Page 57 - Pagetit

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Genes can be turned on or off at different times during the entire life of an
organism. Some genes are turned on or “expressed” only during development.
Others are expressed in response to certain stimuli. Eating certain foods, for
example, can increase the expression of genes that code for the enzymes that
will break down constituents of that food. Being out in the sun can stimulate
the expression of other genes that cause the skin to become more pigmented.
Similarly, drugs of all kinds can cause changes in gene expression in the brain.
Changes in gene expression cause changes in protein synthesis that can have
both short-term and long-term consequences on behaviour. This concept
will be covered in more detail below.
There are both genetic commonalities and differences among all humans.
The basic mechanisms of drug action are common to all. However, there is
considerable individual variation in the response to these drugs, the particular
forms of certain genes, and the way in which these genes interact with the
full complement of genes and with the environment in which that individual
lives. The main genetic differences currently known to be relevant to
dependence will be discussed in Chapter 5.

Cellular and neuronal effects of psychoactive substances
Cellular effects
Psychoactive substances have immediate effects on neurotransmitter release
or second messenger systems, but there are also many changes that occur at
the cellular level, both in the short-term and long-term, following single or
repeated substance use.
The primary sites of action for most psychoactive substances are the cell
membrane receptors, and their associated cascade of signal transduction
processes. The long-term effects brought about during the process of
substance dependence are usually mediated by alterations in gene
transcription, which leads to altered gene expression and subsequent changes
in the proteins synthesised. Since these proteins affect the function of the
neurons, such changes are ultimately manifested in altered behaviour of the
individual. Among the best-established molecular changes following chronic
substance use is the compensatory upregulation or superactivation of the
cyclic AMP (cAMP) pathway. Cyclic AMP is an intracellular second messenger
that can initiate a wide variety of changes in the postsynaptic cell.
The ability of chronic exposure to opioids to upregulate the cAMP
pathway has been known for decades (Sharma, Klee & Nirenberg, 1975). In
addition to opioids, upregulation of the cyclic AMP pathway has been
observed in response to chronic use of alcohol and cocaine (Unterwald et
al., 1993; Lane-Ladd et al., 1997). When a system that has been upregulated
by chronic substance use is acutely exposed to the substance, the acute
effects are diminished, representing cellular tolerance. In the absence of
the substance, the upregulated system contributes to symptoms of

36

Chapter_2 36 19.1.2004, 11:28