Fig 1: Corticostriatal and corticolimbic circuits underlying addiction.

Anatomical locations of (a) and connections between (b) the primary nodes within the corticostriatal and corticolimbic circuits that support reward, emotion, and their regulation and are proposed to influence the binge-intoxication, withdrawal-negative affect, and preoccupation-anticipation stages of addiction. The corticostriatal circuit is critical for reward processing and largely contributes to the binge-intoxication stage of addiction. The striatum (comprised of the putamen, caudate and ventral striatum) is the primary node of this network. Through its connections with other nodes, the striatum supports learning reward contingencies, hedonic responsiveness, generating motivation to pursue rewards and goals, forming and implementing plans to obtain reward, adjusting behavior and plans according to changing contingencies, and coordinating motor movements in the service of obtaining reward¹¹. More specifically, dopaminergic projections from the ventral tegmental area to the nucleus accumbens within the ventral striatum support reward prediction and learning in combination with multimodal sensory information received from the basolateral amygdala and contextual information from the hippocampal formation. Projections from the striatum to the pallidum support hedonic responsiveness through endogenous opioid stimulation and provide motivational signals to the VMPFC (supporting integration of contextual and interoceptive information, bottom-up drive and top-down regulation) and the DLPFC (supporting goal-directed planning) through thalamic relays. Afferents from the PFC to the ventral striatum further serve to facilitate the implementation of plans to obtain reward (DLPFC) as well as flexible behavioral adjustment when expected actions do not obtain predicted outcomes (ACC) and can facilitate or inhibit the motivational significance of reward predictive cues in the environment. The corticolimbic circuit is critical for affective processing and behavioral vigilance; it largely contributes to the withdrawal-negative affect stage of addiction. The amygdala (inclusive of the amygdala and the extended amygdala) is the primary node of this network; through its connections with other nodes it supports responses to environmental challenges, including threat and stress, by generating and regulating emotional responses¹². Low and high resolution sensory information arrives in the basolateral complex of the amygdala from the thalamus and sensory cortices, respectively. Efferent projections from the centromedial and extended amygdala, including the bed nucleus of the stria terminalis (BNST), to autonomic nuclei (such as the parabrachial nucleus), the hypothalamus and the hippocampus drive emotional responses, including fear conditioning and the generation of stress-related physiological changes. Direct and indirect connections between the amygdala and insula facilitate interoception (awareness and importance of our physiological states). Projections from the nucleus basalis of Meynert in the extended amygdala facilitate amygdala-driven arousal and sensitivity of the cortex. Projections from the amygdala to the VMPFC promote subjective awareness and evaluation of emotion and the integration of affective information (such as motivational information conveyed by the ventral striatum projections shown in the upper panel). Projections from the DLPFC and VLPFC to the amygdala through the DMPFC and VMPFC promote the regulation of affective responses and physiological arousal. Both the corticostriatal and corticolimbic circuits support executive function and the regulation of behavior to influence the preoccupation-anticipation stage of addiction by contributing to incentive salience (such as the ventral striatum projections to the VMPFC and OFC within the corticostriatal circuit), interoceptive signals associated with withdrawal physiology and affect (such as the insula within the corticolimbic circuit), as well as the regulation of behavior (through the DLPFC, VLPFC and ACC in both circuits). While there are many additional connections within and between these circuits, we present a heuristic model focusing on those most well linked to addiction. These circuits are explained in greater detail in prior publications^11,12. Note: Unlike prior depictions of the stage-based neurobiological model which show 3 circuits corresponding to each stage, we present the corticostriatal and corticolimbic circuits, which are hypothesized to predominantly drive the binge-intoxication and withdrawal-negative affect stages, respectively. The preoccupation-anticipation stage is undergirded by prefrontal connections within and across these circuits in this model.