Variations in the stimulus salience of cocaine reward influences drug-associated contextual memory

Drugs of abuse act as reinforcers because they influence learning and memory
processes resulting in long-term memory of drug reward. We have previously shown that
mice conditioned by fixed daily dose of cocaine (Fix-C) or daily escalating doses of
cocaine (Esc-C) resulted in short- and long-term persistence of drug memory,
respectively, suggesting different mechanisms in acquisition of cocaine memory. The
present study was undertaken to investigate the differential contribution of N-methyl-Daspartate
receptor (NMDAR) subunits in the formation of Fix-C and Esc-C memory in
C57BL/6 mice. Training by Esc-C resulted in marked elevation in hippocampal
expression of Grin2b mRNA and NR2B protein levels compared to training by Fix-C.
The NR2B-containing NMDAR antagonist ifenprodil had similar attenuating effects on
acquisition and reconsolidation of Fix-C and Esc-C memory. However, the NMDAR
antagonist MK-801 had differential effects: a) higher doses of MK-801 were required for
post-retrieval disruption of reconsolidation of Esc-C memory than Fix-C memory, and b)
pre-retrieval MK-801 inhibited extinction of Fix-C memory but it had no effect on Esc-C
memory. In addition, blockade of NMDAR downstream signaling pathways also showed
differential regulation of Fix-C and Esc-C memory. Inhibition of neuronal nitric oxide
synthase (nNOS) attenuated acquisition and disrupted reconsolidation of Fix-C but not
Esc-C memory. In contrast, the mitogen-activating extracellular kinase (MEK) inhibitor
SL327 attenuated reconsolidation of Esc-C but not Fix-C memory. These results suggest
that NMDAR downstream signaling molecules associated with consolidation and
reconsolidation of cocaine-associated memory may vary upon changes in the salience of
cocaine reward during conditioning.
The role of learning and memory in the reinforcing effects of addictive drugs
continues to garner much attention. Persistent drug-seeking behavior and the inability to
extinguish such maladaptive behavior develop when drugs of abuse exert control over
neural substrates and signaling pathways that encode long-term memory (LTM) (Hyman
et al., 2006). Recently, disruption of persistent drug memory has taken the forefront as a
possible treatment strategy for addiction. Memory reconsolidation is the process whereby
previously consolidated memories, upon retrieval, become labile and are thereby
susceptible to disruption. A number of studies have shown that cocaine-associated
memories are vulnerable to disruption upon retrieval of such memories (Miller &
Marshall, 2005; Kelley et al., 2007; Tronson & Taylor, 2013).
The conditioned place preference (CPP) paradigm, which employs the principles
of Pavlovian learning, can model learning and memory processes pertinent to addictive
behavior (White & Carr, 1985). One caveat in CPP studies is the use of a fixed daily dose
of the drug reinforcer during training. Given that the transition from drug use to drug
addiction involves escalation in drug intake, we posit that investigation of the outcome of
escalating doses of cocaine during conditioning is relevant to the human practice of drug
use and the development of addictive behavior. Our laboratory (Itzhak & Anderson,
2012) has shown that conditioning by escalating doses of cocaine (Esc-C) produced
higher magnitude and more persistent CPP than conditioning by fixed daily doses of
cocaine (Fix-C). This phenomenon was not dose-dependent but rather scheduledependent;
these results were recently confirmed by others (Conrad et al., 2013).
While some studies have used drug self-administration to investigate escalation in
drug exposure, results have shown only a modest escalation in drug self-administration;
about 1.2-1.5-fold increase over a two-week period (Ahmed & Koob, 1998; Perry et al.,
2006; Anker et al., 2012). However, others interpreted these results as a correlate of long
access duration to the drug and not escalated drug intake (Knackstedt & Kalivas, 2007).
We posit that investigation of mechanisms involved in formation of drug memory can be
better modeled in the CPP paradigm by introducing significant changes in the stimulus
salience of the drug reward which apparently facilitates contextual learning.
The N-methyl-D-aspartate receptor (NMDAR) plays a central role in synaptic
plasticity and learning and memory processes (Collingridge, 1987). With respect to
cocaine effects, the NMDAR antagonist MK-801 disrupted acquisition, expression and
reconsolidation of cocaine-associated memory (Kelley et al., 2007; Alaghband &
Marshall, 2013). Functional NMDARs typically exists as heterotetramers between two
compulsory NR1 subunits and two modulatory NR2 subunits (NR2A-D) (Zhou, 2009).
The NR2 subunits of NMDARs are thought to have a major role in learning and memory
(Furukawa et al., 2005). The abundance of specific NR2 subunit appears to be
developmentally regulated where NR2B subunits predominate during early brain
development while NR2A levels increase progressively with development (Yashiro &
Philpot, 2008). The key functional properties of NMDARs are thought to be mediated by
the particular NR2 subunits that comprise the receptor channel (Monyer et al., 1994).
Indeed, compared to NR2A-containing NMDARs, NR2B-containing NMDARs display
longer decay time constant (Cull-Candy & Leszkiewicz, 2004) and carry greater calcium
current per unit charge (Sobcyk et al., 2005). Additionally, it has been reported that
NR2A- and NR2B-containing NMDARs are coupled to different downstream signaling
pathways (Chen et al., 2007).
One downstream effector of calcium influx through NMDAR is neuronal nitric
oxide synthase (nNOS), which catalyzes the production of nitric oxide (NO) (Brenman &
Bredt, 1997). Calcium-dependent nNOS is linked via the post synaptic density protein
PSD-95 to the NR2 subunit of the NMDAR; thus its selective localization renders it
functionally coupled to the NMDAR (Christopherson et al., 1999; Sattler et al., 1999).
Relevant to cocaine effects, NO has been implicated as a major contributor to the
initiation and maintenance of cocaine CPP and behavioral sensitization (Bhargava &
Kumar, 1997; Itzhak et al., 1998; Balda et al., 2006). Another downstream molecule
activated by calcium entry through NMDAR is extracellular signal-regulated kinase
(ERK) (Sweatt, 2001). One of many regulators of the ERK signaling cascade is
RasGRF1, a Ras-specific GDP/GTP exchange factor (GEF) and Ras activator that
specifically binds the NR2B subunit of NMDARs. Hence, NR2B-containing NMDARs
are mediators of the NMDAR-dependent ERK signaling via Ras-Raf-MEK-ERK
signaling (Krapivinsky et al., 2003). With respect to cocaine effects, inhibition of
mitogen-activating extracellular kinase (MEK), the ERK kinase, has been shown to
disrupt cocaine-associated contextual memory (Miller & Marshall, 2005; Valjent et al.,
Because the NMDAR and its downstream molecules have a role in learning and
memory and cocaine effects, this study was undertaken to elucidate the involvement of
NMDAR subunits and downstream signaling pathways in acquisition and reconsolidation
of Fix-C and Esc-C memory.

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