Hypothalamic response to cocaine cues and cocaine addiction severity

The dopaminergic motive system is compromised in cocaine addiction. Abundant research has examined the roles of the dopaminergic midbrain and ventral striatum (VS) in cue-induced craving and habitual drug consumption. Interconnected with the dopaminergic circuits, the hypothalamus is widely implicated in motivated behavior, including food and drug seeking. However, very few studies have investigated how the hypothalamus responds to drug cues and whether hypothalamic responses are related to clinical features such as craving and addiction severity. Here, in 23 cocaine-dependent individuals (CD) exposed to cocaine vs neutral cues during functional magnetic resonance imaging (fMRI), we examined regional responses using established routines. At a corrected threshold, CD demonstrated increased activation to cocaine vs neutral cues in bilateral visual cortex, inferior parietal and middle frontal gyri, and the hypothalamus. The extent of hypothalamus but not other regional response was correlated with craving and cocaine addiction severity, each as assessed by the Cocaine Craving Questionnaire (CCQ) and Cocaine Selective Severity Assessment (CSSA). In contrast, subjective "acute" craving as elicited by cocaine cues during fMRI involved deactivation of bilateral orbitofrontal cortex (OFC) and angular gyri (AG), and the OFC and AG responses were not related to CCQ or CSSA score. These findings distinguished tonic craving as a critical factor in capturing cocaine addiction severity and substantiated a role of the hypothalamus in motivational dysfunction in cocaine addiction.