Effects of Psychomotor Stimulants on Glutamate Receptor Expression - Drugs of Abuse: Neurological Reviews and Protocols - page 12

refers to the progressive enhancement of species-specifi c behavioral responses
that occurs during repeated drug administration and persists even after long
periods of withdrawal. Although most studies have measured sensitization
of locomotor activity, sensitization also occurs to the reinforcing effects of
psychomotor stimulants. Behavioral sensitization is infl uenced by the same
factors that infl uence addiction (stress, conditioning, and drug priming), and is
accompanied by profound cellular and molecular adaptations in the neuronal
circuits that are fundamentally involved in normal motivated behavior as well
as addiction. Like addiction, it is extremely persistent. Robinson and Berridge
(6 , 7) have argued for an incentive-sensitization view of addiction, which holds
that repeated drug administration sensitizes the neuronal systems involved in
drug “wanting” rather than drug “liking.”
It is now acknowledged that the development of sensitization requires
glutamate transmission in the midbrain, where dopamine (DA) cell bodies
are located, whereas its maintenance and expression are associated with
profound changes in glutamate transmission in limbic and cortical brain regions
that receive dopaminergic innervation. To understand the role of glutamate
transmission in sensitization, many studies have examined drug effects on
glutamate transmission in these brain regions. This review focuses on cocaine
and amphetamine effects on glutamate receptor expression in the midbrain
(ventral tegmental area [VTA] and substantia nigra), the striatal complex
(nucleus accumbens [NAc] and dorsal striatum), and the prefrontal cortex
(PFC). Recent studies are emphasized, with the goal of updating a comprehen-
sive review published 4 yr ago (8) .

2. Effects of Psychomotor Stimulants on Glutamate Receptor
Expression in the VTA and Substantia Nigra
2.1. Role of the VTA in Behavioral Sensitization
Many lines of evidence have suggested that the development of behavioral
sensitization is associated with an increase in excitatory drive to VTA DA
neurons (8) . This provided the impetus for examining whether glutamate
transmission is enhanced in the VTA during the early phase of drug withdrawal.
The fi rst evidence to support this hypothesis came from in vivo single-unit
recording studies demonstrating that VTA DA neurons recorded from cocaine-
or amphetamine-sensitized animals were more responsive to the excitatory
effects of iontophoretic glutamate (9) . A subsequent study showed that increased
responsiveness was selective for

-amino-3-hydroxy-5-methylisoxazole-
4-propionic acid (AMPA) (there was no change in sensitivity to N -methyl-
D -aspartate [NMDA] or a metabotropic glutamate receptor agonist) and
transient, present 3 but not 10-14 d after discontinuing repeated drug adminis-