Effects of Psychomotor Stimulants on Glutamate Receptor Expression - Drugs of Abuse: Neurological Reviews and Protocols - page 23

increases at all withdrawal times. For lateral frontal cortex and parietal cortex,
there was no change after 24 h, but increases after 72 h and 14 d. This study
also measured neuronal nitric oxide synthase, but these results will not be
discussed.
4.3. Summary: PFC and Other Cortical and Limbic Regions
Glutamate receptor expression in the PFC undergoes complex changes after
drug administration is discontinued that depend on the withdrawal time and
probably differ between cocaine and amphetamine, at least for NR1. In general,
some results suggest that AMPA receptor subunit expression changes at early
withdrawal times whereas NMDA receptor subunit expression is altered after
longer withdrawals. Because relatively few studies have assessed glutamate
transmission in the PFC of sensitized rats using electrophysiological or
neurochemical approaches, it is diffi cult to assess the functional signifi cance
of observed changes. An exception is the correlation between increased
responsiveness of PFC neurons to glutamate (67) , and increased expression of
GluR1 in the PFC (41 , 42) , after short withdrawals from repeated amphetamine
administration. It will be important to conduct studies on additional brain
regions implicated in addiction, such as the amygdala.
5. Conclusions
It is clear that repeated administration of cocaine or amphetamine infl u-
ences glutamate receptor expression in brain regions important for behavioral
sensitization and addiction. However, to date, the data obtained raise more
questions than they answer. One important problem is that amphetamine and
cocaine produce different patterns of changes, whereas both produce behavioral
sensitization. Either there are multiple ways to achieve a sensitized state, or
the changes in glutamate receptor expression are not directly associated with
sensitization. The picture is made more complex by different effects at different
withdrawal times, different effects with different drug regimens, and lack of
agreement between laboratories using similar drug regimens. Another problem
is that studies of receptor expression have been conducted at the regional
level, precluding identification of the types of cells exhibiting particular
alterations in glutamate receptor expression after stimulant exposure. Without
such information, it is hard to predict the functional effect of these alterations
at the level of neuronal circuits. For example, does the increase in GluR1
expression in the PFC after repeated amphetamine occur in pyramidal neurons
or interneurons, or in a subset of one of these populations? It will be important
to conduct future studies in identifi ed cells, although this is a very challenging