Research reportNucleus accumbens cell firing during maintenance, extinction, and reinstatement of cocaine self-administration behavior in rats
Introduction
It is well established that the Acb is involved in mediating the reinforcing properties of abused substances such as cocaine [28], [29], [30], [42], [44]. The self-administration paradigm has been used in conjunction with chronic extracellular recording procedures in behaving animals to elucidate neural mechanisms that control drug-seeking behavior [1], [4], [5], [6], [7], [8], [10], [11], [31], [36], [37]. In this regard, a number of investigators have reported that particular populations of Acb neurons exhibit patterned discharges that occur within seconds of the reinforced response for cocaine and/or cycle on the order of minutes within the entire inter-infusion interval [1], [4], [5], [6], [7], [8], [10], [11], [36], [37].
This report focuses on an investigation of factors controlling Acb patterned discharges that occur within seconds of the response for intravenous cocaine. Although the terminology used to describe each type of short duration neuronal firing pattern varies across laboratories, the same basic findings are reported. Specifically, one population of Acb neurons exhibits significant increases in the firing rate immediately before the cocaine-reinforced response. We have termed this subset of neurons ‘pre-response’ or ‘PR’ cells [4]. Other Acb cells significantly increase or decrease their firing rate immediately following response completion (termed ‘reinforcement-excitation’, ‘RFe’ cells and ‘reinforcement-inhibition’, ‘RFi’ cells, respectively). A fourth subset of Acb neurons displays dual peak increases in firing that occur immediately before and immediately after the response with an inhibitory period between the two peaks. This neuronal firing pattern was termed ‘PR+RF’ or ‘Cocaine-Specific’ (‘CSp’ cells) since prior studies have shown that this discharge pattern is observed only during cocaine self-administration but not water reinforcement sessions [4], [6]. Collectively, these findings suggest that distinct populations of cells exist in the Acb that encode the ‘critical’ features of cocaine-reinforced responding including response initiation, response execution, and reinforcement delivery.
Given the importance of the Acb to cocaine-reinforced behaviors, additional studies were completed to examine potential factors that may control the various patterned discharges of Acb cells. Results suggest that pre- versus post-response discharge patterns of Acb neurons are controlled by different factors operating within the self-administration context. For example, the pre-response component of PR and CSp cells appears to be associated with initiating the sequence of responses that lead to cocaine reinforcement [6], [8], [10]. This notion was supported by studies showing that increasing the fixed ratio requirement systematically shifted the pre-response discharge component of CSp cells earlier in time, in close correspondence to the first response of the FR series [8]. The post-response component of CSp neurons, however, remained unaltered. Additional studies indicated that post-response discharge patterns exhibited by RFe, RFi, and CSp cells appear to be controlled, at least in part, by stimuli paired with the response-dependent delivery of cocaine. This was evidenced by significant increases (RFe and CSp cells) or decreases (RFi cells) in activity during response-independent presentation of a cocaine-associated stimulus, but no changes in the firing rate relative to the noncontingent delivery of cocaine [6], [7]. The latter finding is consistent with a report by Peoples and colleagues showing that Acb neurons exhibit either nonphasic cell firing or an attenuation in patterned activity when cocaine was given in a response-independent manner [37].
In the present study, a within-session extinction/reinstatement procedure was used to further examine factors controlling Acb patterned activity that occurs within seconds of the reinforced response for intravenous cocaine. Specifically, Acb neurons were recorded during ‘test’ sessions consisting of three phases. In the first phase (termed ‘maintenance’), well-trained animals pressed a lever (FR1 schedule) for an intravenous infusion of cocaine paired with a tone-houselight stimulus. The use of this established protocol enabled a classification of Acb cells into one of the four well-defined neuronal firing patterns described above [4], [5], [6], [7], [8]. Next, the same cells were examined during extinction and drug reinstatement phases completed in the same experimental session. During extinction, animals responded for an intravenous saline infusion (6 s) paired with the stimulus. Once operant responding ceased for 30 min, the reinstatement phase was initiated by ‘priming’ the animals with an intravenous infusion of cocaine to reestablish operant behavior [9], [15]. For two animals, an additional experiment was completed in which the extinction phase was modified so that each response resulted in cocaine delivery without the stimulus (i.e., CS extinction).
Collectively, these manipulations allowed for further examination of factors controlling the now well-documented patterned discharges exhibited by Acb neurons during cocaine self-administration sessions in rats. As noted above, prior studies indicate that differential factors control pre- versus post-response discharge patterns of Acb cells. Thus, it was hypothesized that these cell types would be differentially influenced by the extinction/reinstatement procedures used here. Specifically, neurons that exhibit exclusively pre-response activity (type PR cells) appear to encode information about the initiation and completion of the response for cocaine reinforcement; therefore, it was predicted that these cells would continue to discharge in a phasic manner as long as the operant response was present. In contrast, prior studies show that post-response discharge patterns are influenced by both Instrumental and Pavlovian contingencies. It was therefore hypothesized that these neurons would be most sensitive to extinction/reinstatement procedures.
Section snippets
Cocaine self-administration
Male, Sprague–Dawley rats (Harlan), approximately 90–120-days-old and weighing 275–350 g were used as subjects (N=13). The animals were housed individually and given free access to food (Purina Lab pellets). Water intake was restricted (20–30 ml of water per day) to maintain pre-operative body weights. Surgical and behavioral training procedures for cocaine self-administration have been described in detail elsewhere [4], [5]. Briefly, the subjects were anesthetized with ketamine hydrochloride
Behavior
Fig. 1 illustrates cumulative lever pressing behavior across the three phases of a test session for one representative animal. During the maintenance phase (0–120 min), the animal completed 28 responses with a mean inter-infusion interval of 5.21±0.22 min. Immediately thereafter the cocaine syringe was replaced with saline (indicated by arrow at ‘saline’) and the extinction phase began. The animal responded at a faster rate throughout extinction, completing 29 responses with a mean
Discussion
The present study provides a within-session characterization of Acb cell firing during maintenance, extinction, and reinstatement of cocaine self-administration behavior in rats. Results indicate that Acb neurons exhibiting pre- versus post-response patterned discharges within seconds of the reinforced response for cocaine are differentially influenced by extinction and reinstatement procedures. Specifically, neurons with exclusively anticipatory cell firing during the maintenance phase (type
Acknowledgements
This research was supported by NIDA DA10006 and the Whitehall Foundation. The author wishes to thank Alison Crumling for technical assistance and Dr. Patricia Sue Grigson for comments on this manuscript.
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