In the previous section, we saw that animal models have been developed to investigate the different components of addiction at each stage of the disease; they are thus powerful tools in the addiction research field. But addiction has also been conceptualized, and several “theories of addiction” have been proposed to explain addiction at both the individual and societal levels 124.
4.1 Overview of the current theories of addiction 4.1.1 Aberrant learning theories of addiction
As we saw in the previous section, NAc-related circuitry is involved in reward learning 125. Cues associated with a reward activate VTA DA neurons even more than the reward itself 126, illustrating the role of the mesolimbic DA system in learning. Moreover, drugs of abuse also facilitate some forms of learning 127 and trigger similar types of neuronal adaptations that can be observed in learning 128. That is why some researchers have hypothesized that drugs of abuse are actually able to promote aberrant learning 128–130. In the frame of these theories, drugs of abuse intensify Pavlovian conditioning and responses to the drug-associated cues. Drugs exert these effects by altering neuronal responses to conditioned-cues either in ventral striatum, dorsal striatum, or both 131–133. One of the important characteristics that these theories have in common is the insensitivity to outcome devaluation. This may explain why addicts pursue drug consumption despite negative
consequences 134,135. This process of aberrant learning is thought to be dopamine-dependent, and a ventral-to-dorsal striatal shift in control over drug-taking and seeking occurs as the disease
progresses 134,135.
4.1.2 Frontostriatal-dysfunction (or impulsivity) theory of addiction
First advanced by Jentsch and Taylor in 1999 136, this theory proposes that long-term exposure to drugs of abuse affects regions of the frontal cortex that usually control inhibitory responding (mPFC and OFC). This impairment of frontal cortical cognitive function results in an inability to inhibit inappropriate behaviors, i.e. exaggerated responding to associated-drug cues or to internal states that may be driven by dysfunction of the NAc and the amygdala. This hypothesis drifts a bit from focusing on motivated behaviors to focusing more on impulsivity. Indeed, it has been shown that impulsivity traits associated with poor inhibitory control could predispose individuals to initial drug use and facilitate the transition from use to abuse and dependence137. Moreover, in both animal models and humans, the mPFC has been linked to impulsivity. Rats with lesions of the PFC drastically increase impulsivity traits 138, and a structural MRI study in humans reported that the volume of the mPFC was correlated with the impulsivity of the patients 139. In the frame of this hypothesis, no particular importance is given to drug-related reinforcement, putting drug and natural reward processing on the same level. This seems unlikely, considering the evidence that demonstrates drastic drug-induced neuroadaptations and behavioral changes that are not seen with natural rewards 140.
4.1.3 The opponent-process theory of addiction
This is one of the earliest theories of addiction, proposed by Solomon and Corbits in the early 1970s
141. This theory states that drug consumption induces two types of effects, positive (rewarding) and negative (unpleasant). Initial drug use is under the control of the positive effects, but with repeated drug exposure, a shift in the balance of positive and negative drug effects occurs. This shift is thought to represent a chronic change in the normal reward set-point 142. Indeed, drug consumers develop tolerance to drug-induced euphoria, while the negative drug effects become more and more intense.
If drug use continues, the negative effects become dominant and euphoria no longer follows drug intake, and unpleasant withdrawal symptoms arise as the drug effect fades. According to this theory, chronic drug use recruits stress-related systems rather than the initially involved reward system. This leads to a new emotional state that Koob and Le Moal 142 have named the “hedonic allostatic” state.
This state is characterized by compulsive drug intake and loss of control over drug-taking. This state
is thought to be controlled by the activation of brain circuits involved in compulsive behavior, such as the cortico-striatal-thalamic loop 142.
4.1.4 Incentive-sensitization theory of addiction
The incentive-sensitization theory of addiction states that drug-associated cues provoke excessive motivation for drug, unrelated to internal state 143–145. This theory can be summarized by the following points: 143, first, the general agreement that all drugs of abuse increase mesolimbic DA neurotransmission. Second, the occurrence of a psychological process termed “incentive salience”, which transforms the perception of stimuli, making them more salient and turning these stimuli into attractive, “wanted” stimuli. Third, the hypothesis that in some individuals, there are incremental neuroadaptations that sensitize their mesolimbic DA systems to both drugs and drug-associated cues. Fourth, sensitization of the mesolimbic DA system, responsible for incentive salience (i.e.
“wanting”), occurs independently of changes in neural systems responsible for the subjective pleasurable effects of drugs (“liking”). This last point is crucial because it can explain why sensitization of incentive salience produces addictive behaviors in the absence of pleasurable sensations, such as during withdrawal, or when facing negative consequences, like the loss of a job, social network, or family.
4.1.5 Psychomotor-stimulant theory of addiction
We have reviewed that a commonality of all addictive drugs is that they increase mesolimbic DA transmission. The present theory focuses on another commonality of addictive drugs, their ability to induce psychomotor activation 146. This theory is based on the “biological theory of reinforcement” of Glickman and Schiff 147. In this global theory of motivated behaviors, it is postulated that
reinforcement evolved as a biological mechanism to insure species-typical behavioral responses to appropriate stimuli. These responses are categorized by either approach to or withdrawal from stimuli. A component of the brain circuitry underlying this mechanism is dopaminergic fibers that project up the medial forebrain bundle from the midbrain to limbic and cortical regions. Wise and Bozart built on this theory and suggested that the mesolimbic DA system is the major substrate of the approach system, and thus of the psychomotor sensitization effect.
4.2 Focus on the dopamine hypothesis of addiction
It has been more than forty years now that addiction has mostly been considered to be a disorder of the dopamine neurotransmitter system 148. A PUBMED search with the key words “dopamine” and
“addiction” yields more than 5500 entries. The role of dopamine in addiction has been intensively investigated, but this theory is still controversial, at least for some drugs of abuse. In this section, we will briefly discuss the origins of the theory and the evidence that makes it the leading theory in the field of addiction.
The DA hypothesis of addiction is rooted in the work of Olds and Milner in the 1950s 74. They discovered that rats would willingly electrically self-stimulate specific regions of the brain while neglecting other behaviors, and that this region is very densely populated by DA neurons. Following up, other studies showed that pharmacologically blocking DA receptors impaired the reinforcing properties of psychostimulants in both rats 149–151 and primates 152,153. Two of the addiction theories we discussed above, the incentive-sensitization and the psychomotor-stimulant theories, the two in which dopamine is most prominent, came thirty and forty years later, respectively. Another
breakthrough arose at the end of the 1980s, when the Di Chiara group discovered that not only psychostimulants, but a whole range of other drugs of abuse increased DA release in the NAc 102. This major finding led to a general theory, the so-called dopamine theory of addiction. Originally thought as a “simple” hypothesis, it has now been shown that the situation is a more complex. Indeed, dopamine not only affects the encoding of the rewarding effects of drugs of abuse, but also affects the encoding of attention, psychomotor activation, reward prediction error, and incentive
motivation.