Increasing lines of evidence suggest that retrieval of previously consolidated
memories is a dynamic process that either reinforces or alters memory. Memory retrieval
may initiate two potentially opposing but distinguishable processes: reconsolidation and
extinction (Suzuki et al., 2004). Memory reconsolidation acts to stabilize retrieved
memories whereas extinction tends to weaken the expression of the original memory.
Recently, these two processes have become important targets for reduction of drugassociated
memory. My studies have shown that a) reconsolidation of Fix-C and Esc-C
memory engage NO-dependent and NO-independent signaling pathways, respectively
and b) the extinction of Esc-C memory, which is resistant to extinction by unreinforced
re-exposures the testing context, can be induced by the use of cognitive enhancers in the
form of PDE inhibitors.
The disruption of drug-memory reconsolidation may represent a powerful tool for
the management of addiction. Previously consolidated drug-associated memory, when
retrieved, can be disrupted using pharmacological tools. This disruption subsequently
attenuates the alluring impact of drug-related cues thereby preventing relapse. However,
a complete understanding of the signaling molecules that govern this process is lacking.
In Chapter 2, the contribution of different signaling pathways to Fix-C and Esc-C
memory reconsolidation was investigated. While pharmacological inhibition of NO
signaling disrupted Fix-C memory reconsolidation, it had no effect on Esc-C memory
(Fig. 2.5). Thus, similar to acquisition experiments, the ‘weak’ Fix-C memory is
mediated by NO-dependent signaling while the ‘strong’ Esc-C memory bypasses the
dependence on NO signaling. The lack of effect on Esc-C memory is a novel finding
which now identifies a previously unknown ‘NO-independent’ cocaine-memory
reconsolidation process. It should be noted, however, that it is likely that Esc-C memory
activates nNOS but it appears that conditioning by Esc-C recruits additional signaling
pathways which may over rule the involvement of NO-signaling. Identifying a ‘NOindependent’
cocaine-memory reconsolidation mechanism prompted investigation into
other potential molecular contributors to this process. Because the ERK signaling
pathway plays a role in the formation of cocaine-associated contextual memory (Miller &
Marshall, 2005; Valjent et al., 2006), it represented a possible alternative signaling
pathway to assess for its contribution to Esc-C memory reconsolidation. It was shown
that while inhibition of the ERK kinase MEK disrupted the reconsolidation of Esc-C
memory, it had no effect on the reconsolidation of Fix-C memory (Fig. 2.5). These
findings demonstrate for the first time that different signaling molecules are recruited in
the reconsolidation of cocaine-associated memory depending on the pattern and salience
of cocaine administration. Thus, these findings highlight the importance of understanding
the significance of drug memory strength, which could be relevant to the severity of
addiction, as it relates to the development of pharmacotherapeutics for the management
While one goal of addiction research is to disrupt drug memory reconsolidation,
another equally important addiction management strategy is extinction learning by
‘exposure therapy’ (Carter & Tiffany, 1999; Powell et al., 1993; Siegel & Ramos, 2002).
Extinction typically requires long or multiple re-exposures to a CS (Nader, 2003; Power
et al., 2006). Studies suggest that the extinction process does not eliminate or cause
‘unlearning’ of the initial conditioned response; rather, the organism learns that the CS no
longer elicits the previous stimulus (Bouton, 2002; 2004; Havermans & Jansens, 2003).
Thus, extinction requires new learning (Milad & Quirk, 2002; Santini et al., 2001).
Mice conditioned by Fix-C readily show extinction with multiple unreinforced
exposures to the conditioning context. Alternatively, mice conditioned by Esc-C maintain
preference for the cocaine paired side for greater than 10 days. In Chapter 3, it was
investigated whether acceleration of extinction learning using different PDE inhibitors
(cognitive enhancers) could facilitate extinction learning in mice conditioned by Esc-C.
PDE inhibitors have previously been shown to facilitate learning and memory in animal
models of experimentally-induced learning and memory deficits (Bender & Beavo, 2006;
Blokland et al., 2006; Boswell-Smith et al., 2006; Menniti et al., 2006). It was shown that
the inhibition of PDE9 which increases levels of cGMP in the hippocampus and
amygdala induced extinction learning and prevented cocaine-primed reinstatement in
mice conditioned by Esc-C. However, PDEs that increased levels of cAMP or dualspecific
PDEs (increased both cAMP and cGMP) did not induce extinction learning (Fig.
3.2). These data suggest that PDE9 which is highly localized in all sub-areas of the
hippocampus (van Staveren et al., 2002; 2004; Reyes-Irisarri et al., 2007) has a
prominent role in consolidation of extinction learning. It also appears that targeting a
specific PDE is more critical than targeting any PDE which metabolizes cGMP.
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