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.Key words: cocaine seeking, prefrontal cortex (PFC), nucleus accumbens (NAcc), drug selfadministration, reinstatement, single-unit, electrophysiology, rat _______________________________________________________________________________ Repeated use of amphetamine, cocaine, and related psychomotor stimulants can elicit longlasting changes in behavior. Evidence of this effect in human addicts is a high rate of relapse, which often occurs months or years after the last use. In fact, relapse prevention is perhaps the single biggest challenge to successful treatment of stimulant addiction. Reaching this goal requires an understanding of the neurobiological substrates of addictive behavior. Excellent progress has come from research on the brain circuits underlying the reinstatement of cocaine seeking in experimental animals, typically rats (for review, see . In this report, we describe the reinstatement model and what it has revealed about the role of prefrontal cortex (PFC) in relapse to cocaine seeking. Although most research on the brain substrates of reinstatement has focused on the nucleus accumbens (NAcc), which has long been linked to appetitive behavior and arousal (LeMoal, 1995), increasing evidence implicates the PFC as the final common pathway by which the stimuli that trigger reinstatement converge to drive behavior (Kalivas & Nakamura, 1999).At the neuronal level, however, relatively little information is available on how the PFC processes information related to relapse. A powerful tool that can be used to address this issue is extracellular, single-unit recording from awake, unrestrained animals. Not only is the neuronal circuitry intact and functioning normally in this preparation, but with chronically implanted micro-wires, neuronal activity can be recorded when animals a...

Site-Specific Role of Catechol-O-Methyltransferase in Dopamine Overflow within Prefrontal Cortex and Dorsal Striatum

“…Our data show that the effects of cocaine on the prefrontal cortex may be determined entirely by the increased time of presence of neurotransmitter in the extracellular space after transient release, an indication of the importance of volume transmission in the mechanism of action of cocaine in the prefrontal cortex, particularly in cocaine relapse (McFarland and Kalivas, 2001;Rebec and Sun, 2005).…”

Cocaine-Associated Stimuli Increase Cocaine Seeking and Activate Accumbens Core Neurons after Abstinence

“…This increase in cocaine craving was correlated to frontal lobe activation, areas of the brain highly involved in sensory, motor, and emotional processing (Bonson et al, 2002;Kosten et al, 2006). Activation of Acb core neurons by cocaine cues may be driven by the glutamatergic projection from the prefrontal cortex (PFC) and may represent a critical circuit underlying cocaine-seeking behaviors elicited by drug cues (Kalivas, 2004;Kalivas et al, 2005;Rebec and Sun, 2005). Consistent with this, inactivation of the dorsomedial PFC prevents cocaine-associated stimuli from reinstating extinguished drug-seeking behavior (McLaughlin and See, 2003).…”

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

“…Human imaging studies have associated changes in the mPFC (Volkow et al, 2005;Childress et al, 1999) and NAc (Risinger et al, 2005) with cocaine craving. These reports are paralleled by rodent studies of relapse and reinstatement (for review, see Rebec and Sun, 2005;Kalivas and McFarland, 2003). At the molecular level, abstinence-induced or abstinence-persistent changes in mRNA and protein expression have been described in the mPFC and NAc after cocaine self-administration (Lu et al, 2003;Sutton et al, 2003).…”