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was evaluated in the NAc core and shell, at day 1 and day 21 of abstinence after cocaine
administration. After 1 day of abstinence, cocaine rats did not show LTD in the core or shell,
suggesting that operant lever pressing for cocaine depressed LTD in both structures. Yoked
rats showed similar levels of LTD as the sham-naïve rats, suggesting that the loss of LTD was
not simply due the pharmacological effect of cocaine. After 21 days of abstinence, LTD could
not be induced in the core of the NAc, suggesting long-lasting neuroplasticity specific to this
subregion that can underlie the persistence of cocaine addiction (Martin et al., 2006). These
results are consistent with the role of the core in reward-predictive stimuli (Bassareo and Di
Chiara, 1999; Parkinson et al., 1999, 2000; Ito et al., 2000) and may
contribute to the
reduced behavioral flexibility which characterizes addicts.
Long-term potentiation (LTP) in cocaine addiction
LTP, the basic mechanism of synaptic plasticity, can be induced in the NAc core in
young animals as well as in adults and has been related to NMDA glutamate receptor
activation (Schramm et al., 2002). The first experiments to explore synaptic plasticity in the
NAc of cocaine treated rodents reported the induction of LTD at cortical inputs (Hyman and
Malenka, 2001). However, these experiments were conducted
in vitro
, where the pattern of
neurotransmitter release is different from that taking place
in vivo,
because of a disconnection
of the NAc from its cortical and subcortical afferents. NAc dopaminergic neurons in animals
that have undertaken a treatment for cocaine sensitization exhibit an increase in dendritic
branches and spines on the medium spiny neurons of the NAc (Robinson and Kolb, 1999,
2004). These changes that presumably represent a fundamental reorganization of synaptic
inputs onto the intrinsic cells of the NAc, appears to be predictive of LTP rather than LTD.
Goto & Grace (2005b) investigated whether the cellular mechanisms of synaptic
plasticity, LTP and LTD registered
in vivo
, were altered after a treatment of cocaine
sensitization. Synaptic plasticity was studied at PFC and HPC glutamate projections on the
NAc intrinsic neurons. Changes in dopamine release were also considered. Rodents
underwent 6 days of cocaine sensitization (15 mg/kg per day) followed by 10-18 days of
withdrawal from the drug, after which animals received a challenge with cocaine to assess
locomotion. Rats were also tested with a strategy learning and a goal-directed behavior test
(plus-maze task). A control group of saline treated animals was
also introduced. In order to
study synaptic plasticity in different brain structures, rodents were placed in a stereotaxic
apparatus on 1 and 5 days following behavioral recordings. Stimulant electrodes were placed
in the HPC and in the PFC to evoke LTP or LTD in anesthetized animals and the recordings
were registered from the core and the shell regions of the NAc. This electrode placement was
done to evaluate both the direct and indirect interactions mediated by these structures in the
NAc. In saline treated animals, HPC tetanic stimulation induced LTP at HPC and LTD at the
PFC inputs to the NAc shell. However, in cocaine treated animals, the same tetanic
stimulation failed to induce any persistent changes in the evoked responses to the NAc. On
the other hand, synaptic plasticity induced by tetanic stimulation of the PFC projections to the
NAc was not different when comparing the cocaine and saline groups. These changes in
synaptic plasticity disrupted goal-directed behavior as measured by a plus-maze task in such a
