Conceptual Approach for Understanding Current and Future Medications Development

Overall Neurocircuitry of Addiction

A critical issue for the development of treatments for addiction is that relevant targets should be based on an empirical foundation of the neurobiology of addiction. Three neurobiological circuits have been identified that have value for the study of the neurobiological changes associated with the development and persistence of drug dependence (Figures 9.2–9.4). As outlined in detail in Introduction to the Neuropsychopharmacology of Drug Addiction, the acute reinforcing effects of drugs of abuse that comprise the binge/intoxication stage most likely involve actions on ventral striatal/extended amygdala reward systems and inputs from the midbrain, hippocampus, amygdala, and frontal cortex. In contrast, the symptoms of acute withdrawal, such as negative affect and increased anxiety, associated with the withdrawal/negative affect stage most likely involve decreases in the function of ventral striatal reward systems and recruitment of the extended amygdala brain stress neurocircuitry. The preoccupation/anticipation (craving) stage involves key afferent projections to the extended amygdala and nucleus accumbens, specifically from the prefrontal cortex, insula, basolateral amygdala, and hippocampus. Compulsive drug-seeking behavior engages ventral striatal–ventral–pallidal–thalamic–cortical loops that may then engage dorsal striatal–pallidal–thalamic cortical loops, both of which are exaggerated by concomitant decreased reward function, increased brain stress function, and decreased executive function.

Figure 9.3 Neural circuitry associated with the withdrawal/negative affect stage of the addiction cycle, the drugs that are currently in use for treatment focused on this stage, and the targets identified in this review relevant to this stage. In the withdrawal/negative affect stage, the negative emotional state of withdrawal may engage the activation of the extended amygdala. The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of the stria terminalis, central nucleus of the amygdala, and possibly the medial portion (or shell) of the nucleus accumbens. A major neurotransmitter in the extended amygdala is corticotropin-releasing factor, projecting to the brainstem where noradrenergic neurons provide a major projection reciprocally to the extended amygdala. Green/blue arrows, glutamatergic projections; Orange arrows, dopaminergic projections; Pink arrows, GABAergic projections; AMG, amygdala; BNST, bed nucleus of the stria terminalis; DS, dorsal striatum; GP, globus pallidus; Hippo, hippocampus; NAc, nucleus accumbens; OFC, orbitofrontal cortex; PFC, prefrontal cortex; Thal, thalamus. [Modified with permission from Koob GF, Everitt BJ, Robbins TW. Reward, motivation, and addiction. In: Squire LG, Berg D, Bloom FE, Du Lac S, Ghosh A, Spitzer N (eds) Fundamental Neuroscience, 3rd edition. Academic Press, Amsterdam, 2008, pp. 987–1016.]

Figure 9.4 Neural circuitry associated with the preoccupation/anticipation stage of the addiction cycle, the drugs that are currently in use for treatment focused on this stage, and the targets identified in this review relevant to this stage. This stage involves the processing of conditioned reinforcement in the basolateral amygdala and the processing of contextual information by the hippocampus. Executive control depends on the prefrontal cortex and includes the representation of contingencies, the representation of outcomes, and their value and subjective states (i.e., craving and, presumably, feelings) associated with drugs. The subjective effect called drug craving in humans involves activation of the orbital and anterior cingulate cortex and temporal lobe, including the amygdala, in functional imaging studies. Green/blue arrows, glutamatergic projections; Orange arrows, dopaminergic projections; Pink arrows, GABAergic projections. AMG, amygdala; BNST, bed nucleus of the stria terminalis; DS, dorsal striatum; GP, globus pallidus; Hippo, hippocampus; NAc, nucleus accumbens; OFC, orbitofrontal cortex; PFC, prefrontal cortex; Thal, thalamus. [Modified with permission from Koob GF, Everitt BJ, Robbins TW. Reward, motivation, and addiction. In: Squire LG, Berg D, Bloom FE, Du Lac S, Ghosh A, Spitzer N (eds) Fundamental Neuroscience, 3rd edition. Academic Press, Amsterdam, 2008, pp. 987–1016.]

As discussed in Introduction to the Neuropsychopharmacology, activation of the circuitry related to the origin and terminal regions of the mesocorticolimbic dopamine system, including dopamine and opioid peptides, are a key component of the neurobiology of the positive reinforcing effects of drugs associated with the binge/intoxication stage of the addiction cycle. The neural substrates and neuropharmacological mechanisms of the negative motivational effects of drug withdrawal associated with the withdrawal/negative affect stage of the addiction cycle involve disruptions of the same neural systems implicated in the positive reinforcing effects of drugs and recruitment of the brain stress systems. Common responses during acute withdrawal from all major drugs of abuse include decreased dopaminergic activity, an activated hypothalamic-pituitary-adrenal axis stress response, and an activated brain stress response with activated amygdala corticotropin-releasing factor (CRF). However, repeated cycles of addiction lead to a blunted hypothalamic-pituitary-adrenal response and a sensitized extrahypothalamic CRF stress system response in the amygdala. The preoccupation/anticipation (craving) stage involves key glutamatergic projections to the extended amygdala and nucleus accumbens, specifically from the prefrontal cortex (for drug-induced reinstatement), basolateral amygdala (for cue-induced reinstatement), and hippocampus ( for further reading, see Koob and Volkow, 2010).

TABLE 9.1

Animal and Human Laboratory Models of the Different Stages of the Addiction Cycle.

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