Repeated Cocaine Self-Administration Alters Processing of Cocaine-Related Information in Rat Prefrontal Cortex

Abstract

One of the core symptoms of cocaine addiction is compulsive drug-seeking behavior. Although the precise neural substrates are unknown, it has been hypothesized that this behavior involves cocaine-induced hypofunction of the prefrontal cortex (PFC) or "hypofrontality." To test this hypothesis, PFC neuronal activity was monitored in rats during ϳ3 weeks of cocaine self-administration (SA). Rats were trained to press a lever to self-administer cocaine in daily 2 h sessions. Responding was reinforced contingent on a modified fixed-ratio 5 schedule of reinforcement. In the first SA session, the overall firing rate and burst rate were significantly decreased after cocaine infusions relative to the period immediately before the session. These effects disappeared after Ն10 d of drug SA and were replaced by a significant increase in burst duration and firing rate within a burst. Notably, however, the level of basal activity before the first drug infusion of each SA session decreased significantly after multiple weeks of cocaine exposure. Collectively, these data support the view that although repeated sessions of cocaine SA decrease basal PFC activity, increased burst-related firing in response to cocaine infusions suggests that processing of cocaine-related information is enhanced and may contribute to increased control by cocaine over cocaine-seeking behavior.

Selective presynaptic enhancement of the prefrontal cortex to nucleus accumbens pathway by cocaine

“…The PFC and amygdala, especially the projections from the medial PFC and BLA to NAc, have been critically implicated in a large number of cocaine-induced behavioral alterations, such as increased impulsivity, cue-induced relapse, extinction, and reinstatement/relapse to cocaine administration (7,8,34). Neuroimaging studies in cocaine addicts revealed a reduced PFC activity under baseline conditions, which is paralleled by findings in cocaine self-administering rats (38,39). However, the PFC and NAc are hyperresponsive toward drug-associated cues or cocaine exposure both in humans and rats.…”

Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse

“…For example, basal activity in the prefrontal cortex is blunted in human addicts and in animal models (12,15), and by restoring activity to the prefrontal cortex, N-acetylcysteine could decrease action potential-mediated synaptic glutamate release and elicit homeostatic down-regulation of AMPA receptors (41).…”

“…Similarly, animal models of relapse show that activation of this pathway is necessary and sufficient to reinstate cocaine-seeking behavior (13) and that neuronal activity in pyramidal neurons in prefrontal cortex projecting to medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) region is correlated with cocaine-seeking (14,15). Accordingly, it is thought that prefrontal-to-accumbens synapses undergo enduring potentiation after chronic cocaine use that contributes to relapse vulnerability (4,6,16).…”

Disrupting Effect of Drug-Induced Reward on Spatial But Not Cue-Guided Learning: Implication of the Striatal Protein Kinase A/cAMP Response Element-Binding Protein Pathway

“…DA-dependent alteration of prefrontohippocampal circuits involved in the consolidation of events linked to the reward could thus account for the spatial deficit in drug-reinforced subjects. Interestingly, chronic intake of drugs of abuse induce a hypofrontality-like syndrome in animals (Jentsch and Taylor, 1999;Homayoun and Moghaddam, 2006;Sun and Rebec, 2006) and addicted humans (Goldstein and Volkow, 2002;Kalivas et al, 2005;Goldstein et al, 2007). Morphine-induced increases in DA release within other brain regions may have occurred: activation of the basolateral amygdala elicited by emotionally charged events impairs hippocampus-dependent learning and synaptic plasticity (Akirav and Richter-Levin, 1999;Kim and Diamond, 2002;Layton and Krikorian, 2002).…”