Persistent neural processing of information regarding drug-predictive environmental stimuli may be involved in motivating drug abusers to engage in drug seeking after abstinence. The addictive effects of various drugs depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens. We used single-unit recording in rats to test whether accumbens neurons exhibit responses to a discriminative stimulus (SD) tone previously paired with cocaine availability during cocaine self-administration. Presentation of the tone after 3-4 weeks of abstinence resulted in a cue-induced relapse of drug seeking under extinction conditions. Accumbens neurons did not exhibit tone-evoked activity before cocaine self-administration training but exhibited significant SD tone-evoked activity during extinction. Under extinction conditions, shell neurons exhibited significantly greater activity evoked by the SD tone than that evoked by a neutral tone (i.e., never paired with reinforcement). In contrast, core neurons responded indiscriminately to presentations of the SD tone or the neutral tone. Accumbens shell neurons exhibited significantly greater SD tone-evoked activity than did accumbens core neurons. Although the onset of SD tone-evoked activity occurred well before the earliest movements commenced (150 msec), this activity often persisted beyond the onset of tone-evoked movements. These results indicate that accumbens shell neurons exhibit persistent processing of information regarding reward-related stimuli after prolonged drug abstinence. Moreover, the accumbens shell appears to be involved in discriminating the motivational value of reward-related associative stimuli, whereas the accumbens core does not.

The ventral pallidum (VP) is necessary for drug-seeking behavior. VP contains ventromedial (VPvm) and dorsolateral (VPdl) subregions which receive projections from the nucleus accumbens shell and core, respectively. To date, no study has investigated the behavioral functions of the VPdl and VPvm subregions. To address this issue, we investigated whether changes in firing rate (FR) differed between VP subregions during four events: approaching toward, responding on, or retreating away from a cocaine-reinforced operandum, and a cocaine-associated cue. Baseline FR and waveform characteristics did not differ between subregions. VPdl neurons exhibited a greater change in FR compared to VPvm neurons during approaches toward, as well as responses on, the cocaine-reinforced operandum. VPdl neurons were more likely to exhibit a similar change in FR (direction and magnitude) during approach and response than VPvm neurons. In contrast, VPvm firing patterns were heterogeneous, changing FRs during approach or response alone, or both. VP neurons did not discriminate cued behaviors from uncued behaviors. No differences were found between subregions during the retreat and no VP neurons exhibited patterned changes in FR in response to the cocaine-associated cue. The stronger, sustained FR changes of VPdl neurons during approach and response may implicate VPdl in the processing of drug-seeking and drug-taking behavior via projections to subthalamic nucleus and substantia nigra pars reticulata. In contrast, heterogeneous firing patterns of VPvm neurons may implicate VPvm in facilitating mesocortical structures with information related to the sequence of behaviors predicting cocaine self-infusions via projections to mediodorsal thalamus and ventral tegmental area.

Ghitza, Udi E., Anthony T. Fabbricatore, Volodymyr F. Prokopenko, and Mark O. West. Differences between accumbens core and shell neurons exhibiting phasic firing patterns related to drug-seeking behavior during a discriminative-stimulus task. J Neurophysiol 92: 1608 -1614, 2004. First published May 19, 2004 10.1152/jn.00268. 2004. The habit-forming effects of abused drugs depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens (NAcc). To examine whether different NAcc subterritories (core and medial shell) exhibit a differential distribution of neurons showing phasic firing patterns correlated with drug-seeking behavior, rats were trained to self-administer cocaine, and activity of single NAcc neurons was recorded. In the presence of a discriminative-stimulus (S D ) tone, a single lever press produced an intravenous infusion of cocaine (0.35 mg/kg), terminated the tone, and started an intertone interval ranging from 3 to 6 min. Lever presses during this intertone interval had no programmed consequences. In addition to evaluating neuronal firing patterns associated with cocaine-reinforced presses, we also evaluated firing patterns associated with unreinforced lever presses to allow interpretation of firing free of factors other than the instrumental response (such as tone-off and onset of the pump signaling drug infusion). Core neurons exhibited a greater change in firing than medial shell neurons both in the seconds preceding the reinforced and unreinforced lever press response and in the seconds following the unreinforced response. Core and medial shell neurons exhibited similar changes in firing during the seconds following the cocaine-reinforced press. The differential distribution of neurons exhibiting phasic changes in firing preceding the lever press suggests that the physiological activity of core neurons may play a greater role than that of medial shell neurons in processes related to the execution of conditioned drug-seeking responses.

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 Day 13 -17 of cocaine self-administration (0.77 mg/kg/0.2mL infusion; fixed-ratio 1 schedule of reinforcement; 6 hr daily sessions). Pre-press rapid phasic firing rate changes were greater in lateral accumbal (core, ventrolateral shell) relative to medial accumbal (dorsal shell, 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. Keywords addiction; drug abuse; neurophysiology; reward; ventral striatumThe nucleus accumbens' (NAcc) putative role in reward and drug-taking behavior has prompted numerous studies in recent years that measured various physiological changes in the NAcc during drug self-administration. Several laboratories have investigated whether NAcc neural firing patterns during cocaine self-administration are temporally linked to events such as drug infusion or appetitive behavior (Carelli et al, 1993;Chang et al, 1994;Peoples & West, 1996, Woodward et al, 1999Carelli, 2002). Two main categories of lever press-related firing patterns have been identified: slow phasic and rapid phasic.* Correspondence to: Anthony T. Fabbricatore, Ph.D., Rutgers, the State University of NJ, Department of Psychology, 152 Frelinghuysen Road, Piscataway, NJ 08854, Phone: (732) Fax: (732) 445-2263, tonio@rci.rutgers.edu. Dr. Ghitza's current affiliation: Center for the Clinical Trials Network, National Institute on Drug Abuse (NIDA) National Institutes of Health (NIH), Bethesda, Maryland, USA. NIH Public Access Author ManuscriptEur J Neurosci. Author manuscript; available in PMC 2011 May 1. NIH-PA Author ManuscriptNIH-PA Author Manuscr...

Given the increasing research emphasis on putative accumbal functional compartmentation, we sought to determine whether neurons that demonstrate changes in tonic firing rate during cocaine self-administration are differentially distributed across subregions of the NAcc. Rats were implanted with jugular catheters and microwire arrays targeting NAcc subregions (Core, Dorsal Shell, Ventromedial Shell, Ventrolateral Shell, Rostral Pole Shell). Recordings were obtained after acquisition of stable cocaine self-administration (0.77 mg/kg/0.2mL infusion; fixed-ratio 1 schedule of reinforcement; 6 hour daily sessions). During the self-administration phase of the experiment, neurons demonstrated either: 1) tonic suppression (or decrease), 2) tonic activation (or increase) or 3) no tonic change in firing rate with respect to rates of firing during pre-and post-drug phases. Consistent with earlier observations, tonic decrease was the predominant firing pattern observed. Differences in the prevalence of tonic increase firing were observed between the core and the dorsal shell and dorsal shell-core border regions, with the latter two areas exhibiting a virtual absence of tonic increases. Tonic suppression was exhibited to a greater extent by the dorsal shell-core border region relative to the core. These differences could reflect distinct subregional afferent processing and/or differential sensitivity of subpopulations of NAcc neurons to cocaine. Ventrolateral Shell firing topographies resembled those of core neurons. Taken together, these observations are consistent with an emerging body of literature that differentiates the accumbens mediolaterally and further advances the likelihood that distinct functions are subserved by NAcc subregions in appetitive processing. Keywords addiction; drug abuse; neurophysiology; reward; ventral striatumThe nucleus accumbens (NAcc), commonly regarded as the brain's limbic-extrapyramidal motor interface (Nauta & Domesick,1978;Mogenson et al., 1980), has been shown to be involved in the processing of natural rewards (Hernandez & Hoebel, 1988; Smith & Sneider, 1988;Robbins et al., 1989;Schultz et al., 1992;Damsma et al., 1992;Young et al., 1992;Salamone, 1992) and drug taking behaviors (Caine et al., 1995;Carlezon & Wise, 1996;Di Chiara, 1998;Cornish & Kalivas, 2000;Robinson & Berridge, 2000;Nicola et al., 2000). Substantial advances have begun to resolve physiological distinctions between the two principal compartments of the NAcc, the core and shell, and their differential involvement in drug reward (Deutsch & Cameron, 1992;Pennartz et al., 1992;Robledo & Koob, 1993 Jongen-Relo et al., 1994b;Pontieri et al., 1994;Voorn et al., 1994;O'Donnell & Grace, 1995;Ikemoto et al., 1995;Pontieri et al., 1995;Meredith, 1999;Rodd-Henricks et al., 2002). Measurements of the physiological changes that occur in the NAcc in acute preparations (DeFrance et al., 1985a,b;White & Wang, 1986;White, 1987White, , 1990Boeijinga et al., 1990Boeijinga et al., , 1993White et al., 1993;O'Donnell & Grace, 1993;...