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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

2000). All of these phenomena are mediated by increased mesolimbic
dopamine. Thus, activity in these circuits can mediate not only the primary
rewarding effects of the drugs, but also the conditioning of secondary stimuli,
and the subsequent ability of these stimuli to trigger cravings and relapse.
Functional brain imaging techniques (see Chapter 2) are beginning to
revolutionize the study of previously obscure concepts such as craving, which
can now be “visualized” in discrete brain regions. For example, activation of
the mesolimbic dopamine system and other brain regions by cocaine (Breiter
et al., 1997), heroin (Sell et al., 1999), alcohol (Wang et al., 2000), nicotine
(Volkow et al., 1999), or any other psychoactive substance, can be observed
using functional imaging techniques. Moreover, brain responses to predictors
of the drugs, or cues associated with drug use can also be measured. This is
very important in terms of studying craving and relapse. When visual or verbal
cues associated with heroin and cocaine are presented to people who use
these substances, they result in metabolic activation in brain regions
associated with expectancy of reward and learning (Childress et al., 1999;
Sell et al., 1999; Wang et al., 1999; Sell et al., 2000). These studies also found
that self-reports of “craving” and “urge to use” strongly correlated with
metabolic changes in specific brain regions. This indicates that previously
unmeasurable concepts such as craving are now beginning to be quantifiable,
measurable phenomena associated with specific brain regions. In addition,
the conditioning of secondary stimuli with drug effects can also be measured.

Dopamine and incentive sensitization
Dopamine was originally thought to mediate the rewarding or hedonic
properties of drug and non-drug reinforcers (Wise, 1982). However, evidence
obtained subsequently suggested that dopamine was affecting the motivation
to respond for reward, rather than the experience of reward itself (Phillips
&Fibiger, 1979; Gray & Wise, 1980). On this basis it was hypothesized that
dopamine mediates the incentive-motivational properties of both primary
reinforcers (rewards) and secondary reinforcers (Gray & Wise, 1980).
The above hypothesis has been further modified to distinguish between
the rewarding properties of drugs, and the response-eliciting properties of
drugs. Mesolimbic dopamine has been assigned a role in response-eliciting
but not in rewarding (Robinson and Berridge 1993; Berridge 1996; Berridge
& Robinson 1998; Robinson & Berridge, 2000). In other words, the reasons
that people enjoy the primary effects of psychoactive substances may have
to do with their effects on several different neurotransmitter systems, but
the desire to repeat using the drugs comes from the activation of the brain
mesolimbic dopamine system that guides motivated behaviour. Because
psychoactive substances activate the mesolimbic dopamine system, and
because the mesolimbic dopamine system has a primary role in guiding
motivated behaviour, the repeated exposure of the brain to psychoactive
substances leads to strong associations being formed. The mechanism by

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