The infralimbic cortex regulates the consolidation of extinction after cocaine self-administration

Abstract

The infralimbic cortex (IL) regulates the consolidation of extinction learning for fear conditioning. Whether the IL influences the consolidation of extinction learning for cocaine self-administration is unknown. To address this issue, male Sprague -Dawley rats underwent 2 wk of cocaine self-administration followed by extinction training. On the first 5 d of extinction, rats underwent brief (15-or 30-min) extinction sessions and received intra-IL microinjections immediately after each extinction session. On days 6-12 of extinction, rats underwent full-length (2-h) extinction sessions that were used to assess the retention of the extinction learning from the short sessions. IL inactivation via microinjections of the GABA agonists baclofen and muscimol (BM) immediately after the extinction sessions (days 1-5) impaired the retention of extinction learning. Control experiments demonstrated that this effect was not due to inactivation of the prelimbic cortex or due to effects of the drugs on the subsequent day's behavior. In contrast, post-training intra-IL microinjections of the allosteric AMPA receptor potentiator 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetamide (PEPA) enhanced retention of the extinction learning. As evidence suggests a role for the b-adrenergic receptors in memory consolidation, other rats received microinjections of the b 2 -adrenergic receptor agonist clenbuterol or antagonist ICI-118,551 (ICI). Post-training intra-IL administration of clenbuterol or pre-training administration of ICI enhanced or impaired, respectively, the retention of extinction learning. These data indicate that the IL, and specifically the glutamatergic and b-adrenergic systems in the IL, regulates the consolidation of extinction of cocaine self-administration and that the IL can be manipulated to influence the retention of extinction.

Compound Stimulus Presentation and the Norepinephrine Reuptake Inhibitor Atomoxetine Enhance Long-Term Extinction of Cocaine-Seeking Behavior

“…This result is difficult to explain solely in terms of enhanced consolidation and strongly suggests that NE signaling can also enhance extinction learning. This is consistent with previous demonstrations that pre-training but not posttraining b-adrenergic receptor blockade can impair extinction (Mueller et al, 2008;LaLumiere et al, 2010). Together, these results are most consistent with the view that NE can promote learning-related plasticity, but that the type of learning that is either enhanced or impaired will depend on the details of the experimental design.…”

“…Importantly, many of these effects ultimately rely on action at the b-adrenergic receptors (Ferry et al, 1999;Roozendaal et al, 2002;Berlau and McGaugh, 2006;Mueller et al, 2008;LaLumiere et al, 2010). Thus, taken together with our propranolol results, it is likely that the results reported here with atomoxetine result from increases in synaptic NE levels that allow for greater potential activity at the b-adrenergic receptor.…”

“…The current results extend those found with post-training drug treatments that target the consolidation or reconsolidation of extinction and suggest that a single pre-training treatment that activates the NE system can also promote the extinction of a cocaine-seeking response and its stimulus control and that this effect is persistent, lasting at least 4 weeks. Together with the memory enhancements seen with posttraining augmentation of NE signaling, it is likely that there is some increase in endogenous NE activity during extinction training, blockade of which impairs extinction, and that post-training pharmacological activation of b-adrenergic receptors is additive to that occurring in the session itself (LaLumiere et al, 2010). Thus, it could be argued that the current results can be explained by enhanced consolidation.…”

“…For example, LaLumiere et al (2010) found that repeated post-training administration of the b2-adrenergic agonist clenbuterol within the infralimbic cortex enhanced retention of extinction, as evidenced by lower responding in subsequent sessions. Other past work has found that interference with the NE system can disrupt stable memory formation as post-retrieval administration of propranolol can impair cocaine-conditioned place preference (Bernardi et al, 2006(Bernardi et al, , 2009Fricks-Gleason and Marshall, 2008) or conditioned reinforcement (Milton et al, 2008).…”

Inhibition of β-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement

“…Furthermore, it is well accepted that norepinephrine facilitates, rather than impedes, memory formation through b-receptor activation (McGaugh, 2000). Finally, research has demonstrated that propranolol impairs extinction learning (for review see Mueller and Cahill, 2010) in both aversive (Do-Monte et al, 2010;Merlo and Izquierdo, 1967;Mueller et al, 2008;Ouyang and Thomas, 2005) and appetitive paradigms (LaLumiere et al, 2010).…”