The Temporal Sequence of Changes in Gene Expression by Drugs of Abuse - Drugs of Abuse: Neurological Reviews and Protocols - page 5

expression and protein function associated with D1 receptor signaling fall into
this category, including an induction in protein kinase A, mitogen-activated
protein (MAP) kinase, and phospho-cAMP response element binding protein
(phospho-CREB) (24) . Accordingly, genes regulated by phospho-CREB,
such as preprodynorphin, are also altered by repeated cocaine administration
and endure for weeks after the last injection (27 , 28) . Likewise, while gene
expression may not be altered, proteins regulated by protein kinase A (PKA),
CdK5, or MAP kinase phosphorylation demonstrate altered function for an
extended withdrawal period after the last drug injection, including sodium
channels and the cystine/glutamate antiporter in the striatum (29) . In addition,
proteins related to glutamate transmission show the slow change/slow return
pattern of expression, including mGluR5, which has been recently linked
to cocaine reward (30 , 31) . Also, proteins involved in other neurotransmitter
systems in the striatal complex, including histidine decarboxylase and the
adenosine transporter, show this temporal pattern (30 , 32 , 33) . These changes
play a signifi cant role in some of the enduring changes in excitability in spiny
cells in the nucleus accumbens and striatum. Notably, spiny cells show more
avid inhibition in response to D1 receptor stimulation and have a decreased
postsynaptic response to -amino-3-hydroxy-5-methyl-4-isoxazole propionic

acid (AMPA) receptor stimulation or long-term potentiation in response
to tetanic stimulation of glutamatergic afferents to the nucleus accumbens
(19 , 34) .

6. Changes Only During Withdrawal, Enduring for Weeks,
Predominately in the Prefrontal Cortex and Nucleus Accumbens
Members of this category of genes have undergone recent intensive study
and the changes in expression generally appear after only a week or more
of withdrawal from repeated drug administration. The changes are almost
exclusively in the prefrontal cortex and nucleus accumbens and include a
variety of gene products involved in neurotransmission, cell signaling, and
glial function. However, the changes are notable in that they endure for weeks
and involve a predominance of genes affecting glutamate transmission relative
to dopamine transmission. Genes in this category altered by cocaine encode
mGluR1, mGluR2/3, homer1bc , GluR5 , A1 adenosine receptor, TrkB , BDNF ,
AGS3 , Giα , GFAP, and vimentin. These changes in expression combine to
produce a generalized decrease in signaling through group I and group II
mGluR and in general serve to decrease excitability of cells in the nucleus
accumbens (30 , 35 , 36) . In addition, the changes in glial fi brillary acidic protein
(GFAP) and vimentin suggest an enduring activation of glia, which may
contribute to the reduction in extracellular glutamate in the nucleus accumbens
that is associated with repeated cocaine administration (37) .