Conceptual Approach for Understanding Current and Future Medications Development
Stages of the Addiction Cycle – Animal Models
The three stages of addiction conceptualized in What is Addiction? – binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation – also have value for understanding the medications currently used in the treatment of addiction and in developing future medications (Figures 9.2–9.4). The different animal models that are used to study the neurobiology of addiction can be superimposed on these three stages, which are conceptualized as feeding into each other, becoming more intense, and ultimately leading to the pathological state known as addiction. Animal models for medications development for the binge/intoxication stage of the addiction cycle incorporate the construct of drug reinforcement and include drug and alcohol self-administration (Table 9.1). For the withdrawal/negative affect stage, animal models exist for the somatic signs of withdrawal for virtually all drugs of abuse. However, more relevant for addiction are the animal models of components of the motivational signs of withdrawal and the negative reinforcing effects of dependence that are beginning to be used to explore how the nervous system adapts to drug use. These adaptations include anxiety-like responses, conditioned place aversion, elevated reward thresholds, and withdrawal-induced increases in drug self-administration. For the preoccupation/anticipation stage, the models include drug-, cue-, and stress-induced reinstatement of drug seeking behavior. Animal models of craving can also include the conditioned rewarding effects of drugs of abuse, measures of the conditioned aversive effects of withdrawal, and signs and symptoms of protracted abstinence.
INVESTIGATIONAL NEW DRUG APPLICATION
Several aspects of an Investigational New Drug (IND) application are unique for drugs being developed for the treatment of addiction. One unique aspect is that the pharmaceutical industry is likely to have other indications for a drug that may be of significant value to addiction. Such a situation has both advantages and disadvantages. The disadvantage is obvious – addiction trials could be seen as counterproductive to the main commercial goal and thus be delayed or eliminated from development. Nevertheless, a reliable mechanism for generating INDs is to have an investigator initiate an IND application on a drug that already has another indication. Approval for studies on addiction is relatively straightforward if the drug is approved for other indications as long as the dose range required for addiction treatment is the same as that for the approved medication. This process will also work for drugs approved outside of the United States. A key element and critical point for medication development is submitting an IND application to the US FDA (Food and Drug Administration) (or its equivalent in other countries) so that the drug can be tested in humans. The International Commission on Harmonization (ICH) developed strict regulations and requirements that have been mandated by the FDA for the testing of a substance (drug) for a previously unapproved therapeutic indication by an investigator. ICH guidelines have also been incorporated by regulatory agencies in most other countries, resulting in a high degree of consistency in the requirements for chemistry, manufacturing, control, safety, and toxicology prior to testing the drug in humans. In the US, the application for the initial clinical testing of a compound by an individual is governed by the sponsor-investigator submission of an IND application. The data that must be supplied, in addition to the proposed clinical trial protocol and information on the investigators, include detailed information about the chemistry (i.e., synthesis, formulation, stability), toxicology, pharmacology, and prior human studies.
Figure 9.2 Neural circuitry associated with the binge/intoxication 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 binge/intoxication stage, reinforcing effects of drugs may engage associative mechanisms and reward neurotransmitters in the nucleus accumbens shell and core and then engage stimulus-response habits that depend on the dorsal striatum. 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.]