Neuronal substrates of relapse to cocaine-seeking behavior: role of prefrontal cortex

Abstract

The return to drug seeking, even after prolonged periods of abstinence, is a defining feature of cocaine addiction. The neural circuitry underlying relapse has been identified in neuropharmacological studies of experimental animals, typically rats, and supported in brain imaging studies of human addicts. Although the nucleus accumbens (NAcc), which has long been implicated in goal-directed behavior, plays a critical role in this circuit, the prefrontal cortex (PFC) appears to process the events that directly trigger relapse: exposure to acute stress, cues previously associated with the drug, and the drug itself. In this paper, we review animal models of relapse and what they have revealed about the mechanisms underlying the involvement of the NAcc and PFC in cocaine-seeking behavior. We also present electrophysiological data from PFC illustrating how the hedonic, motor, motivational, and reinforcing effects of cocaine can be analyzed at the neuronal level. Our preliminary findings suggest a role for PFC in processing information related to cocaine seeking but not the hedonic effects of the drug. Further use of this recording technology can help dissect the functions of PFC and other components of the neural circuitry underlying relapse.

Figure 1. Cue-related activation of neuronal activity in PFC (Cg1–PLC) of one rat during cocaine self-administration.

The upper part of the figure is a raster display in which each dot represents a spike from the recorded neuron and each row represents an individual trial. Black triangles indicate lever presses; lever presses that occur at Time 0 trigger cue presentation and activation of the pump for cocaine infusion. The PETH in the lower part of the figure represents the average firing rate around the time of cue onset. The Y axis depicts firing rate (spikes /s); bin size is 100 ms. Note the increase in firing rate that begins within 500 ms of cue onset and that persists for ∼700 ms.

Figure 2. PFC (Cg1–PLC) activity during a cocaine self-administration session in which the cue is omitted on a random 50% of trials.

Data are presented as in Figure 1. Left: Trials with cue. Note that as in Figure 1, the transient activation of neuronal activity was within 500 ms after cue onset. Right: Trials without cue. Note the complete absence of neuronal activation during the same period after cue onset. Interestingly, a late period of activation emerged on trials without cue at the time of houselight onset (4 s after cue onset).

Figure 3. PFC (Cg1–PLC) activity during a cocaine self-administration session in which the cocaine infusion is omitted on a random 50% of trials.

Data are presented as in Figure 1. Left: Trials with cocaine infusion (infusion pump on from 0–4 s). Note the brief activation of unit activity almost immediately after cue onset. Right: Trials without cocaine infusion. Note the similarity of the left and right PETHs throughout the 20-s period after cue onset.

Figure 4. PFC (Cg1–PLC) activity during conditioned (left) and cue-primed (right) reinstatement.

Data are presented as in Figure 1, but bin size is 50 ms. In both graphs, transient, cue-related activation is evident within 500 ms after cue onset. Over the course of both reinstatement sessions, lever pressing (black triangles) exceeded that during extinction by 4 times (left; a total of 36 lever presses; 13 are shown) and 12 times (right; a total of 20 lever presses; one is shown). During conditioned reinstatement, cue presentation follows an FR-5 schedule.