Effects of Psychomotor Stimulants on Glutamate Receptor Expression - Drugs of Abuse: Neurological Reviews and Protocols - page 14

area after 16-24 h of withdrawal from repeated amphetamine or cocaine
treatment (15) . Importantly, this study (15) also failed to fi nd a change in GluR1
immunoreactivity after 3 or 14 d of withdrawal from the same amphetamine
regimen that resulted in enhanced electrophysiological (10) and neurochemical
(11) responsiveness to intra-VTA AMPA at the 3-d withdrawal time. Thus,
although part of the discrepancy between results from different labs may be
attributable to different drug regimens, our fi ndings suggest that increased
GluR1 expression is unlikely to explain our electrophysiological or neurochemi-
cal fi ndings of increased responsiveness to AMPA. Other possible reasons for
differences between our immunoautoradiography studies and prior Western
blotting studies have been discussed previously (15) .
Another fi nding relevant to this controversy is that overexpression of GluR1
in the rostral VTA using a herpes simplex virus resulted in intensifi cation of the
locomotor stimulant and rewarding properties of morphine (16 , 17) . Although
this is an interesting fi nding, it does not necessarily imply that increased
GluR1 expression is involved in the naturally occurring pathways that produce
behavioral sensitization to morphine or psychomotor stimulants. A state
resembling behavioral sensitization can be produced by a number of diverse
experimental manipulations, all sharing the ability to produce brief but intense
activation of VTA DA cells. These include repeated electrical stimulation of
the VTA (18) or PFC (19) , and pharmacological disinhibition of VTA DA
cells (20) .
In contrast to discrepant results at the protein level, all studies agree that
mRNA levels for AMPA receptor subunits in the VTA are not altered during
withdrawal from repeated amphetamine or cocaine. We found no change in
GluR1 mRNA using reverse transcriptase-polymerase chain reaction (RT-PCR)
in the VTA of rats killed 16-18 h after discontinuing repeated amphetamine or
cocaine administration (15) . Similarly, Bardo et al. (21) used RNase protection
assays to quantify GluR1-4 mRNA levels in the ventral mesencephalon of
rats killed 30 min after the third or tenth amphetamine injection in a repeated
regimen and observed no signifi cant changes, although behavioral sensitization
was demonstrated. Ghasemzadeh et al. (22) used RT-PCR to determine mRNA
levels for GluR1-4, NR1, and mGluR5 in the VTA 3 wk after discontinuing
repeated cocaine or saline injections, and found no signifi cant changes as
a result of repeated cocaine treatment, although acute cocaine challenge
produced a small reduction in NR1 mRNA levels in the VTA of both naïve
and sensitized rats.
As noted previously, Western blotting studies have found increased NR1
levels in the VTA of rats killed 16-24 h (but not 3 wk) after discontinuing
repeated cocaine administration, suggesting that the increase is transient
(12 , 14) . In contrast, using immunohistochemical methods, Loftis and Janowsky