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ated with behavioral sensitization and drug-seeking behavior. There is some
agreement that GluR1 and NR1 levels are not altered in the NAc after short
withdrawals (1-3 d) from repeated cocaine or amphetamine administration. At
longer withdrawal times (2-3 wk), cocaine-treated rats may show increases in
GluR1, NR1, and NR2B, whereas amphetamine-treated rats show decreases
in GluR1, GluR2, and NR1. There may also be persistent changes in the
expression and function of group I mGluRs. The delayed onset of many of the
reported changes in glutamate receptor expression is consistent with a role for
the NAc in the long-term maintenance of sensitization and other drug-induced
behavioral changes. However, it is diffi cult to reconcile opposite effects of
cocaine and amphetamine on glutamate receptor expression with a role for
these changes in the maintenance and expression of sensitization, as both
drugs produce similar behavioral effects (augmented locomotor response) in
sensitized rats. It should be kept in mind that the NAc contains heterogeneous
populations of projection neurons and interneurons, and we do not know the
phenotype of the neurons that experience changes in glutamate receptor subunit
expression (e.g.,
42
,
52
). Moreover, other types of drug-induced changes
may contribute importantly to the excitability of NAc neurons. For example,
Zhang et al.
(43)
found reduced sodium currents in NAc neurons after a short
withdrawal from repeated cocaine, while Thomas et al.
(58)
found evidence
for LTD in the NAc after long-term withdrawal from cocaine. In fact, growing
evidence suggests that abnormal synaptic plasticity in the NAc, triggered
by chronic drug treatment, leads to dysregulation of motivation- and reward-
related circuits and thereby contributes to addiction
(2)
. It will be important to
determine whether alterations in glutamate receptor expression contribute to
the induction of altered plasticity, are involved in its expression, or represent
compensatory responses to changes in the activity of glutamate-containing
projections.
4. Effect of Psychomotor Stimulants on Glutamate Receptor
Expression in the PFC and Other Cortical or Limbic Regions
4.1. Role of the Prefrontal Cortex in Behavioral Sensitization
The PFC is now acknowledged to play an important role in behavioral
sensitization. Excitotoxic lesions of the PFC prevent the development of
sensitization
(59-61)
as well as cellular changes in DA systems that are
closely associated with sensitization
(61)
. The role of PFC in the expression
of behavioral sensitization in response to psychostimulant challenge is more
controversial. Some evidence suggests that expression of sensitization requires
glutamatergic transmission between the dorsal PFC and the NAc core
(62)
.
On the other hand, excitotoxic lesions of the PFC that are suffi cient to prevent
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