Dependence as a learning process involving key brain regions
The development of dependence can be seen as part of a learning process, in the sense that enduring changes in behaviour result from interactions with psychoactive substances and their associated environments. A person takes a substance and experiences the psychoactive effect, which is highly rewarding or reinforcing, and which activates circuits in the brain that will make it more likely that this behaviour will be repeated.
However, the rewarding effects of substances alone cannot account for why some psychoactive substances can lead to all of the behaviours associated with dependence (Box 2). Similarly, physical dependence on substances, as evidenced by withdrawal symptoms when substance use is discontinued, may contribute to substance use and dependence, but cannot alone explain why substance dependence develops and is maintained, especially after long periods of abstinence. What is it about psychoactive substances that causes people to lose their jobs and families in pursuit of these substances? What is the process by which substance- taking behaviour, in certain individuals, evolves into compulsive patterns of substance-seeking and substance-taking behaviour that take place at the expense of most other activities; and what causes the inability to cease substance-taking, that is, the problem of relapse? A complex interplay of psychological, neurobiological and social factors appears to be responsible.
Biobehavioural processes underlying dependence
The brain has systems that have evolved to guide and direct behaviour toward stimuli that are critical to survival. For example, stimuli associated with food, water, and a mate all activate specific pathways, and reinforce the behaviours that lead to the obtaining of corresponding goals. Psychoactive substances artificially activate these same pathways, but very strongly, leading to enhanced motivation to continue this behaviour. Thus, according to this theory, dependence is the result of a complex interaction of the physiological effects of substances on brain areas associated with motivation and emotion, combined with ‘‘learning’’ about the relationship between substances and substance-related cues.
Mesolimbic dopamine pathway
Although each class of psychoactive substance has its own unique primary pharmacological mechanism of action
(Table 4), many also activate the mesolimbic dopamine pathway
(See Fig. 5), although through different mechanisms depending on the substance. The mesolimbic dopamine pathway resides in an area of the brain known as the midbrain, and is the system that is most strongly implicated in the dependence-producing potential of psychoactive substances (17). Two areas that are very important in substance dependence are the ventral tegmental area (VTA), and a region that it communicates with, known as the nucleus accumbens. The ventral tegmental area is an area that is rich in neurons containing the neurotransmitter dopamine. The cell bodies of these neurons send projections to regions of the brain involved in emotions, thoughts, memories, and planning and executing behaviours. The nucleus accumbens is a very important brain area involved in motivation and learning, and signalling the motivational value of stimuli (18, 19). Psychoactive substances increase the release of dopamine in the nucleus accumbens, which is thought to be an important event in reinforcement.
Motivation and incentive
Motivation and incentive are important concepts with regard to substance dependence. The mesolimbic dopamine pathway of the brain has been shown to be closely involved in motivational processes: that is to say, stimuli that are recognized as being important to survival are given special importance in the brain. Motivation is the allotment of attentional and behavioural resources to stimuli in relation to their predicted consequences. Incentives are stimuli that elicit a response on the basis of their predicted consequences. For example, if a person is not hungry, the visual and olfactory stimuli associated with food (incentives) will have little effect on his or her behaviour or attention (motivation). However, if the person is hungry, the sight and smell of food may cause him or her to pay attention, and to take steps to obtain food. If the person is starving and has no means of obtaining food, he or she might even steal or commit a crime to obtain it. This is known as incentive- motivational responding, or responding in terms of both the incentive value of the stimulus and the motivation to obtain the stimulus.
In substance dependence, psychoactive substances repeatedly activate the motivational systems of the brain that are normally activated by such important stimuli as food, water, danger, and mates. The brain is ‘‘tricked’’ by the substances into responding as if the substances and their associated stimuli are biologically needed. With repeated exposure, the association becomes stronger and stronger, evoking a larger behavioural and neurochemical response. This is known as incentive sensitization, whereby psychoactive substances and the stimuli associated with their use take on increasing motivational and behavioural significance (20). Through associative learning processes, the motivation to use psychoactive substances can be strongly activated by stimuli (environments, people, objects) associated with substance use, causing the desire or craving that can overwhelm people and cause relapse to substance use, even after long periods of abstinence. This also contributes to our understanding of why withdrawal symptoms alone are not enough to explain the full spectrum of substance dependence, because even people who have completely withdrawn from a particular substance can relapse to substance use in response to a variety of different situations.