Biomedical Engineering Reference
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DA-releasing stimulants could promote LTP by decreasing the opposing
infl uence of LTD, as D2 receptor activation inhibits LTD in midbrain slices
(29
,
30)
. Psychostimulant-induced increases in VTA glutamate levels may
also promote LTP
(31
,
32)
. Of course, mechanisms unrelated to LTP may also
contribute to increased excitability of VTA DA neurons, including inhibition of
mGluR-mediated inhibitory postsynaptic potentials (IPSPs)
(33
,
34)
. Finally, it
should be noted that glutamate transmission in the VTA may be infl uenced by
drug-induced alterations in other transmitter systems. Mechanisms that may
contribute to sensitization-related plasticity in the VTA have been reviewed
elsewhere
(2
,
35)
.
An interesting future direction is to study sensitization in transgenic mice
with alterations in glutamate receptors or signaling pathways implicated in
LT P. Chiamulera et al.
(36)
reported that mGluR5 knockout mice do not exhibit
locomotor activation when injected with acute cocaine, and do not acquire
cocaine self-administration. Mao et al.
(37)
found that mGluR1 knockout mice
have augmented locomotor responses to amphetamine, perhaps due to impaired
mobilization of inhibitory dynorphin systems that normally regulate responses
to amphetamine. Using GluR1 knockout mice, Vekovischeva et al.
(38)
found
that sensitization was normal when mice received repeated morphine injections
in the same environment in which they were ultimately tested (context-dependent
sensitization) but did not develop when the repeated treatment was given in home
cages (context-independent sensitization), whereas wild-type mice developed
sensitization under both conditions. Although all of these results are potentially
important, it is hard to draw fi rm conclusions because of the possibility of
altered neuronal development in glutamate receptor defi cient mice.
3. Effect of Psychomotor Stimulants on Glutamate Receptor
Expression in the Nucleus Accumbens and Dorsal Striatum
3.1. Role of the NAc and Striatum in Behavioral Sensitization
The NAc occupies a key position in the neural circuitry of motivation
and reward. Not surprisingly, it is also critical for behavioral sensitization.
While psychostimulants act in the midbrain to trigger the development of
sensitization, drug actions in the NAc lead to the expression of a sensitized
response. Accordingly, the VTA is associated with transient cellular adaptations
during the early withdrawal period, while the NAc is the site of more persistent
adaptations (
see
refs.
10
and
39
). The output neurons of the NAc, medium spiny
-aminobutyric acid (GABA) neurons, are regulated by convergent DA and
glutamate inputs, although the nature of the interaction between DA and gluta-
mate is complex and remains controversial
(40)
. Repeated psychostimulant
administration leads to profound changes in both DA and glutamate trans-
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