NO-dependent and NO-independent cocaine-associated memory

The CPP paradigm which employs the principles of Pavlovian learning is often
used to investigate the incentive value of drugs of abuse. One caveat to conditioned
reward studies is the use of a fixed daily dose of the addictive drug during training.
However, the transition from drug use to addiction in human addicts involves an
escalation in drug intake (Gawin, 1991). Thus, a paradigm that can effectively simulate
increases in drug intake will better model the human drug use pattern.
Research investigating differences in the pattern of cocaine dosing schedule in a
CPP paradigm have shown that the schedule of cocaine administration, rather than the
dose of cocaine, has a significant impact on the development of drug associated memory
(Itzhak & Anderson, 2012; Conrad et al., 2013). This suggests that different mechanisms
may govern the formation of cocaine-associated memory developed by different
schedules of cocaine administration during conditioning.
Evidence from studies by Rescorla and Wagner (1972) on natural reinforcement
suggests that learning is dependent on the discrepancy between expected and obtained
reward. Schultz’s work extended this theory to say that if background reward is
unchanged or elevated and the conditioned stimulus is unchanged then “reward
prediction” is reduced and thus learning is diminished (Bermudez & Schultz, 2010).
Accordingly, if reward outcome is greater than expected, a positive prediction error is
encoded; when reward is lower than expected a negative prediction error occurs and
extinction ensues; when reward is as expected then no prediction error occurs and no
further behavioral changes will occur (Schultz,1998; Schultz & Dickinson, 2000). Along
this vein, it is plausible that conditioning by Esc-C where the reward is increased during
conditioning may produce positive prediction error and thereby create a strong/stable
memory. On the other hand, conditioning by Fix-C (which essentially was devoid of
prediction error) may create a more labile memory which could be easily manipulated.
In Chapter 2 it was shown that the NR2B subunit of the NMDAR was markedly
elevated in hippocampus of the enhanced and persistent ‘strong’ Esc-C memory
compared to ‘weak’ Fix-C memory (Fig. 2.1). Given the role of the NR2B subunit in
learning and memory (Wang et al., 2009; Zhao et al., 2005), the elevation in NR2B may
have contributed to the increased strength of the Esc-C memory. Pharmacological
antagonism of NR2B-containing NMDARs effectively attenuated the acquisition of both
Fix-C and Esc-C memory. However, administration of the nNOS inhibitor 7-NI
attenuated the acquisition of Fix-C memory but it had no effect on Esc-C memory (Fig.
2.2). While the blockade of Fix-C memory was expected since previous work from our
lab has shown this effect (Itzhak et al., 1998), the finding that nNOS inhibition was
ineffective against Esc-C memory was novel. The current findings therefore highlight for
the first time that the pattern of cocaine administration, rather than the dose of cocaine,
resulted in the differential recruitment of signaling molecules downstream of NR2Bcontaining
NMDARs that were essential to the formation of Fix-C and Esc-C memory.


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