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2. BRAIN MECHANISMS: NEUROBIOLOGY AND NEUROANATOMY

withdrawal (Nestler & Aghajanian, 1997). Effects of an upregulated cAMP
system have been demonstrated in many of the relevant brain regions, such
as the nucleus accumbens, striatum, VTA, locus coeruleus and peria-
queductal gray (Cole et al., 1995; Lane-Ladd et al., 1997; Nestler & Aghaja-
nian, 1997).

Role of cyclic AMP response element binding protein (CREB)
Cyclic AMP stimulates the expression of cAMP response element binding
protein (CREB), which is a transcription factor. Gene transcription and
expression in neurons are regulated by numerous transcription factors.
Transcription factors are proteins that bind to regions of genes to increase or
decrease their expression. It has been shown that the functions of several
transcription factors are altered by substance use and therefore are implicated
in dependence.
Alterations in the CREB-regulated pathways are among the best-
characterized adaptations related to chronic exposure to psychoactive
substances and there is evidence for upregulation and sensitization of the
cAMP/CREB-linked mechanisms (Nestler, 2001).

Role of transcriptional regulator Fos

Other transcription factors induced by exposure to psychoactive substances
belong to the Fos protein family of immediate early genes. The products of
these genes are induced very rapidly (hence the name) and play important
roles in transducing receptor-mediated signals into changes in gene
expression. These changes in gene expression affect neuronal protein
expression and function. Single administrations of a substance cause
transient increases in several members of the Fos protein family but with
chronic use, a modified variant of FosB, ∆FosB, which is more stable,
accumulates and persists in the nucleus accumbens (Hope et al., 1994).
DFosB, once generated, has an unusually prolonged half-life resulting in
persistently elevated levels (Keltz & Nestler, 2000). The accumulation of ∆FosB
has been shown to occur following chronic use of cocaine, opioids,
amphetamine, nicotine, phencyclidine and alcohol (Keltz & Nestler, 2000).
This occurs in the nucleus accumbens and dorsal striatum, and constitutes
a process specific for psychoactive drugs (Moratalla et al., 1996; Keltz
&Nestler, 2000). The elevated ∆FosB can then continue to affect the
expression of many other genes within the same neurons, which in turn by
alterations in synaptic transmission will be able to affect many neuronal
functions locally and in other areas of brain, to which these neurons project.
This provides some insight into the nature of the long-lasting changes in
neuronal composition that occur and persist well beyond the time frame of
the acute drug effects.

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