[Show abstract][Hide abstract] ABSTRACT: Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in theNAcis altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse.
Preview · Article · Jan 2016 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Principal component regression, a multivariate calibration technique, is an invaluable tool for the analysis of voltammetric data collected in vivo with acutely implanted microelectrodes. This method utilizes training sets to separate cyclic voltammograms into contributions from multiple electroactive species. The introduction of chronically implanted microelectrodes permits longitudinal measurements at the same electrode and brain location over multiple recordings. The reliability of these measurements depends on a consistent calibration methodology. One published approach has been the use of training sets built with data from separate electrodes and animals to evaluate neurochemical signals in multiple subjects. Alternatively, responses to unpredicted rewards have been used to generate calibration data. This study addresses these approaches using voltammetric data from three different experiments in freely-moving rats obtained with acutely implanted microelectrodes. The findings demonstrate critical issues arising from the misuse of principal component regression that result in significant underestimates of concentrations and improper statistical model validation that, in turn, can lead to inaccurate data interpretation. Therefore, the calibration methodology for chronically implanted microelectrodes needs to be revisited and improved before measurements can be considered reliable.
No preview · Article · Oct 2015 · Analytical Chemistry
[Show abstract][Hide abstract] ABSTRACT: Although rewards are physical stimuli and objects, their value for survival and reproduction is subjective. The phasic, neurophysiological and voltammetric dopamine reward prediction error response signals subjective reward value. The signal incorporates crucial reward aspects such as amount, probability, type, risk, delay and effort. Differences of dopamine release dynamics with temporal delay and effort in rodents may derive from methodological issues and require further study. Recent designs using concepts and behavioral tools from experimental economics allow to formally characterize the subjective value signal as economic utility and thus to establish a neuronal value function. With these properties, the dopamine response constitutes a utility prediction error signal.
[Show abstract][Hide abstract] ABSTRACT: Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shellDArelease decreased predominantly during the TL. These release dynamics suggest parallelDAsignals capable of supporting distinct theories of appetitive behavior.
No preview · Article · Aug 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
[Show abstract][Hide abstract] ABSTRACT: In a preclinical model of natural reward devaluation by cocaine, taste cues elicit aversive taste reactivity when they predict impending but delayed cocaine self-administration. Here, we investigated this negative affective state as a function of cocaine dose. Male, Sprague-Dawley rats were given 45 brief intraoral infusions of a 0.15% saccharin solution before 2 h cocaine self-administration for 14 days. Rats were video recorded; taste reactivity and patterns of self-administration were quantified on the first and last days. On day 14, a significant decrease in appetitive taste reactivity and increase in aversive taste reactivity was observed (compared with day 1) that did not vary as a function of cocaine dose. In contrast, patterns of cocaine self-administration (i.e. the total number of lever presses and load-up behavior) varied as a function of dose across days. Further, load-up behavior was positively correlated with aversive taste reactivity (i.e. gapes) on day 14 across all doses tested. Collectively, these findings indicate that the emergence of negative affect in this preclinical model is not dependent on cocaine dose.
No preview · Article · Mar 2015 · Behavioural Pharmacology
[Show abstract][Hide abstract] ABSTRACT: To make appropriate choices, organisms must weigh the costs and benefits of potential valuable outcomes, a process known to involve the nucleus accumbens (NAc) and its dopaminergic input. However, it is currently unknown if dopamine dynamically tracks alterations in expected reward value ‘on-line’ as behavioral preferences change, and if so, if it is causally linked to specific components of value such as reward magnitude and/or delay to reinforcement.Methods
Electrochemical methods were used to measure subsecond NAc dopamine release during a delay discounting task where magnitude was fixed but delay varied across blocks (n=7 rats). Next, to assess whether this dopamine signaling was causally related to specific components of choice behavior, we employed selective optogenetic stimulation of dopamine terminals in the NAc using a modified delay discounting task in which both delay and magnitude varied independently (n=23 rats).ResultsCues predictive of available choices evoked dopamine release that scaled with the rat’s preferred choices, and dynamically shifted as delay to reinforcement for the large reward increased. In the second experiment, dopamine signaling was causally related to features of decision making, as optogenetically-enhanced dopamine release within the NAc during predictive cue presentation was sufficient to alter subsequent value-related choices. Importantly, this dopamine-mediated shift in choice was limited to delay-based, but not magnitude-based decisions.Conclusions
These findings indicate that NAc dopamine dynamically tracks delay discounting, and establishes a causal role for this signaling in a subset of value-based associative strategies.
No preview · Article · Nov 2014 · Biological Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Reinforcement-based learning models predict that the strength of association between cues and outcomes is driven by aspects of outcome value. However, animals routinely make associations between contingent stimuli in the world, even if those associations hold no value to the organism. At the neural level, the nucleus accumbens (NAc) is known to encode associative information, but it is not known whether this encoding is specific for value-based information (consistent with reinforcement-based models) or if the NAc additionally plays a more general role in forming predictive associations, independent of outcome value. To test this, we employed a sensory preconditioning (SPC) task where rats initially (Preconditioning) received either contingent pairings of 2 neutral stimuli (e.g., tone [A] and light [X]; "Paired"), or random noncontingent presentations ("Unpaired"). After cue X was subsequently conditioned with food (First-Order Conditioning), the effect of preconditioning was assessed in Phase 3 (Test) by presentations of cue A alone. Electrophysiological recordings from the NAc core showed significant increases in phasic encoding for the stimuli in the Paired (but not Unpaired) condition as well as during test. Further, these effects were only seen in Paired rats that showed successful behavior during test (Good Learners), but not those who did not (Poor Learners) or Unpaired controls. These findings reveal a role for the NAc in the encoding of associative contingencies independent of value, and suggest that this structure also plays a more general role in forming associations necessary for predictive behavior. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
No preview · Article · Oct 2014 · Behavioral Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Dopamine neurons track reward by increasing or decreasing their firing rate when a reward is present or absent. In this issue of Neuron, Stopper et al. (2014) demonstrate that artificially eliminating these dopamine bursts or dips can alter risky decision-making.
[Show abstract][Hide abstract] ABSTRACT: Electrophysiological studies show that distinct subsets of nucleus accumbens (NAc) neurons differentially encode information about goal-directed behaviors for intravenous cocaine versus natural (food/water) rewards. Further, NAc rapid dopamine signaling occurs on a timescale similar to phasic cell firing during cocaine and natural reward-seeking behaviors. However, it is not known whether dopamine signaling is reinforcer specific (i.e., is released during responding for only one type of reinforcer) within discrete NAc locations, similar to neural firing dynamics. Here, fast-scan cyclic voltammetry (FSCV) was used to measure rapid dopamine release during multiple schedules involving sucrose reward and cocaine self-administration (n=8 rats) and, in a separate group of rats (n = 6), during a sucrose/food multiple schedule. During the sucrose/cocaine multiple schedule, dopamine increased within seconds of operant responding for both reinforcers. Although dopamine release was not reinforcer specific, more subtle differences were observed in peak dopamine concentration [DA] across reinforcer conditions. Specifically, peak [DA] was higher during the first phase of the multiple schedule, regardless of reinforcer type. Further, the time to reach peak [DA] was delayed during cocaine-responding compared to sucrose. During the sucrose/food multiple schedule, increases in dopamine release were also observed relative to operant responding for both natural rewards. However, peak [DA] was higher relative to responding for sucrose than food, regardless of reinforcer order. Overall, the results reveal the dynamics of rapid dopamine signaling in discrete locations in the NAc across reward conditions, and provide novel insight into the functional role of this system in reward-seeking behaviors.
No preview · Article · Aug 2014 · Neuropharmacology
[Show abstract][Hide abstract] ABSTRACT: Cocaine stimuli often trigger relapse of drug-taking, even following periods of prolonged abstinence. Here, electrophysiological recordings were made in rats (n = 29) to determine how neurons in the prelimbic (PrL) or infralimbic (IL) regions of the medial prefrontal cortex (mPFC) encode cocaine-associated stimuli and cocaine-seeking, and whether this processing is differentially altered after 1 month of cocaine abstinence. After self-administration training, neurons (n = 308) in the mPFC were recorded during a single test session conducted either the next day or 1 month later. Test sessions consisted of three phases during which (i) the tone-houselight stimulus previously paired with cocaine infusion during self-administration was randomly presented by the experimenter, (ii) rats responded on the lever previously associated with cocaine during extinction and (iii) the tone-houselight was presented randomly between cocaine-reinforced responding during resumption of cocaine self-administration. PrL neurons showed enhanced encoding of the cocaine stimulus and drug-seeking behavior (under extinction and self-administration) following 30 days of abstinence. In contrast, although IL neurons encoded cocaine cues and cocaine-seeking, there were no pronounced changes in IL responsiveness following 30 days of abstinence. Importantly, cue-related changes do not represent a generalised stimulus-evoked discharge as PrL and IL neurons in control animals (n = 4) exhibited negligible recruitment by the tone-houselight stimulus. The results support the view that, following abstinence, neural encoding in the PrL but not IL may play a key role in enhanced cocaine-seeking, particularly following re-exposure to cocaine-associated cues.
No preview · Article · Apr 2014 · European Journal of Neuroscience
[Show abstract][Hide abstract] ABSTRACT: To make appropriate decisions, organisms must evaluate the risks and benefits of action selection. The nucleus accumbens (NAc) has been shown to be critical for this processing and is necessary for appropriate risk-based decision-making behavior. However, it is not clear how NAc neurons encode this information to promote appropriate behavioral responding.
Here, rats (n = 17) were trained to perform a risky decision-making task in which discrete visual cues predicted the availability to respond for a smaller certain (safer) or larger uncertain (riskier) reward. Electrophysiological recordings were made in the NAc core and shell to evaluate neural activity during task performance.
At test, animals exhibited individual differences in risk-taking behavior; some displayed a preference for the risky option, some the safe option, and some did not have a preference. Electrophysiological analysis indicated that NAc neurons differentially encoded information related to risk versus safe outcomes. Further, during free choice trials, neural activity during reward-predictive cues reflected individual behavioral preferences. In addition, neural encoding of reward outcomes was correlated with risk-taking behavior, with safe-preferring and risk-preferring rats showing differential activity in the NAc core and shell during reward omissions.
Consistent with previously demonstrated alterations in prospective reward value with effort and delay, NAc neurons encode information during reward-predictive cues and outcomes in a risk task that tracked the rats' preferred responses. This processing appears to contribute to subjective encoding of anticipated outcomes and thus may function to bias future risk-based decisions.
No preview · Article · Oct 2013 · Biological psychiatry
[Show abstract][Hide abstract] ABSTRACT: Cocaine use is often associated with diminished cognitive function, persisting even after abstinence from the drug. Likely targets for these changes are the core and shell of the nucleus accumbens (NAc), which are critical for mediating the rewarding aspects of drugs of abuse as well as supporting associative learning. To understand this deficit, we recorded neural activity in the NAc of rats with a history of cocaine self-administration or control subjects while they learned Pavlovian first- and second-order associations.
Rats were trained for 2 weeks to self-administer intravenous cocaine or water. Later, rats learned a first-order Pavlovian discrimination where a conditioned stimulus (CS)+ predicted food, and a control (CS-) did not. Rats then learned a second-order association where, absent any food reinforcement, a novel cued (SOC+) predicted the CS+ and another (SOC-) predicted the CS-. Electrophysiological recordings were taken during performance of these tasks in the NAc core and shell.
Both control subjects and cocaine-experienced rats learned the first-order association, but only control subjects learned the second-order association. Neural recordings indicated that core and shell neurons encoded task-relevant information that correlated with behavioral performance, whereas this type of encoding was abolished in cocaine-experienced rats.
The NAc core and shell perform complementary roles in supporting normal associative learning, functions that are impaired after cocaine experience. This impoverished encoding of motivational behavior, even after abstinence from the drug, might provide a key mechanism to understand why addiction remains a chronically relapsing disorder despite repeated attempts at sobriety.
No preview · Article · Sep 2013 · Biological psychiatry
[Show abstract][Hide abstract] ABSTRACT: An important feature of cocaine addiction in humans is the emergence of negative affect (e.g., dysphoria, irritability, anhedonia), postulated to play a key role in craving and relapse. Indeed, the DSM-IV recognizes that social, occupational and/or recreational activities become reduced as a consequence of repeated drug use where previously rewarding experiences (e.g., food, job, family) become devalued as the addict continues to seek and use drug despite serious negative consequences. Here, research in the Carelli laboratory is reviewed that examined neurobiological mechanisms that may underlie these processes using a novel animal model. Oromotor responses (taste reactivity) were examined as rats learned that intraoral infusion of a sweet (e.g., saccharin) predicts impending but delayed access to cocaine self-administration. We showed that rats exhibit aversive taste reactivity (i.e., gapes/rejection responses) during infusion of the sweet paired with impending cocaine, similar to aversive responses observed during infusion of quinine, a bitter tastant. Critically, the expression of this pronounced aversion to the sweet predicted the subsequent motivation to self-administer cocaine. Electrophysiology studies show that this shift in palatability corresponds to an alteration in nucleus accumbens (NAc) cell firing; neurons that previously responded with inhibition during infusion of the palatable sweet shifted to excitatory activity during infusion of the cocaine-devalued tastant. This excitatory response profile is typically observed during infusion of quinine, indicating that the once palatable sweet becomes aversive following its association with impending but delayed cocaine, and NAc neurons encode this aversive state. We also review electrochemical studies showing a shift (from increase to decrease) in rapid NAc dopamine release during infusion of the cocaine-paired tastant as the aversive state developed, again, resulting in responses similar to quinine infusion. Collectively, our findings suggest that cocaine-conditioned cues elicit a cocaine-need state that is aversive, is encoded by a distinct subset of NAc neurons and rapid dopamine signaling, and promotes cocaine-seeking behavior. Finally, we present data showing that experimentally induced abstinence (30 days) exacerbates this natural reward devaluation by cocaine, and this effect is correlated with a greater motivation to lever press during extinction. Dissecting the neural mechanisms underlying these detrimental consequences of addiction is critical since it may lead to novel treatments that ameliorate negative affective states associated with drug use and decrease the drive (craving) for the drug.
No preview · Article · Apr 2013 · Neuropharmacology
[Show abstract][Hide abstract] ABSTRACT: Simultaneous electrochemical and electrophysiological data were recorded to evaluate the effects of controlled local application of dopaminergic agonists and antagonists in awake rats. Measurements were made with a probe consisting of a carbon-fiber microelectrode fused to three iontophoretic barrels that were used to introduce the drugs of interest. The probe and the manipulator used to position it in the brain of behaving animals were optimized to improve their performance. The effect of the dopamine autoreceptor on electrically stimulated release was demonstrated. Dopamine inhibited the release of endogenous dopamine whereas raclopride, a D2 antagonist, enhanced it, with similar responses in anesthetized and awake animals. We also examined changes in the firing rate of nucleus accumbens (NAc) neurons in awake animals during and after brief (15 s) iontophoretic ejections of SCH 23390 (D1 receptor antagonist) or raclopride. Changes in response to these antagonists were seen both immediately and on a prolonged timescale. Application of raclopride increased the firing rate in 40% of medium spiny neurons (MSNs), of which half responded immediately. Decreases in firing rate were observed in 46% of MSNs after SCH 23390 application. Only 11% of MSNs responded to both antagonists and one MSN (3%) showed no response to either drug. The same prolonged response in firing rate was seen for electrically stimulated and locally applied dopamine in 75% of MSNs. These results confirm previously reported distributions for dopamine receptor subtypes on MSNs and probe the effects of dopamine on these cell populations.
No preview · Article · Mar 2013 · ACS Chemical Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.
Preview · Article · Jan 2013 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: The catecholamine dopamine (DA) has been implicated in a host of neural processes as diverse as schizophrenia, parkinsonism and reward encoding. Importantly, these distinct features of DA function are due in large part to separate neural circuits involving connections arising from different DA-releasing nuclei and projections to separate afferent targets. Emerging data has suggested that this same principle of separate neural circuits may be applicable within structural subregions, such as the core and shell of the nucleus accumbens (NAc). Further, DA may act selectively on smaller ensembles of cells (or, microcircuits) via differential DA receptor density and distinct inputs and outputs of the microcircuits, thus enabling new learning about Pavlovian cues, instrumental responses, subjective reward processing and decision-making. In this review, by taking advantage of studies using subsecond voltammetric techniques in behaving animals to study how rapid changes in DA levels affect behavior, we examine the spatial and temporal features of DA release and how it relates to both normal learning and similarities to pathological learning in the form of addiction.
No preview · Article · Jan 2013 · Frontiers in bioscience (Elite edition)
[Show abstract][Hide abstract] ABSTRACT: Background:
While studies suggest that both dopamine and norepinephrine neurotransmission support reinforcement learning, the role of dopamine has been emphasized. As a result, little is known about norepinephrine signaling during reward learning and extinction. Both dopamine and norepinephrine projections innervate distinct regions of the bed nucleus of the stria terminalis (BNST), a structure that mediates behavioral and autonomic responses to stress and anxiety. We investigated whether norepinephrine release in the ventral BNST (vBNST) and dopamine release in the dorsolateral BNST (dlBNT) correlate with reward learning during intracranial self-stimulation (ICSS).
Using fast-scan cyclic voltammetry, norepinephrine concentration changes in the vBNST (n = 12 animals) during ICSS were compared with dopamine changes in the dlBNST (n = 7 animals) and nucleus accumbens (NAc) (n = 5 animals). Electrical stimulation was in the ventral tegmental area/substantia nigra region.
Whereas dopamine release was evoked by presentation of a cue predicting reward availability in both dlBNST and NAc, cue-evoked norepinephrine release did not occur in the vBNST. Release of both catecholamines was evoked by the electrical stimulation. Extracellular changes in norepinephrine were also studied during extinction of ICSS and compared with results obtained for dopamine. During extinction of ICSS, norepinephrine release in the vBNST occurred at the time where the stimulation was anticipated, whereas dopamine release transiently decreased.
The data demonstrate that norepinephrine release in the vBNST differs from dopamine release in the dlBNST and the NAc in that it signals the absence of reward rather than responding to reward predictive cues.
No preview · Article · Dec 2012 · Biological psychiatry
[Show abstract][Hide abstract] ABSTRACT: Mesolimbic dopamine projections to the nucleus accumbens (NAc) have been implicated in goal-directed behaviors for natural rewards and in learning processes involving cue-reward associations. The NAc has been traditionally subdivided into two anatomically distinct sub-regions with different functional properties: the shell and the core. The aim of the present study was to characterize rapid dopamine transmission across the two NAc sub-regions during cue-signaled operant behavior for a natural (sucrose) reward in rats. Using fast-scan cyclic voltammetry (FSCV) we observed differences in the magnitude and dynamics of dopamine release events between the shell and core. Specifically, although cue-evoked dopamine release was observed in both sub-regions, it was larger and longer lasting in the shell compared with the core. Further, secondary dopamine release events were observed following the lever press response for sucrose in the NAc shell, but not the core. These findings demonstrate that the NAc displays regional specificity in dopamine transmission patterns during cued operant behavior for natural reward.
[Show abstract][Hide abstract] ABSTRACT: Distinct subsets of nucleus accumbens (NAc) neurons differentially encode goal-directed behaviors for natural vs. drug rewards [R. M. Carelli et al. (2000)The Journal of Neuroscience, 20, 4255-4266], and the encoding of cocaine-seeking is altered following cocaine abstinence [J. A. Hollander & R. M. Carelli (2007) The Journal of Neuroscience, 27, 3535-3539]. Here, electrophysiological recording procedures were used to determine if the selective encoding of natural vs. cocaine reward by NAc neurons is: (i) maintained when the natural reinforcer is a highly palatable sweet tastant and (ii) altered by cocaine abstinence. Rats (n = 14) were trained on a multiple schedule of sucrose reinforcement and cocaine self-administration (2-3 weeks) and NAc activity was recorded during the task before and after 30 days of cocaine abstinence. Of 130 cells recorded before abstinence, 82 (63%) displayed patterned discharges (increases or decreases in firing rate, termed phasic activity) relative to operant responding for sucrose or cocaine. As in previous reports, the majority of those cells displayed nonoverlapping patterns of activity during responding for sucrose vs. cocaine. Specifically, only 17 (21%) showed similar patterns of activity (i.e. overlapping activity) across the two reinforcer conditions. After abstinence, this pattern was largely maintained, 23 of 70 phasic cells (33%) were overlapping. However, cocaine abstinence altered the overall percentage of selectively active neurons across reinforcer conditions. Specifically, significantly more neurons became selectively activated during cocaine-directed behaviors than during sucrose-directed behaviors. The results indicate that, although the selective encoding of cocaine and natural rewards is maintained even with a highly palatable substance, 30 days of cocaine abstinence dynamically alters the overall population encoding of natural and drug rewards by NAc neurons.
Preview · Article · Feb 2012 · European Journal of Neuroscience