Development of pharmacotherapies for drug addiction: a Rosetta stone approach

Abstract

Current pharmacotherapies for addiction represent opportunities for facilitating treatment and are forming a foundation for evaluating new medications. Furthermore, validated animal models of addiction and a surge in understanding of neurocircuitry and neuropharmacological mechanisms involved in the development and maintenance of addiction - such as the neuroadaptive changes that account for the transition to dependence and the vulnerability to relapse - have provided numerous potential therapeutic targets. Here, we emphasize a 'Rosetta Stone approach', whereby existing pharmacotherapies for addiction are used to validate and improve animal and human laboratory models to identify viable new treatment candidates. This approach will promote translational research and provide a heuristic framework for developing efficient and effective pharmacotherapies for addiction.

Figure 1. The ‘Rosetta Stone approach‘ to drug development

A crucial aspect of the proposed Rosetta Stone approach is the dynamic feedback from animal models and clinical data which can be used to identify treatments for drug addiction that are likely to succeed in clinical trials and to facilitate further development of animal and human models. These data may ultimately provide a rational basis for combination therapies such that multiple components of the addiction cycle can be treated by a given pharmacological strategy.

Figure 2. Neural circuitry, current drugs and potential targets associated with the three stages of the addiction cycle

In the binge–intoxication stage, reinforcing effects of drugs may engage associative mechanisms and neurotransmitters that signal reward in the shell (or medial portion) and core of the nucleus accumbens (Acb) and then engage stimulus response habits that depend on the dorsal striatum (DS). In the withdrawal–negative affect stage, the extended amygdala (AMG) may be activated. It consists of several basal forebrain structures, including the bed nucleus of the stria terminalis (BNST), the central nucleus of the amygdala (CeA), and a transition area in the shell of the nucleus accumbens. Neurons containing a key neurotransmitter in the extended amygdala, corticotropin-releasing factor (CRF), project to the brainstem, from which noradrenergic neurons provide a major reciprocal projection. In the preoccupation–anticipation (craving) stage, conditioned reinforcement is processed in the basolateral amygdala (BLA) and contextual information is processed in the hippocampus. Executive control depends on the prefrontal cortex and includes representation of contingencies, representation of outcomes, and their value and subjective states (that is, craving and feelings) associated with drugs. Functional imaging studies have shown that the subjective states, called drug craving in humans, involve activation of the orbital and anterior cingulate cortex and the temporal lobe, including the amygdala. For each stage of the addiction process, the existing medications and potential future medications for addiction treatment that are particularly relevant to that stage are shown. Dashed arrows represent output circuits. CRF₁, CRF receptor 1; DA, dopamine; DGP, dorsal globus pallidus; GP, globus pallidus; mPFC (AC), medial prefrontal cortex (anterior cingulate); NA, noradrenaline; OFC, orbitofrontal cortex; SNc, substantia nigra pars compacta; VGP, ventral globus pallidus; VS, ventral striatum; VTA, ventral tegmental area. Figure is modified, with permission, from REF. © (2008) Academic Press.