Biology Reference
In-Depth Information
currents (NMDAR EPSCs) ratio on excitatory synapses in the VTA DA neurons was
increased 24 hrs after animals experienced an episode of acute stress plus a saline injection
when compared to animals that received only a saline injection (Saal et al., 2003). In a similar
study, cocaine administration immediately after acute stress was not found to cause any
additional increase in the AMPA/NMDA ratio. The interpretation of these results depends on
the possibility of there being a “ceiling” effect, the maximum AMPA/NMDA ratio that can be
achieved. If cocaine and stress had increased synaptic strength in the VTA by independent
mechanisms, the magnitude of the increase in synaptic strength would have been greater in
animals experiencing stress and cocaine combined compared to animals experiencing only
stress. Thus, the results of the study suggest that drugs of abuse and stress induce LTP in the
VTA through the same mechanism of action. However, these results do not allow any
conclusion to be drawn about the neurobiological mechanisms underlying the increased
AMPA/NMDA ratio (Dong et al., 2004).
One of the major consequences of acute stress is an enhancement in the activity of the
hypothalamic-pituitary-adrenal axis (HPA) with an increased secretion of glucocorticoids and
activation of their receptors (GRs). Saal et al., (2003) studied whether GR plays a role in the
strengthening of synaptic plasticity induced by stress. Rodents were treated with the GR
antagonist RU486 before being placed in cold water. The GR antagonist blocked LTP (i.e.,
increased AMPAR to NMDAR EPSC ratio) that had been induced by stress. Nevertheless,
the GR antagonist did not block the LTP induced by cocaine. On the hand, Dong et al. (2004)
found that administration of D1 receptor antagonists blocked those cellular mechanisms of
LTP that were induced by cocaine but not those induced by stress. According to these results,
although cocaine and stress are able to induce similar cellular adaptations in the VTA,
potentiating activity of DA neurons in this midbrain areas, the neurobiological mechanisms of
action of those effects (cocaine or stress) are different.
BDNF
A
ND
S
YNAPTIC
P
LASTICITY IN THE
VTA
The protein BDNF has been found to exert a potent effect in behavioral sensitization
induced by cocaine. When BDNF is infused for two weeks into the VTA, rats showed a
progressive increase in locomotor activity, compared with saline infused animals (Horger et
al., 1999). However, it is during withdrawal that the expression of BDNF in the VTA is more
significant, facilitating LTP induction and hence synaptic plasticity in the VTA.
The role of BDNF has been studied using animal models of cocaine craving and relapse
by Grimm and his colleagues. Rats, divided in two groups, were trained to press a lever for 10
days (instrumental learning), receiving cocaine (experimental group) or sucrose (control
group) as a reward. After cocaine withdrawal, behavioral measures of lever pressing during
extinction were recorded over 90 days. Reward seeking, as measured by the rate of lever
pressing, increased progressively over 90 days or longer. BDNF levels in the VTA were also
studied during withdrawal. It was found that BDNF levels rose significantly and
progressively in the VTA after ceasing cocaine, but BDNF did not increase in the same brain
region and the same time period in the control group (Grimm et al., 2003). The role of BDNF
in cocaine withdrawal was further studied by the same laboratory using the same animal
model. This second study included, an exogenous BDNF infusion into the VTA and the SN
