Effects of Psychomotor Stimulants on Glutamate Receptor Expression - Drugs of Abuse: Neurological Reviews and Protocols - page 15

(23) compared rats treated with repeated cocaine or saline and found signifi cant
increases in NR1 immunoreactivity in the cocaine group after 3 and 14 d
of withdrawal and a trend toward an increase after 24 h. Using the same
regimen as Churchill et al. (14) , Ghasemzadeh et al. (22) found no signifi cant
changes in NR1 mRNA levels in VTA using RT-PCR. We used quantitative
immunoautoradiography to examine NR1 expression in VTA, substantia
nigra, and a transitional area in rats killed 3 or 14 d after discontinuing
repeated amphetamine administration. No changes were observed after 3 d
of withdrawal, whereas NR1 immunolabeling was signifi cantly decreased in
the intermediate and caudal portions of the substantia nigra, but not in other
midbrain regions, after 14 d of withdrawal (24) . NR1 levels in the NAc and
prefrontal cortex were also decreased at this withdrawal time (24) . It may
be relevant to note that although NMDA receptor transmission in the VTA
is required for the induction of sensitization, repeated stimulation of NMDA
receptors in the VTA is not suffi cient to elicit sensitization (25 , 26) .
2.3. Summary: VTA and Substantia Nigra
As reviewed in Subheading 2.1. , both neurochemical and electrophysi-
ological studies suggest that there is an enhancement in the responsiveness of
VTA DA neurons to the excitatory effects of AMPA shortly after discontinuing
repeated psychostimulant administration. An increase in AMPA receptor
expression in the VTA would provide a simple explanation for these results.
However, although Western blotting studies have found increased GluR1 and
NR1 levels in the VTA shortly after cocaine administration is discontinued,
this is not observed with immunoautoradiography following either cocaine
or amphetamine administration (see 15 for discussion). More importantly,
after the same drug regimens and withdrawal times that are associated with
increased responsiveness of VTA DA neurons to AMPA, no changes in GluR1
are observed. Thus, although considerable evidence suggests that enhanced
responsiveness of VTA DA neurons to AMPA is closely linked to the induc-
tion of sensitization, the mechanisms are likely to be more complex than a
generalized increase in GluR1 expression within the VTA.
As LTP is expressed as a potentiation of AMPA receptor transmission,
an alternative explanation is that sensitization is accompanied by LTP-like
changes that increase the effi ciency of glutamate transmission in the VTA.
Although LTP appears to involve insertion of AMPA receptor subunits into
synaptic sites (27) , there is no evidence that this is accompanied by increases in
total cellular expression of AMPA receptor subunits. Supporting the involve-
ment of LTP in the development of sensitization, a single systemic injection of
cocaine to mice (suffi cient to elicit behavioral sensitization) produced LTP in
midbrain DA neurons (28) . The mechanisms responsible are probably complex.