Addiction is, first and foremost, a disease of the brain's reward system. This system uses the neurotransmitter dopamine (DA) as its major currency to relay information. Brain DA plays a key role in the processing of information about saliency [1
], which is at the heart of its ability to regulate or influence reward [3
], reward expectation [5
], motivation, emotions, and the feelings of pleasure. Transient release of DA in the brain's ventral striatum is a necessary, albeit not sufficient, event in the complex processes that engender the sensation of reward: the increase in DA appears to be positively related to the intensity of “high” that subjects experience. Conditioned responses are only elicited when DA is repeatedly released as these sharp, transient, surges, in response to drugs or drug-associated cues.
Interestingly, directly or indirectly, all addictive drugs work by triggering exaggerated but transient increases in extracellular DA in a key region of the reward (limbic) system [6
], specifically, in the nucleus accumbens (Nac) located in the ventral striatum. Such DA surges resemble, and in some instances greatly surpass, the physiological increases triggered by naturally pleasurable stimuli (usually referred to as natural reinforcers or rewards). As we would have expected, human brain imaging studies using positron emission tomography (PET), have clearly shown that the DA increases induced by different classes of drugs (e.g
. stimulants (), [8
], nicotine [10
], and alcohol [11
]) within the ventral striatum, are linked to the subjective experience of euphoria (or high) during intoxication [12
]. Since PET studies can be done in awake human subjects it is also possible to plot the relationship between the subjective reports of drug effects and the relative changes in DA levels. Most studies have reported that those displaying the greatest DA increases following drug exposures [amphetamine, nicotine, alcohol, methylphenidate (MPH)] also report the most intense high or euphoria ().
Figure 1 Stimulant-dependent DA increases in the striatum are associated with the feeling of “high.” A: Distribution volume (DV) images of [11C]raclopride for one of the subjects at baseline and after administration of 0.025 and 0.1 mg/kg i.v. (more ...)
Animal and human studies have demonstrated that the speed with which a drug enters, acts upon, and leaves the brain (i.e.
its pharmacokinetic profile) plays a fundamental role in determining its reinforcing effects. Indeed, every drug of abuse whose brain pharmacokinetics have been measured with PET (cocaine, MPH, methamphetamine, and nicotine) exhibits the same profile when the administration is intravenous, i.e.
, peak levels in the human brain are reached within 10 min ()and this fast uptake is associated with the “high” (). Based on this association, it follows that making sure that an addictive drug enters the brain as slowly as possible should be an effective way of minimizing its reinforcing potential, hence its abuse liability. We designed an experiment to test precisely this hypothesis with the stimulant drug MPH, which, like cocaine, increases DA by slowing down its transport back into the presynaptic neuron (i.e.
by blocking DA transporters), thus magnifying the DA signal. Indeed, we found that, while intravenous administration of MPH is often euphorigenic, orally administered MPH, which also increases DA in the striatum [15
], but with 6- to 12-fold slower pharmacokinetics, is not typically perceived as reinforcing [16
]. Thus, the failure of oral MPH – or amphetamine [18
] for that matter – to induce a high is likely the reflection of their slow uptake into the brain [19
]. Therefore, it is reasonable to propose the existence of a close correlation between the rate at which a drug of abuse enters the brain, which determines the speed at which DA increases in the ventral striatum, and its reinforcing effects [20
]. In other words, for a drug to exert reinforcing effects it has to raise DA abruptly. Why should this be so?
Figure 2 A: Axial brain images of the distribution of [11C]methamphetamine at different times (minutes) after its administration. B: Time activity curve for the concentration of [11C]methamphetamine in striatum alongside the temporal course for the “high” (more ...)
Based on the magnitude and duration of neuronal firing, DA signaling can take one of two basic forms: phasic or tonic. Phasic signaling is characterized by high amplitude and short burst firing, whereas tonic signaling has typically low amplitude and a more protracted or sustained time course. The distinction is important because it turns out that phasic DA signaling is necessary for drugs of abuse to induce “conditioned responses,” which is one of the initial neuroadaptations that follow exposure to reinforcing stimuli (including a drug). One of the distinguishing aspects that links phasic signaling with conditioning is the involvement of D2R and glutamate n
-aspartic acid (NMDA) receptors [23
]. On the other hand, tonic DA signaling plays a role in the modulation of working memory and other executive processes. Some of the features that distinguish this mode of signaling from the phasic type are that it operates mostly through lower affinity DA receptors (DA D1 receptors). However, and in spite of the different mechanisms involved, protracted drug exposure (and changes in tonic DA signaling through these receptors) has also been implicated in the neuroplastic changes that ultimately result in conditioning [25
] through the modification of NMDA and and alpha-amino-3-hydroxyl-5-methyl-4-isoxazone-propionate (AMPA) glutamate receptors [24
The evidence indicates that abrupt drug-induced increases in DA mimic phasic DA cell firing. This helps explain why the chronic use of an addictive substance can engender such powerful conditioned responses to the drug itself, its expectation, and myriad cues (people, things and places) associated with its use. However, while the acute reinforcing effects of drugs of abuse that depend on such fast DA increases are likely “necessary” for the development of addiction, they are clearly not “sufficient.” Repeated drug exposure causes changes in DA brain function that take time to develop because they result from secondary neuroadaptations in other neurotransmitter systems (e.g.
] and perhaps also γ-aminobutyiric acid (GABA)) that, eventually, affect additional brain circuits modulated by DA. These circuits are the focus of the next sections.