Evidence for incentive salience sensitization as a pathway to alcohol use disorder

Abstract

The incentive salience sensitization (ISS) theory of addiction holds that addictive behavior stems from the ability of drugs to progressively sensitize the brain circuitry that mediates attribution of incentive salience (IS) to reward-predictive cues and its behavioral manifestations. In this article, we establish the plausibility of ISS as an etiological pathway to alcohol use disorder (AUD). We provide a comprehensive and critical review of evidence for: (1) the ability of alcohol to sensitize the brain circuitry of IS attribution and expression; and (2) attribution of IS to alcohol-predictive cues and its sensitization in humans and non-human animals. We point out gaps in the literature and how these might be addressed. We also highlight how individuals with different alcohol subjective response phenotypes may differ in susceptibility to ISS as a pathway to AUD. Finally, we discuss important implications of this neuropsychological mechanism in AUD for psychological and pharmacological interventions attempting to attenuate alcohol craving and cue reactivity.

Keywords: Alcohol sensitivity; Alcohol use disorder; Craving; Cue reactivity; Etiology; Incentive salience; Relapse; Sensitization; Treatment.

Figure 1.

The incentive salience (IS) attribution and expression system: a simplified schematic. “S” refers to an exteroceptive or interoceptive stimulus. “CS” and “UCS” refer to the Pavlovian conditional stimulus (cue) and unconditional stimulus (reward), respectively. Inspired by Figure 2 in Robinson & Berridge (1993).

Figure 2.

Paths mediating incentive salience (IS) sensitization (ISS). Components: memory systems, IS attributor, IS expressors, response effector systems. A-type paths: input from memory systems into the IS attributor. B-type paths: IS attributor output to the IS expressors. C-type paths: IS expressors output to response effector systems that are responsible for manifestations of IS in behavioral output across levels of biological organization. The vulnerability of the different paths and IS system components to the adaptations mediating alcohol cue ISS is theorized to increase progressively over the alcohol use history as a function of the frequency, intensity, and pattern of drinking. A 3-color gradient is used to represent an increasing extent or number of adaptations accrued within each component. Adaptations may occur in one component without occurring in another and the accrual rate may vary by component.

Figure 3.

Example of the kinds of persistent adaptations ethanol (EtOH) exposure might induce over time (t) to mediate alcohol cue ISS and how these might unfold over exposure relative to one another. Conjecture is informed by findings reviewed in the main text. Increased phasic DA release (from synchronized high-frequency action potentials at terminal boutons arising from the IS attributor) must occur at synapses involved in maintaining memory for the alcohol cue or its expression (viz., synapses in memory systems or in the IS expressors). Increased excitatory drive may occur at specific synapses across the IS system components including at the IS attributor. Decreased tonic DA release (from asynchronous low-frequency action potentials at terminal boutons arising from the IS attributor) will naturally affect many more synapses than those immediately involved in alcohol cue memory/expression. Increased excitatory tone, decreased inhibitory tone, and increased intrinsic excitability will naturally affect many cells across the IS system components including at the IS attributor.