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Afterwards, rats received microinjections of NMDA and AMPA glutamate receptor
antagonists inside the VTA prior to each cocaine place-conditioning trial. Glutamate
antagonist completely blocked the development of cocaine CPP, whereas antagonists
administered outside of the VTA did not alter cocaine conditioning. These results suggest that
plasticity in the VTA also plays a role in learning an association between the neutral place
and the primary reward, in this case cocaine (Harris and Aston-Jones, 2003).
Although synaptic plasticity in the VTA appears to be a mechanism for up or down
regulating the excitability of the entire ensemble of dopaminergic neurons (Jones et al., 2000),
this brain region is not likely to be the specific site of cue-conditioning. In other words, the
VTA is the site of action for transient synaptic plasticity which plays an essential role in
triggering adaptations after drug exposure in regions innervated by DA neurons, including the
NAc, dorsal striatum, amygdala and PFC (Nestler, 2001, 2002). These areas are involved in
appetitive associative learning and all undergo activity-dependent synaptic plasticity related
to cocaine consumption, which may account for long-term consequences of addiction. This
proposed role for VTA is consistent with the idea that activity of dopamine neurons in the
VTA are necessary for attributing motivational significance to the stimuli (Schultz, 2002).
Potentiation of excitatory synapses on VTA DA neurons with repeated drug administration
may contribute to the incentive salience attributed to the drugs, even for the learned
association between context and drug experience (Robinson and Berridge, 1993, 2001).
Excitatory synapses on dopamine neurons of the VTA exhibit LTD as well as LTP
(Thomas et al., 2000). If LTD is related to development of sensitization and to increase of
strength at excitatory synapses in the VTA, psychostimulants must decrease or block LTD at
VTA. In fact, Thomas et al. (2000) reported that amphetamines block LTD at VTA synapses
though dopamine acting on D2 receptors in dopamine neurons. LTD also requires voltage-
dependent CA2+ channels but is independent of NMDAR receptors. The inhibition of LTD
makes the induction of LTP easier (Thomas et al., 2000).
S TRESS A ND S YNAPTIC P LASTICITY IN THE VTA
Stress is a potent trigger of relapse in humans and in many animal addiction models
(Marinelli and Piazza, 2002; Stewart, 2003). Individuals can be abstinent for months or even
years and are still susceptible to experience cravings that can stimulate drug-seeking and
relapse (O'Brien, 1997). Exposure to stress also facilitates the initial acquisition and
maintenance of drug self-administration in animal models of addiction (Piazza and Le Moal,
1998; Shaham et al., 2000). From the neurobiological point of view, stress acts in a similar
way to drugs of abuse, causing an increase in DA levels in the NAc and prefrontal cortex
(Horger and Roth, 1996; Piazza and Le Moal, 1998). Stress also produces inhibition of LTP
and enhances LTD in various brain structures, such as the hippocampus, modifying synaptic
plasticity (Shors et al., 1989; Kim et al., 1996).
Acute stress, like cocaine, can also induce changes in excitatory synaptic strength on
midbrain dopamine neurons. One of the studies used a forced swimming task to induce acute
stress (Saal et al., 2003). Then animals were sacrificed and underwent the above-mentioned
general experimental procedure to study potentiation at excitatory synapses in the VTA. The
receptor mediated synaptic currents (AMPA EPSCs) to NMDA receptor mediated synaptic
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