Biology Reference
In-Depth Information
BDNF
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OCAINE
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BDNF and its intracellular signaling mechanisms modulate LTP and LTD (Bramham and
Messaoudi, 2005) and hence can modify synaptic plasticity (Bramham and Messaoudi, 2005)
and its consequence on learning and memory (Lee et al., 2004; Yamada et al., 2002). There is
also experimental evidence that BDNF can modify the reward-related properties of the
conditioned stimuli in the context of cocaine addiction.
Horger et al. (1999) reported that BDNF infusions within the Nac strengthened the ability
of a stimulus to act as a conditioned reinforcer and increased the cocaine-induced response to
the conditioned reinforcer. The strengthening of cocaine effects in BDNF-treated rats
persisted for more than a month after the BDNF infusions had finished. These results support
the hypothesis that BDNF promotes long-lasting changes in the mesolimbic dopamine system
by activating mechanisms of associative learning that underlie the persistent addictive
behavior that endures long after withdrawal (Horger et al.,1999). The role of BDNF in drug-
associated stimuli is supported by studies in heterozygous knockout mice. Using a
conditioned place preference paradigm (CPP), BDNF (+/-) mice showed attenuated effects of
cocaine reward and a decreased ability to learn a new association between the drug and the
place where it was administered (Hall et al., 2003). Overall, these results show that BDNF
modulates synaptic plasticity potentiating learning processes (Bramham and Messaoudi,
2005; Lee et al., 2004; Yamada et al., 2002) and strengthening conditioned responses to
cocaine.
BDNF effects are mediated through its intracellular signal transduction systems,
including the MAP kinase/ERK and PI3-kinase pathway (Kaplan and Miller, 2000;
Patapoutian and Reichardt, 2001) (see figure 1). In a experimental design used by Valjent
(2006) to study cocaine sensitization, mice showed an association between the effects of the
drug and the context where the drug was administered. Animals displayed conditioned
locomotor responses in the environment previously paired with cocaine, even in the absence
of the drug. These conditioned locomotor responses have many similarities with Pavlovian
conditioning, by which environmental cues become associated to the effects of the drug. The
conditioned responses were completely blocked in mice pre-treated with SL327 before each
injection with cocaine, suggesting a crucial role for ERK in these responses (Valjent et al.,
2006). The role of ERK in the association between environmental stimuli and drugs of abuse
has also been assessed with a CPP paradigm. After behavior became conditioned, ERK
activity increased in the NAc core but not in the shell (Miller and Marshall, 2005). The
selective increase of ERK in the NAc core is consistent with the involvement of the reward
regions in conditioned emotional responses and in cue-elicited drug seeking (Cardinal et al.,
2002; Ito et al., 2000). In the study of Miller and Marshall (2005), administration of U0126
intra-NAc, an inhibitor of ERK activity, prevented the activation of the ERK signaling
pathway and blocked the expression of the preference for the environment previously paired
with cocaine. Locomotor activity was not affected. Blockade of the place preference
conditioning lasted for 14 days after the injection of different MEK inhibitors (Miller and
Marshall, 2005). Taken together, these findings suggest that ERK intracellular cascade in the
Nac core is part of the molecular mechanisms for drug-paired contextual cue memories, by
which environmental stimuli exert a motivational influence on drug-seeking behavior.
