Neurobiology of addiction: a neurocircuitry analysis

Abstract

Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.

Figure 1:. Model of interacting circuits in which disruptions contribute to compulsive-like behaviours underlying drug addiction

The overall neurocircuitry domains correspond to three functional domains: binge/intoxication (reward and incentive salience: basal ganglia [blue]), withdrawal/negative affect (negative emotional states and stress: extended amygdala and habenula [red]), and preoccupation/anticipation (craving, impulsivity, and executive function: PFC, insula, and allocortex [green]). Arrows depict major circuit connections between domains, and numbers refer to neurochemical and neurocircuit-specific pathways known to support brain changes that contribute to the allostatic state of addiction. PFC=prefrontal cortex. ACC=anterior cingulate cortex. OFC=orbitofrontal cortex. NAc-VTA=nucleus accumbens-ventral tegmental area. Modified from Koob and Volkow (2010) with permission from Nature Publishing Group.

Figure 2:. Correspondence between rat and human brain regions relevant to the addiction process

Rats are commonly studied to unveil the neurobiological mechanisms of addiction because they have a well characterised central nervous system whose neurochemical and molecular pathways in subcortical areas correspond reasonably well to those in humans. ACC=anterior cingulate cortex. PL=prelimbic cortex. IL=infralimbic cortex. OFC=orbitofrontal cortex. INS=insula. dlPFC=dorsolateral prefrontal cortex. vlPFC=ventrolateral prefrontal cortex. vmPFC=ventromedial prefrontal cortex. DS=dorsal striatum. GP=globus pallidus. NAc=nucleus accumbens. BNST=bed nucleus of the stria terminalis. CeA=central nucleus of the amygdala. HPC=hippocampus. Modified with permission from George and colleagues (2012), Koob and colleagues (2014), and the National Academy of Sciences.