Selective encoding of cocaine versus natural rewards by nucleus accumbens neurons is not related to chronic drug exposure

Abstract

We reported previously that subsets of nucleus accumbens (Acb) neurons differentially encode information about goal-directed behaviors for "natural" (food and water) versus cocaine reward in animals well trained to self-administer the drug (Carelli et al., 2000). Here, we examined whether repeated exposure to cocaine is the crucial determinate of the selective encoding of cocaine versus water reinforcement by Acb neurons. Acb cells were recorded during a water-cocaine multiple schedule from the first day of cocaine exposure as well as during repeated sessions. Specifically, animals were initially trained to press a lever for water and were then surgically prepared for extracellular recording in the Acb. After 1 week, Acb cells were recorded during acquisition of the water-cocaine multiple schedule. Because behavioral responding for water was already established, training on the multiple schedule was divided into three components corresponding to acquisition of self-administration: (1) "initial" (day 1 of self-administration), (2) "reliable" (self-administration behavior was present but erratic), and (3) "stable" (cocaine responding was stable). During the initial component, the percentage of water-selective neurons was high compared with cocaine neurons. However, this became approximately equal with repeated self-administration experience (i.e., during the stable component). Remarkably, the percentage of neurons showing overlapping (similar) neuronal firing patterns during initial exposure to cocaine was low (<8%) and remained low during reliable and stable components. These findings support the view that separate neural circuits in the Acb differentially encode information about cocaine versus natural reward, and that this functional organization is not a direct consequence of chronic drug exposure.

Figure 1.

Cumulative records showing the behavioral (lever press) response pattern for a single animal during acquisition of self-administration in a water-cocaine multiple schedule. During the first session of cocaine exposure (initial), the animal completed 28 responses for water with a mean INT of 22.19 sec. During the self-administration phase, water was placed on the cocaine lever three times (indicated by open arrowheads), and the animal was primed several times (indicated by closed arrowheads). During the first session of reliable responding, lever pressing for water remained stable (16 presses; INT, 22.08), and responding for intravenous cocaine was present but erratic. During the stable component (day 7), behavioral responding was stable for both water (21 responses; mean INT, 42.85 sec) and cocaine (22 responses; mean INT, 6.13 min).

Figure 2.

PEHs showing three types of neuronal firing patterns observed within seconds of the lever-press response (FR1) for water reinforcement. Top, Example of an Acb neuron displaying increased firing rates within seconds preceding the reinforced response (PR). Middle, Another neuron showing increased firing immediately after response completion (RFe). Bottom, A third Acb cell displaying a marked inhibition in background firing rates within seconds before and after the response (RFi). R, Reinforced responses. Each PEH contains 250 bins here and in subsequent figures.

Figure 3.

Emergence of cocaine-selective Acb patterned discharge during the initial exposure to cocaine in the water-cocaine multiple schedule. Cumulative record shows behavioral response patterns during the cocaine self-administration component on day 1 of the multiple schedule. Note that the animal responded quickly for intravenous cocaine at the start of the phase followed by several priming infusions. Thereafter, behavioral responding for cocaine was observed, although somewhat erratic. Stripcharts show Acb cell firing relative to lever-press responding at the start of the self-administration component (top left, indicated by arrows) during priming infusions of cocaine (top center, indicated by arrows) and relative to the last four lever-press responses in the session (bottom right, indicated by arrows). Note the onset of RFe patterned activity during the end of the session. The same neuron exhibited NP firing relative to water-reinforced responding (data not shown).

Figure 4.

An example of water-selective cell firing during Session 1 of the multiple schedule. Left, PEHs show that the Acb cell exhibited RFe activity relative to the water-reinforced response (top). The same Acb cell exhibited NP activity relative to the cocaine-reinforced response (bottom). Right, Raster display shows the activity of the same neuron shown in the PEHs across all trials of the session. The cell exhibited RFe activity during the water reinforcement phase and within the first three trials of responding for cocaine. This was followed by a shift to nonphasic activity that continued during priming infusions (indicated by primes in raster) and during the remainder of the self-administration phase.

Figure 5.

Composite PEHs of normalized firing of all neurons exhibiting patterned discharges relative only to the cocaine-reinforced response during the first day of the multiple schedule. Left, PEHs show that populations of neurons exhibited NP activity relative to the reinforced response for water. Right, The same cells exhibited one of three well defined types of patterned discharges (PR, RFe, RFi) relative to the cocaine-reinforced response.

Figure 6.

Composite PEHs of normalized firing of all neurons exhibiting patterned discharges relative only to the water-reinforced response during the first day of the multiple schedule. Left, PEHs show that populations of neurons exhibited three types of patterned discharges (PR, RFe, RFi) relative to the reinforced response for water. Right, The same cells exhibited NP activity relative to cocaine-reinforced responding.

Figure 7.

PEHs showing water-selective (left) and cocaine-selective (right) neurons during reliable responding on the water-cocaine multiple schedule. Left, PEHs show a single Acb neuron (cell 1) exhibiting an increase in firing rate immediately after the reinforced response for water (RFe; top) and nonphasic firing relative to the reinforced response for cocaine (bottom). Right, Another Acb neuron (cell 2) recorded in a second animal exhibited nonphasic firing during the water-reinforcement phase and a shift to PR+RF activity during self-administration.

Figure 8.

Distribution of water-selective versus cocaine-selective neurons during acquisition of self-administration during the water-cocaine multiple schedule. Percentage of phasic cells is plotted as a function of cell type classification across the three components (initial, reliable, stable) of self-administration training during the multiple schedule. Wat, Neurons that exhibited one of three types of patterned discharges relative only to water-reinforced responding; Coc, neurons that exhibited one of four types of patterned discharges relative only to cocaine-reinforced responding; Both, neurons exhibiting similar, overlapping neuronal firing patterns across the two reinforcer (water and cocaine) conditions.