Brain Structures and Functions Relevant to the Three Stages of the Addiction Cycle

Preoccupation/Anticipation Stage - Prefrontal Cortex

The preoccupation/anticipation ("craving") stage involves key elements of the prefrontal cortex. The global function of the prefrontal cortex is to mediate executive function. Executive function can be conceptualized as the ability to organize thoughts and activities, prioritize tasks, manage time, and make decisions. To accomplish such complex tasks in the context of the neurobiology of addiction, the prefrontal cortex can be divided into two opposing systems: the Go system and the Stop system. The Go system engages habit systems, possibly even subconsciously and automatically. The Stop system inhibits such systems. The result of the interactions between these two systems produces the well-known impulsivity associated with the addiction process, both during the initiation of drug intake and relapse.

The Go system involves the anterior cingulate cortex and dorsolateral prefrontal cortex. The anterior cingulate cortex facilitates the maintenance and selection of responses, particularly under high attentional demands (like comprehending the information contained in this book), planning (for the midterm exam), self-initiation (getting yourself to class), and self-monitoring of goal-directed behaviors. The functions of the dorsolateral prefrontal cortex involve working memory, planning, and strategy.

The Stop system largely involves the ventrolateral prefrontal cortex and orbitofrontal cortex. The functions of the ventrolateral prefrontal cortex involve response inhibition, sustained attention, memory retrieval, rule generation, and shifting. The functions of the orbitofrontal cortex, including the ventromedial prefrontal cortex, include the assignment of value (valuation) and integration of reward and punishment (Figure 2.23). The anterior cingulate cortex and dorsolateral prefrontal cortex in humans correspond to the anterior cingulate cortex and prelimbic cortex in rats, and the ventromedial prefrontal cortex and orbitofrontal cortex in humans correspond to the infralimbic cortex and orbitofrontal cortex in rats (Figure 2.24).

The preoccupation/anticipation stage of the addiction cycle is a key element of relapse in humans, defining addiction as a chronic relapsing disorder. Although often linked to the construct of craving, the concept of craving per se has been difficult to measure in human clinical studies and often does not correlate with relapse. Nevertheless, the stage of the addiction cycle at which an individual reinstates drug seeking behavior after abstinence remains a challenging focus of neurobiological studies and medication development.

Animal models of craving can be divided into two domains: i) Drug seeking induced by the drug or stimuli paired with drug taking (reward craving), and

ii) Drug seeking induced by an acute stressor or state of stress (relief craving; TABLE 2.24).

Drug-induced reinstatement appears to be localized to a medial prefrontal cortex/ventral striatum circuit mediated by the neurotransmitter glutamate. Cue-induced reinstatement appears to involve the basolateral amygdala, with a possible feed-forward mechanism that goes through the same prefrontal cortex system involved in drug-induced reinstatement. Neurotransmitter systems involved in drug-induced reinstatement include a glutamate projection from the frontal cortex to nucleus accumbens that is modulated by dopamine in the frontal cortex. Cue-induced reinstatement also involves a glutamate projection from the basolateral amygdala and ventral subiculum to the nucleus accumbens. Stress-induced reinstatement depends on activation of both CRF and norepinephrine in the extended amygdala. Protracted abstinence, largely described in alcohol dependence models, involves both an overactive glutamatergic Go system and sensitized CRF systems. Brain CRF stress systems remain hyperactive during protracted abstinence, and this hyperactivity has motivational significance for excessive alcohol drinking.

Figure 2.23 Brain regions recruited during the preoccupation/anticipation stage of the addiction cycle. [Modified with permission from Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology Reviews, 2010, (35), 217-238 (erratum: 35: 1051).]

Executive control over incentive salience is essential to maintain goal-directed behavior and the flexibility of stimulus-response associations. The prefrontal cortex sends glutamatergic projections directly to mesocortical dopamine neurons in the ventral tegmental area, exerting excitatory control on dopamine in the prefrontal cortex. Thus, the ventral part of the prefrontal cortex (the Stop system) can inhibit incentive salience and suppress conditioned behavior when a salient cue is present. It follows that lesions of the prefrontal cortex can induce impulsivity. Withdrawal from alcohol is associated with increased glutamate release in the nucleus accumbens and other brain areas. However, cue-induced reinstatement of psychostimulant-seeking behavior dramatically increases dorsal prefrontal cortex activity (Go system) and glutamate release in the nucleus accumbens. The increased activity of the prefrontal–glutamatergic system during relapse may elicit a dramatic glutamatergic response that may in turn mediate craving-like responses during the preoccupation/anticipation stage.

Figure 2.24 Correspondence between rat and human brain regions that are relevant to the addiction process. Rats are commonly studied to unveil the neurobiological mechanisms of addiction because they have a well-characterized central nervous system whose neurochemical and molecular pathways in subcortical areas correspond reasonably well to those in humans. ACC, anterior cinculate cortex; PL, prelimbic cortex; IL, infralimbic cortex; OFC, orbitofrontal cortex; INS, insula; dlPFC, dorsolateral prefrontal cortex; vlPFC, ventrolateral prefrontal cortex; DS, dorsal striatum; Thal, thalamus; 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 O, Koob GF. Control of craving by the prefrontal cortex. Proceedings of the National Academy of Sciences USA, 2013, (110), 4165-4166.]

Behavioral procedures have been developed to reinstate drug self-administration using previously neutral stimuli that are paired with alcohol self-administration or that predict alcohol self-administration. Cue-induced reinstatement can by blocked by opioid receptor antagonists, dopamine D1 and D2 receptor antagonists, and glutamate receptor antagonists. Stress exposure can also reinstate responding for drugs in rats that are extinguished from drug-seeking behavior. Such stress-induced reinstatement can be blocked by CRF antagonists, dynorphin antagonists, and norepinephrine antagonists.

Human imaging studies reveal similar circuit dysregulation during the preoccupation/anticipation stage to that demonstrated in animal models. Decreased frontal cortex activity parallels deficits in executive function in neuropsychologically challenging tasks. Individuals with alcoholism exhibit impairments in the maintenance of spatial information, disruption of decision making, and impairments in behavioral inhibition. Such frontal cortex-derived executive function disorders have been linked to the ineffectiveness of some behavioral treatments in individuals with alcoholism. Thus, individual differences in the prefrontal cortical control of incentive salience may also explain individual differences in the vulnerability to addiction. Excessive attribution of incentive salience to drug-related cues and residual hypersensitivity of the brain stress systems may perpetuate excessive drug intake, compulsive behavior, and relapse.


Drug Craving

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