunted Dopamine Release Dynamics during a Delay Discounting Task Independent of Cocaine History.

The inability to wait for a large, delayed reward when faced with a small, immediate one, known as delay discounting, has been implicated in a number of disorders including substance abuse. Individual differences in impulsivity on the delay discounting task are reflected in differences in neural function, including in the nucleus accumbens (NAc) core. We examined the role of a history of cocaine self-administration, as well as individual differences in impulsivity, on rapid dopamine (DA) release dynamics in the NAc core. Rats with a history of cocaine or water/saline self-administration were tested on delay discounting while being simultaneously assayed for rapid DA release using electrochemical methods. In controls, we found that cue DA release was modulated by reward delay and magnitude, consistent with prior reports. A history of cocaine had no effect on either delay discounting or DA release dynamics. Nonetheless, independent of drug history, individual differences in impulsivity were related to DA release in the NAc core. First, high impulsive animals exhibited dampened cue DA release during the delay discounting task. Second, reward delay and magnitude in high impulsive animals failed to robustly modulate changes in cue DA release. Importantly, these two DAergic mechanisms were uncorrelated with each other and, together, accounted for a high degree of variance in impulsive behavior. Collectively, these findings demonstrate two distinct mechanisms by which rapid DA signaling may influence impulsivity, and illustrate the importance of NAc core DA release dynamics in impulsive behavior.

Prior Cocaine Experience Impairs Normal Phasic Dopamine Signals of Reward Value in Accumbens Shell.

Dopamine signals have repeatedly been linked to associative learning and motivational processes. However, there is considerably less agreement on a role for dopamine in reward processing, and therefore whether neuroplastic changes in dopamine function following chronic exposure to drugs of abuse such as cocaine may impair appropriate valuation of rewarding stimuli. To quantify this, we voltammetrically measured real-time dopamine release in the nucleus accumbens (NAc) core or shell while rats received unsignaled deliveries of either a small (1 pellet) or large (2 pellets) reward. In drug-naive controls, core dopamine signals did not discriminate between reward size at any point, while in the shell dopamine encoded magnitude differences only in a slower postpeak period. Despite this lack of discrimination between rewards by the peak DA response, controls easily discriminated between reward options in a subsequent choice task. In contrast, phasic dopamine reward signals were strongly altered by cocaine experience; core dopamine decreased peak response but increased discrimination between reward magnitudes while shell lost phasic responses to reward receipt altogether. Notably, animals with cocaine-associated alterations in dopamine signals for reward magnitude failed to subsequently discriminate between reward options. These findings suggest that cocaine self-administration alters the ability for dopamine signals to appropriately assign value to rewards and thus may in part contribute to later deficits in behaviors that depend on appropriate outcome valuation.

One month of cocaine abstinence potentiates rapid dopamine signaling in the nucleus accumbens core.

Cocaine addiction is a chronic relapsing disorder that is difficult to treat in part because addicts relapse even after extended periods of abstinence. Given the importance of the mesolimbic dopamine (DA) system in drug addiction, we sought to characterize cocaine abstinence induced changes in rapid DA signaling in the nucleus accumbens (NAc). Here, rats were trained to self-administer cocaine for 14 consecutive days, then divided into two groups. Day 1 rats (D1; n = 7) underwent 24 h of abstinence; Day 30 rats (D30; n = 7) underwent one month of abstinence. After abstinence, all rats underwent a single extinction session. Immediately after, rats were deeply anesthetized and fast scan cyclic voltammetry (FSCV) was used to measure DA release and uptake dynamics in the NAc core before and following a single cocaine injection. We show that one month of cocaine abstinence potentiates the peak concentration of electrically evoked DA in the NAc core following an acute injection of cocaine. This potentiation is not related to alterations in DA uptake parameters, which are unchanged following abstinence, but may reflect alterations in release. These results further support the abundance of literature showing that cocaine abstinence induces neuroplasticity in brain areas implicated in drug reward and relapse. The present findings also demonstrate critical differences between abstinence-induced neuroadaptations in DA signaling and those caused by drug exposure itself.