Biology Reference
In-Depth Information
Excitatory synapses on dopamine neurons in the midbrain dopamine regions, the VTA,
and the substantia nigra (SN) can undergo LTP and LTD (Thomas and Malenka, 2003), the
major mechanisms of synaptic plasticity. These mechanisms cause changes at the excitatory
synpases in the VTA DA neurons, by potentiating some of them and depotentiating others.
The effects of cocaine within the VTA was assessed in a serial of studies done by
Malenka and his colleagues (Borgland et al., 2004; Saal et al., 2003; Ungless et al., 2001). To
study cocaine effects on the VTA, rodents received a single cocaine injection (15 mg/kg), the
same dose used in the protocols that induce behavioral sensitization. One day later, rodents
are sacrificed so that midbrain slices can be obtained and prepared to measure synaptic
strength (as the magnitude of EPSCs) with whole-cell recording techniques in the manner
described above. A single exposure to cocaine (15 mg/kg) enhances VTA dopamine neurons'
responsiveness, measured as the magnitude of EPSCs in this brain region. Enhancement in
EPSCs is due to an increase in AMPAR/NMDAR ratios, a form of LTP at excitatory
synapses in the VTA DA neurons. Moreover, this enhanced AMPAR/NMDAR ratio is due to
an increase in the number, function, or both, of AMPA receptors in the post-synaptic
membrane of the VTA cells (Ungless et al., 2001). A similar increase in the AMPAR to
NMDAR ratio was also reported in other studies after acute cocaine exposure (Borgland et
al., 2004).
Cocaine-induced potentiation of excitatory synapses in the VTA can be blocked when a
NMDA (Nmethyl-D-aspartate) receptor antagonist is administered with cocaine (Kalivas and
Alesdatter, 1993; Ungless et al., 2001; Vezina and Queen, 2000). In a similar way,
glutamatergic input to the VTA can also trigger relapse and blockade of glutamate receptors
in this brain region inhibiting cocaine seeking (Vorel et al., 2001). The increased
AMPAR/NMDAR ratio is specific to the VTA since it was not observed in other regions such
as the hippocampus (Ungless et al., 2001). Furthermore, these neuroplastic changes appear to
be specific for addictive drugs, since it was not observed after administration of non-addictive
substances such as fluoxetine or carbamazepine (Saal et al., 2003).
Potentiation of synaptic activity in midbrain cells induced by cocaine is thought to be
transient. To explore the length of the acute effects of cocaine on the VTA, midbrain slices
were prepared 5 and 10 days after injection. The AMPAR/NMDAR was increased after 5
days of acute cocaine administration but not after 10 days (see figure 4). These results
indicate that cocaine-induced potentiation of activity at VTA cells are not long-lasting. Thus,
synaptic potentiation at VTA cells after cocaine administration, may only be responsible for
the early stages of behavioral sensitization and the early stages of the development of human
addiction (Ungless et al., 2001).
Other studies have assessed the effects of repeated and intermittent cocaine
administration across 7 days on electrical VTA cell responses as well as on locomotor activity
in cocaine treated rodents. The aim was to study the possible relationship between behavioral
and neurobiological effects induced by repeated cocaine. In naïve animals, a single dose of
cocaine induces an enhancement in locomotor activity correlated with the magnitude of
synaptic enhancement (the ratio AMPAR/NMDAR on the VTA) measured 1 day after the
injection (see figure 4). Nevertheless, this correlation was not found after repeated cocaine
treatment (Borgland et al., 2004). When cocaine doses are administered across 7 days, the
AMPAR/NMDAR ratio at the VTA synapses remained at the same level as the levels found
after 24 hours of a single cocaine injection. These results suggest that cocaine-induced
synaptic plasticity in the VTA is not only transient but also has a ceiling effect. (Borgland et
