Neurobiologic processes in drug reward and addiction

Abstract

Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state. These"hard-wired"changes in the brain are considered critical for the transition from casual to addictive drug use. This review of preclinical and clinical (primarily neuroimaging) studies will describe how the delineation between pleasure, reward, and addiction has evolved as our understanding of the biologic mechanisms underlying these processes has progressed. Although the mesolimbic dopaminergic efflux associated with drug reward was previously considered the biologic equivalent of pleasure, dopaminergic activation occurs in the presence of unexpected and novel stimuli (either pleasurable or aversive) and appears to determine the motivational state of wanting or expectation. The persistent release of dopamine during chronic drug use progressively recruits limbic brain regions and the prefrontal cortex, embedding drug cues into the amygdala (through glutaminergic mechanisms) and involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex in the obsessive craving for drugs. The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug, contextual drug cues, craving, or stress, with each process defined by a relatively distinct brain region or neural pathway. The compulsive drive toward drug use is complemented by deficits in impulse control and decision making, which are also mediated by the orbitofrontal cortex and anterior cingulate. Within this framework, future targets for pharmacologic treatment are suggested.

Figures

FIGURE 1

Brain regions relevant to the addictions (see text box for description of regions). Right panel represents an MRI of the sagittal brain (from SPM96) at Talairach coordinates x = 4–16; left panel, at x = 34–46. Each Talaraich coordinate represents a one mm MRI sagittal slice, and 13 slices were averaged for each displayed image. Amyg, amygdala; ant cing, anterior cingulate; DLPFC, dorsolateral prefrontal cortex; LOFC, lateral orbitofrontal cortex; MOFC, medial orbitofrontal cortex (ventromedial cortex); NAc, nucleus accumbens; VTA, ventral tegmental area. The MRI template was obtained from SPM96-MRI.

FIGURE 2

The compulsive drive toward drug use describes relapse in response to a priming dose of drug, drug cues, craving, or stress. These triggers for a return to drug use are mediated by overlapping brain regions/circuits: mesolimbic (priming), mesolimbic and amygdala (drug cues), striato-thalamo-orbitofrontal (obsessive thoughts), and extrahypothalamic CRF and the HPA axis (stress). A deficit in inhibitory control and poor decision making, mediated in part by the OFC cortex and anterior cingulate, may result in relapse even in the absence of a compulsive drug trigger. Adapted from Koob & Moal and Jenstch & Taylor.

FIGURE 3

Decreased blood flow in the medial and lateral orbitofrontal cortex may contribute to the deficits in inhibitory control observed in addicted subjects. The figure demonstrates decreased rCBF (p < 0.01, in blue) in the orbitofrontal cortex of 37 two- to four-week abstinent cocaine-dependent men and women relative to 36 age-matched controls. Sagittal view (left panel) is at Talairach coordinate x = 28; coronal view (right panel), at y = 30 (right is to reader’s left). From Adinoff and colleagues, unpublished data.