Accumbens activity during a multiple schedule for water and sucrose reinforcement in rats

Electrophysiological recording procedures were used to examine nucleus accumbens (Acb) cell firing during operant responding for water reinforcement vs. a highly palatable sweet solution (0.6 M sucrose). Rats (n = 8) were trained on a multiple schedule to press one lever for water (fixed ratio 1, FR1; 15 min) followed by a 20-sec timeout period (chamber dark, levers retracted), and extension of a second spatially distinct lever that the animals pressed for sucrose reinforcement (FR1; 15 min). Of 84 cells, 55 neurons (65%) displayed one of three types of patterned discharges (increases or decreases in firing rate) immediately before or following the sucrose- or water-reinforced response. The major finding of this report was that the majority of these neurons (36/55 cells; 65%) showed similar types of neuronal firing patterns across the two reinforcer conditions. The remaining cells (19/55; 35%) exhibited patterned activity specific to responding for one reinforcer only (water or sucrose). These findings are discussed with respect to how Acb neurons encode goal-directed behaviors for "natural" reinforcers including food, water, and a palatable sweet solution.     

Anatomic distribution of reinforcer selective cell firing in the core and shell of the nucleus accumbens

We have previously reported that distinct populations of nucleus accumbens (NAc) neurons differentially encode information about goal-directed behaviors for "natural" (food/water) vs. cocaine reinforcement [J Neurosci 20:4255-4266, (2000)]. Here, the anatomic distribution of reinforcer-selective cell firing was examined within the core and shell of the NAc. Rats (n=8) were trained on a multiple schedule for water reinforcement and cocaine (0.33 mg/infusion) self-administration. Next, microelectrode arrays (eight wires/array) were bilaterally positioned in the NAc core and shell, and cell firing was recorded during the multiple schedule. All electrode tip placements were then "marked," and histological reconstruction of each electrode position was completed. Of 93 NAc cells, 44 neurons (47%) exhibited 1 of 4 types of well-documented patterned discharges relative to the water- or cocaine-reinforced response. Of the 44 phasic cells, 39 neurons (89%) displayed differential, nonoverlapping neuronal firing patterns across the two reinforcer conditions (i.e., reinforcer-selective activity). Histological reconstruction of electrode placement revealed that NAc patterned discharges, specific to goal-directed behaviors for water or cocaine, were not limited to one NAc subregion but were evenly distributed and intermixed throughout the core and shell. These findings are discussed with respect to the functional organization of the NAc.     

Cocaine abstinence alters nucleus accumbens firing dynamics during goal-directed behaviors for cocaine and sucrose

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.     

An examination of nucleus accumbens cell firing during extinction and reinstatement of water reinforcement behavior in rats

Electrophysiological recording procedures were used to examine nucleus accumbens (Acb) cell firing in rats (n = 13) during water reinforcement sessions consisting of three phases. During phase one (maintenance), a lever press resulted in water reinforcement (fixed ratio 1; 0.05 ml/press) paired with an auditory stimulus (0.5 s). Of 128 Acb neurons recorded during maintenance, 40 cells (31%) exhibited one of three types of neuronal firing patterns described previously [J. Neurosci. 14 (12) (1994) 7735-7746; J. Neurosci. 20 (11) (2000) 4255-4266]. Briefly, Acb neurons exhibited increases in firing rate within seconds preceding the reinforced response (type PR) or increases (type RFe) or decreases (type RFi) in activity seconds following response completion. In phase two (extinction), subsequent lever pressing had no programmed consequences (i.e., water reinforcement and the auditory stimulus were not presented). After 30 min of no responding, animals were given water reinforcement/auditory stimulus 'primes' to reestablish lever pressing behavior during the third phase (reinstatement). Results indicated that all types of phasic neurons (PR, RFe and RFi) exhibited an attenuated firing rate during extinction, and in some cases recovery of patterned discharges were observed during reinstatement. No significant changes in cell firing were observed for any cell type during presentation of the stimulus prime used to reestablish operant responding following extinction. These findings are discussed in terms of how Acb neurons process information related to 'natural' reinforcers versus drugs of abuse.     

Prefrontal cortical cell firing during maintenance, extinction, and reinstatement of goal-directed behavior for natural reward

The prefrontal cortex (PFC) is important for higher cognitive functioning and the processing of reward-related information. Here, electrophysiological recording procedures were used to examine cell firing in the PFC in rats (n = 12) during water reinforcement sessions consisting of three phases. In phase one (maintenance), animals pressed a lever (fixed ratio 1) for water reinforcement (0.05 ml/press) paired with an auditory stimulus. Of 62 neurons recorded during maintenance, 39 (63%) exhibited one of three types of patterned discharges relative to the reinforced response for water. Specifically, PFC neurons exhibited increases in firing rate within seconds preceding the response (type PR; n = 9 cells) or increases (type RFe; n = 16 cells) or decreases (type RFi; n = 14 cells) in firing rate immediately following response completion. The remaining neurons did not alter their firing profiles relative to the reinforced response (type nonphasic cells; n = 23 cells). In phase two (extinction), lever press responses had no programmed consequences (i.e., water reinforcement and the auditory stimulus were not presented). After 30 min of no responding, phase three (reinstatement) began, during which each lever press response was again associated with water reinforcement paired with the stimulus. Results indicate differential effects of extinction/reinstatement on cell firing rates and patterns dependent on cell type. These findings are discussed with respect to the adaptive nature of PFC activity during goal-directed behaviors for "natural" rewards, and are considered relative to prior studies that examined nucleus accumbens cell firing during a similar behavioral task.     

Operant behavior during sessions of intravenous cocaine infusion is necessary and sufficient for phasic firing of single nucleus accumbens neurons

The activity of individual accumbens neurons in rats was recorded in relation to intravenous cocaine infusions that were either response (i.e., lever press) contingent or response non-contingent. Neural firing was additionally recorded in relation to non-reinforced lever presses. Comparisons of firing under the three conditions showed that operant behavior was necessary and sufficient for preinfusion firing to occur. Surprisingly, the same was true, in many cases, for firing that occurred during the infusion. For other neurons, firing during the infusion was unrelated to operant behavior and possibly related to infusion stimuli. The relationship to operant behavior exhibited by the majority of NAcc neurons is consistent with previous studies that demonstrated a necessary relationship between NAcc neurons and cocaine reinforced operant behavior.     

Nucleus accumbens neurons encode Pavlovian approach behaviors: evidence from an autoshaping paradigm

Environmental stimuli predictive of appetitive events can elicit Pavlovian approach responses that enhance an organism's ability to track and secure natural rewards, but may also contribute to the compulsive nature of drug addiction. Here, we examined the activity of individual nucleus accumbens (NAc) neurons during an autoshaping paradigm. One conditioned stimulus (CS+, a retractable lever presented for 10 s) was immediately followed by the delivery of a 45-mg sucrose pellet to a food receptacle, while another stimulus (CS-, a separate retractable lever presented for 10 s) was never followed by sucrose. Approach responses directed at the CS+ and CS- were recorded as lever presses and had no experimental consequence. Rats (n = 9) selectively approached the CS+ on more than 80% of trials and were surgically prepared for electrophysiological recording. Of 76 NAc neurons, 57 cells (75%) exhibited increases and/or decreases in firing rate (i.e. termed 'phasically active') during the CS+ presentation and corresponding approach response. Forty-seven percent of phasically active cells (27 out of 57) were characterized by time-locked but transient increases in cell firing, while 53% (30 out of 57) showed a significant reduction in firing for the duration of the CS+. In contrast, the same excitatory subpopulation exhibited smaller increases in activity relative to CS- onset, while the inhibitory subpopulation showed no change in firing during the CS- period. The magnitude and prevalence of cue-related neural responses reported here indicates that the NAc encodes biologically significant, repetitive approach responses that may model the compulsive nature of drug addiction in humans.     

Firing rate of nucleus accumbens neurons is dopamine-dependent and reflects the timing of cocaine-seeking behavior in rats on a progressive ratio schedule of reinforcement.

The progressive ratio (PR) schedule of reinforcement is used to determine the reinforcing properties of rewards such as drugs of abuse. In this schedule, the animal is required to press a lever a progressively increasing number of times to receive a reward; the highest ratio obtained before the animal ceases responding is termed "breakpoint." We recorded neuronal spike activity from cells in the nucleus accumbens (NAc) of rats responding on a PR schedule for cocaine reinforcement. A common subtype of NAc cells demonstrated firing rates that varied according to the time between cocaine deliveries. The firing rate was inversely related to the NAc cocaine level predicted by a pharmacokinetic model. At higher response-to-reward ratios, inter-reward intervals were increased, resulting in a decrease in modeled cocaine level and a concomitant increase in firing rate over the session. The final increase in firing rate above a threshold value suggests a neural correlate of breakpoint. The effects of preadministration of dopamine D1 or D2 antagonists on the animals' behavior were similar in that both reduced breakpoint; however, each antagonist had markedly different effects on NAc cell firing. The D1 antagonist SCH23390 reduced firing rates, even at low cocaine levels, whereas the D2 antagonist eticlopride induced a rightward shift in the dose dependence of NAc cell firing relative to modeled cocaine level. Our results suggest that the firing of NAc cells reflects changes in cocaine levels and thereby contributes to the temporal spacing of self-administration and to the cessation of responding at breakpoint.     

Antagonism of nucleus accumbens M(2) muscarinic receptors disrupts operant responding for sucrose under a progressive ratio reinforcement schedule

Diverse cholinergic signaling mechanisms regulate the excitability of striatal principal neurons and modulate striatal-dependent behavior. These effects are mediated, in part, by action at muscarinic receptors (mAChR), subtypes of which exhibit distinct patterns of expression across striatal neuronal populations. Non-selective mAChR blockade within the nucleus accumbens (NAc) has been shown to disrupt operant responding for food and to inhibit food consumption. However, the specific receptor subtypes mediating these effects are not known. Thus, we evaluated effects of intra-NAc infusions of pirenzepine and methoctramine, mAChR antagonisits with distinct binding affinity profiles, on operant responding for sucrose reward under a progressive ratio (PR) reinforcement schedule. Moderate to high doses of methoctramine disrupted operant responding and reduced behavioral breakpoint. In contrast, pirenzepine failed to impact operant performance at any dose tested. Methoctramine failed to affect latencies to complete appetitive-consummatory response sequences or to impact measures of acoustic startle, suggesting that its' disruptive effects on operant behavior were not consequent to gross motor impairment. Since methoctramine has a greater affinity for M(2) receptors compared to pirenzepine, which has a greater relative affinity for M(1) and M(3) receptors, these findings suggest that M(2) mAChRs within the NAc regulate behavioral processes underling the acquisition of reward.     

Session-long modulations of accumbal firing during sucrose-reinforced operant behavior

The nucleus accumbens is involved in the selection and expression of motivated behaviors. Attempts to understand how activity of single neurons in the accumbens relates to behavior have largely concentrated on brief modulations in accumbal firing that occur in the seconds around events during operant sessions. However, a small number of studies have reported modulations that last the entire duration of a behavioral session. In all of these reports, the operant session was a drug self-administration session. The present study tested the hypothesis that session-long modulations, like phasic firing patterns, are components of normal accumbal activity during periods of instrumental behavior. Eight rats were chronically implanted (unilaterally) with microwire arrays in the nucleus accumbens, and trained to lever press on a Fixed-Ratio 1 schedule of sucrose reinforcement. Activity of 51 single units was recorded, and both session-long increases (n = 14) and session-long decreases (n = 13) were observed. These findings show that session-long modulations are a normal component of the response of accumbal neurons during periods of operant behavior. Moreover, although session-long modulations during cocaine self-administration sessions might reflect pharmacological actions, aspects of the modulations might additionally or alternatively correspond to afferent-driven responses. Further characterization of the firing patterns may elucidate novel mechanisms that mediate accumbal contributions to behavior.     

Selective activation of accumbens neurons by cocaine-associated stimuli during a water/cocaine multiple schedule

Electrophysiological recording procedures were used to examine the responsiveness of nucleus accumbens (Acb) neurons to stimuli associated with cocaine delivery during a multiple schedule for water reinforcement and cocaine self-administration. Rats (n=9) were trained to press one lever for water reinforcement (0.05 ml/resp.; fixed ratio 1; FR1; 15 min) and a second spatially distinct lever for intravenous cocaine (0.33 mg/infusion; FR1; 2 h). The delivery of each reinforcer was signaled by different auditory stimuli. Of 101 neurons, 52 cells were classified as phasically active, exhibiting one of four well-defined types of patterned discharges relative to the water- or cocaine-reinforced response [J. Neurosci., 14(12) (1994) 7735; J. Neurosci., 20(11) (2000) 4255]. Acb cells were examined in test sessions consisting of 'probe' trials during which the stimulus previously paired with cocaine infusion was randomly presented in a response-independent manner during the self-administration portion of the session. Results showed that only neurons that exhibited changes in firing rate within seconds following the reinforced response for cocaine (but not water) were activated by the stimulus. This finding indicates that the responsiveness of cocaine selective neurons to cocaine-associated stimuli likely represents a conditioned response as opposed to a generalized stimulus-evoked discharge.     

Lever pressing responses under a fixed-ratio schedule of mice with 6-hydroxydopamine-induced dopamine depletion in the nucleus accumbens

In order to investigate the relationship between dopamine transmission in the nucleus accumbens and operant behavior in mice, mice with 6-hydroxydopamine (6-OHDA)-induced dopamine depletion in the nucleus accumbens were tested for their performance in lever pressing tasks under FR schedules with 8 ratios from FR5 to FR120. The mice were given one 20-mg food pellet per completed FR schedule in FR5, FR10, and FR20; they were given 2 pellets in FR40, and one more cumulatively in the rest of the schedules. Before the 6-OHDA injection surgery, all mice were trained to press a lever under all FR schedules. Then, 6-OHDA or ascorbate was injected into the nucleus accumbens. Postoperatively, the mice were tested under each FR schedule, with 3 sessions per schedule. 6-OHDA-treated mice exhibited an increase in lever pressing latency, i.e., the time interval between the last presentation of the reward and the next lever press, and a decrease in inter-response intervals, i.e., the time interval between 2 lever presses excluding lever pressing latency, irrespective of the FR ratios. Furthermore, in these 6-OHDA-treated mice, the number of lever presses during the first 300s of the session decreased under FR schedules with low ratios (5, 10, and 20). Open field activity, food motivation, and the amount of food consumed were not affected by dopamine depletion in the nucleus accumbens. These results suggest that the dopamine system in the nucleus accumbens had an important role in the control of lever pressing latency and inter-response intervals under FR reinforcement schedules.     

Contrasting effects of dopamine and glutamate receptor antagonist injection in the nucleus accumbens suggest a neural mechanism underlying cue-evoked goal-directed behavior

Discriminative stimuli (DSs) inform animals that reward can be obtained contingent on the performance of a specific behavior. Such stimuli reinstate drug-seeking behavior, evoke dopamine release in the nucleus accumbens (NAc) and excite and inhibit specific subpopulations of NAc neurons. Here we show in rats that DSs can reinstate food-seeking behavior. In addition, we compare the effects of injecting dopamine receptor antagonists into the NAc with those of general NAc inactivation on the performance of a DS task. Selective antagonism of D1 receptors reduced responding to the DS and increased the latency to respond, whereas general inactivation of NAc neuronal activity increased the latency to respond to the DS and increased behaviors extraneous to the task, such as responding in the absence of cues and responding on the inactive lever. Based on these results and our previous findings that NAc neuronal responses to DSs are dependent on the ventral tegmental area, we propose a model for the functional role of NAc neurons in controlling behavioral responses to reward-predictive stimuli.     

Electrophysiological evidence of mediolateral functional dichotomy in the rat nucleus accumbens during cocaine self‐administration II: phasic firing patterns

In the cocaine self‐administering rat, individual nucleus accumbens (NAcc) neurons exhibit phasic changes in firing rate within minutes and/or seconds of lever presses (i.e. slow phasic and rapid phasic changes, respectively). To determine whether neurons that demonstrate these changes during self‐administration sessions are differentially distributed in the NAcc, rats were implanted with jugular catheters and microwire arrays in different NAcc subregions (core, dorsal shell, ventromedial shell, ventrolateral shell, or rostral pole). Neural recording sessions were typically conducted on days 13–17 of cocaine self‐administration (0.77 mg/kg per 0.2‐mL infusion; fixed‐ratio 1 schedule of reinforcement; 6‐h daily sessions). Pre‐press rapid phasic firing rate changes were greater in lateral accumbal (core and ventrolateral shell) than in medial accumbal (dorsal shell and rostral pole shell) subregions. Slow phasic pattern analysis revealed that reversal latencies of neurons that exhibited change + reversal patterns differed mediolaterally: medial NAcc neurons exhibited more early reversals and fewer progressive/late reversals than lateral NAcc neurons. Comparisons of firing patterns within individual neurons across time bases indicated that lateral NAcc pre‐press rapid phasic increases were correlated with tonic increases. Tonic decreases were correlated with slow phasic patterns in individual medial NAcc neurons, indicative of greater pharmacological sensitivity of neurons in this region. On the other hand, the bias of the lateral NAcc towards increased pre‐press rapid phasic activity, coupled with a greater prevalence of tonic increase firing, may reflect particular sensitivity of these neurons to excitatory afferent signaling and perhaps differential pharmacological influences on firing rates between regions.     

Dorsomedial and dorsolateral striatum exhibit distinct phasic neuronal activity during alcohol self‐administration in rats

The development of alcoholism may involve a shift from goal‐directed to habitual drinking. These action control systems are distinct in the dorsal striatum, with the dorsomedial striatum (DMS) important for goal‐directed behavior and the dorsolateral striatum (DLS) required for habit formation. Goal‐directed behavior can be modeled in rats with a fixed ratio (FR) reinforcement schedule, while a variable interval (VI) schedule promotes habitual behavior (e.g. insensitivity to contingency degradation). Using extracellular recordings from chronically implanted electrodes, we investigated how DMS and DLS neurons encoded lever‐press responses and conditioned cues during operant alcohol self‐administration in these two models. In rats self‐administering 10% alcohol on an FR schedule, the DMS neuronal population showed increased firing at the onset of start‐of‐session stimuli. During self‐administration, the most prominent phasic firing patterns in the DMS occurred at the time of reinforcement and reinforcement‐associated cues, while the most prominent phasic activity in the DLS surrounded the lever response. Neural recordings from an additional cohort of rats trained on a VI schedule revealed a similar pattern of results; however, phasic changes in firing were smaller and differences between the medial and lateral dorsal striatum were less marked. In summary, the DMS and DLS exhibited overlapping but specialized phasic firing patterns: DMS excitations were typically time‐locked to reinforcement, while DLS excitations were generally associated with lever responses. Furthermore, the regional specificities and magnitudes of phasic firing differed between reinforcement schedules, which may reflect differences in behavioral flexibility, reward expectancy and the action sequences required to procure reinforcement.     

Electrophysiological evidence of alterations to the nucleus accumbens and dorsolateral striatum during chronic cocaine self‐administration

As drug use becomes chronic, aberrant striatal processing contributes to the development of perseverative drug‐taking behaviors. Two particular portions of the striatum, the nucleus accumbens (NAc) and the dorsolateral striatum (DLS), are known to undergo neurobiological changes from acute to chronic drug use. However, little is known about the exact progression of changes in functional striatal processing as drug intake persists. We sampled single‐unit activity in the NAc and DLS throughout 24 daily sessions of chronic long‐access cocaine self‐administration, and longitudinally tracked firing rates (FR) specifically during the operant response, an upward vertical head movement. A total of 103 neurons were held longitudinally and immunohistochemically localised to either NAc Medial Shell (n = 29), NAc Core (n = 30), or DLS (n = 54). We modeled changes representative of each category as a whole. Results demonstrated that FRs of DLS Head Movement neurons were significantly increased relative to baseline during all sessions, while FRs of DLS Uncategorised neurons were significantly reduced relative to baseline during all sessions. NAc Shell neurons' FRs were also significantly decreased relative to baseline during all sessions while FRs of NAc Core neurons were reduced relative to baseline only during training days 1–18 but were not significantly reduced on the remaining sessions (19–24). The data suggest that all striatal subregions show changes in FR during the operant response relative to baseline, but longitudinal changes in response firing patterns were observed only in the NAc Core, suggesting that this region is particularly susceptible to plastic changes induced by abused drugs.     

Reward, memory and substance abuse: functional neuronal circuits in the nucleus accumbens

The firing patterns of neurons in the nucleus accumbens (NA) are examined and discussed with respect to different types of rewards and reward conditions. Comparisons and contrasts between individually identified NA neuron responses to cocaine self-administration and water reinforcement are presented with an emphasis on the fact that the same neurons do not respond in a phasic manner to both types of rewards. However, the phasic firing patterns, even though segregated for each reinforcer, are quite similar, suggesting that the method of differentiation between rewarding stimuli in the NA is by sorting cell populations into distinct ensembles or networks for each type of reinforcer. These neural networks appear to be ‘tuned’ to respond to particular associative behavioral contexts that couple response execution to reward delivery, and in the process acquire a reciprocity to firing within reward contexts. This maintains the specificity of each reinforcer for the response and associated stimuli that produce it and, makes it possible to attach different NA networks to different reinforcing circumstances. Comparisons of cocaine and water reinforced NA cell firing patterns during rapid switching between these two reinforcers suggests that the networks are negatively coupled and mutually inhibit each other to maintain accurate encoding of immediately experienced, as well as expected (i.e. future) reward contingencies.     

Nucleus accumbens neurons in the rat exhibit differential activity to conditioned reinforcers and primary reinforcers within a second-order schedule of saccharin reinforcement

The nucleus accumbens has been associated with processing information related to primary reinforcement and reward. Most neurophysiological studies report that nucleus accumbens neurons are phasically excited in response to the onsets of salient events during the seeking of reinforcement and to the delivery of primary reinforcers. However, a minority of studies report inhibition during primary reinforcement. We recorded from 65 neurons in the nucleus accumbens whilst thirsty rats performed under a second-order schedule of saccharin reinforcement. This allowed us to analyse neural activity and behaviour during reinforcer-seeking in the presence of conditioned reinforcers (second-order stimuli, also called 'conditioned stimuli'), and during primary reinforcer consumption. Specifically, we sought to examine the valence of potential neural responses to primary reinforcement, to compare these responses to second-order stimulus-evoked responses, and to determine whether responses were differential to second-order stimuli presented at different time points within the schedule. Fifty out of 65 neurons we sampled responded to the second-order stimulus and/or consumption of the primary reinforcer. Most neurons in our sample exhibited excitation following the second-order stimulus and inhibition to the primary reinforcer, a pattern also present over the average response of the neural population. However, there was no systematic variation in neural responses evoked by second-order stimuli presented at different temporal proximities to primary reinforcement. Our results provide evidence that partially overlapping mechanisms within the nucleus accumbens differentially process conditioned reinforcers and primary reinforcers.     

Nucleus accumbens neurons encode predicted and ongoing reward costs in rats

Efficient decision-making requires that animals consider both the benefits and the costs of potential actions, such as the amount of effort or temporal delay involved in reward seeking. The nucleus accumbens (NAc) has been implicated in the ability to choose between options with different costs and overcome high costs when necessary, but it is not clear how NAc processing contributes to this role. Here, neuronal activity in the rat NAc was monitored using multi-neuron electrophysiology during two cost-based decision tasks in which either reward effort or reward delay was manipulated. In each task, distinct visual cues predicted high-value (low effort/immediate) and low-value (high effort/delayed) rewards. After training, animals exhibited a behavioral preference for high-value rewards, yet overcame high costs when necessary to obtain rewards. Electrophysiological analysis indicated that a subgroup of NAc neurons exhibited phasic increases in firing rate during cue presentations. In the effort-based decision task (but not the delay-based task), this population reflected the cost-discounted value of the future response. In contrast, other subgroups of cells were activated during response initiation or reward delivery, but activity did not differ on the basis of reward cost. Finally, another population of cells exhibited sustained changes in firing rate while animals completed high-effort requirements or waited for delayed rewards. These findings are consistent with previous reports that implicate NAc function in reward prediction and behavioral allocation during reward-seeking behavior, and suggest a mechanism by which NAc activity contributes to both cost-based decisions and actual cost expenditure.     

Evidence for opiate-dopamine cross-sensitization in nucleus accumbens: Studies of conditioned reward

We investigated opiate-amphetamine interactions within the nucleus accumbens in responding for conditioned reward. Separate groups of animals received 4-day intra-accumbens treatment with either saline, morphine (0.5 microgram/0.5 microliter), [D-Ala2 NMe-Phe4 Gly-ol5]-Enkephalin (DAMGO; 1.0 micrograms/0.5 microliter), or [D-Pen2,5]-Enkephalin (DPEN; 2.0 micrograms/0.5 microliter). One two subsequent test days, these rats were given a challenge of d-amphetamine (2.0 and 10.0 micrograms/0.5 microliter) and responding for conditioned reward was measured. In the conditioned reinforcement (CR) procedure, food-deprived animals were trained in an initial phase to associate a food reward (primary reinforcement) with a compound stimulus (light/click). In the next phase, a lever was introduced and responding on the lever produced the compound stimulus alone (secondary reinforcement). Previous evidence shows that psychostimulants but not opiates markedly potentiate responding for conditioned reward. In the present design, animals previously treated with either morphine or DAMGO (preferential mu agonists) showed potentiated lever responding following amphetamine challenges, relative to either DPEN- or saline-treated animals. These findings show that prior exposure of nucleus accumbens neurons to mu-selective opiates induces sensitization to the effects of amphetamine. The results are discussed in terms of opioid effects on dopamine transmission and second messenger systems.