Theoretical Frameworks and Mechanistic Aspects of Alcohol Addiction: Alcohol Addiction as a Reward Deficit/Stress Surfeit Disorder.

Alcohol use disorder (AUD) can be defined by a compulsion to seek and take alcohol, the loss of control in limiting intake, and the emergence of a negative emotional state when access to alcohol is prevented. Alcohol use disorder impacts multiple motivational mechanisms and can be conceptualized as a disorder that includes a progression from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). Compulsive drug seeking that is associated with AUD can be derived from multiple neuroadaptations, but the thesis argued herein is that a key component involves the construct of negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from the dysregulation of specific neurochemical elements that are involved in reward and stress within basal forebrain structures that involve the ventral striatum and extended amygdala, respectively. Specific neurochemical elements in these structures include decreases in reward neurotransmission (e.g., decreases in dopamine and opioid peptide function in the ventral striatum) and the recruitment of brain stress systems (e.g., corticotropin-releasing factor [CRF]) in the extended amygdala, which contributes to hyperkatifeia and greater alcohol intake that is associated with dependence. Glucocorticoids and mineralocorticoids may play a role in sensitizing the extended amygdala CRF system. Other components of brain stress systems in the extended amygdala that may contribute to the negative motivational state of withdrawal include norepinephrine in the bed nucleus of the stria terminalis, dynorphin in the nucleus accumbens, hypocretin and vasopressin in the central nucleus of the amygdala, and neuroimmune modulation. Decreases in the activity of neuropeptide Y, nociception, endocannabinoids, and oxytocin in the extended amygdala may also contribute to hyperkatifeia that is associated with alcohol withdrawal. Such dysregulation of emotional processing may also significantly contribute to pain that is associated with alcohol withdrawal and negative urgency (i.e., impulsivity that is associated with hyperkatifeia during hyperkatifeia). Thus, an overactive brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of AUD. The combination of the loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement that at least partially drives the compulsivity of AUD.