Neurobiology of negative reinforcement as a driving force in alcohol addiction.

Alcohol addiction is a chronically relapsing disorder, characterized by compulsive alcohol seeking and taking, the loss of control in limiting intake, and the emergence of hyperkatifeia (a sensitized negative emotional state) during withdrawal. The hypothesis of this review is that alcohol addiction represents a break with homeostatic brain regulatory mechanisms that regulate the emotional state of the individual via three stages of the addiction cycle and three respective domains of dysfunction. As addiction develops, the withdrawal/negative affect stage, which mediates the development of a panoply of negative emotional symptoms (termed hyperkatifeia), takes on a more prominent role. Hyperkatifeia then drives compulsive-like drug seeking via negative reinforcement and is mediated by a decrease in the function of brain reward systems that involve key neurotransmitter systems, such as dopamine and opioid peptides, and the recruitment/sensitization of brain stress systems, including corticotropin-releasing factor, dynorphin, hypocretin, ghrelin, norepinephrine, and neuroimmune modulation. These changes are hypothesized to be triggered and maintained by neuroadaptations of the hypothalamic-pituitary-adrenal axis and the sensitization of glucocorticoid receptor signaling. Anti-stress systems, such as neuropeptide Y, nociceptin, endocannabinoids, and oxytocin, may be compromised and contribute to the development and maintenance of hyperkatifeia. Neuroanatomical substrates for hyperkatifeia have a focus on the extended amygdala and elements of the basal ganglia. Neurocircuitry analyses are now identifying cellular and molecular targets for genetic and epigenetic vulnerability within an allostasis framework that shows therapeutic promise for this often-neglected domain of the etiology and perpetuation of alcohol addiction.