Novel Targets for Medication Development

The premise is that different components of the addiction cycle can be targeted by different medications based on evaluating three pieces of key information: i) Basic neurobiological mechanisms for the different stages of the addiction cycle, ii) Information about the actions of known effective medications in the treatment of addiction on animal models of the different stages of the addiction cycle, and iii) Information derived from clinical studies of known medications for other indications that may overlap with specific components of addiction (Figures 9.29.4, Table 9.5). The following section explores four neurotransmitter systems – dopamine, GABA, CRF, and glutamate – as potential targets for the treatment of addiction. Each of these systems has targets that can restore homeostatically dysregulated reward, stress, or executive function systems via the binge/intoxication stage (Figure 9.2), withdrawal/negative affect stage (Figure 9.3), and preoccupation/anticipation stage (Figure 9.4). From a broad perspective, none of these targets are completely new or novel (GABA, glutamate, or CRF), but they all have the potential for providing novel medications from the validation framework elaborated here. Finally, in this section, the innovative drug vaccine approach will be elaborated, which largely involves pharmacokinetically limiting the reinstatement of drug taking.

Seven medications are currently on the market in the United States for the treatment of addiction, including (in chronological order of US approval) disulfiram (Antabuse), methadone (Dolophine), nicotine substitution (gum, lozenge, patch), naltrexone (ReVia, Vivitrol), bupropion (Zyban), buprenorphine (Subutex, Suboxone), acamprosate (Campral), and varenicline (Chantix; Figures 9.29.4, Tables 9.29.4). One validation procedure has been termed the “Rosetta Stone” approach (or “reverse validity” approach). Drugs that are known to be effective in human clinical studies can be used to validate animal models, and human laboratory models can provide a means of refining such models.

The following section explores four neurotransmitter systems – dopamine, GABA, CRF, and glutamate – as potential targets for the treatment of addiction. Each of these systems has targets that can restore homeostatically dysregulated reward, stress, or executive function systems via the binge/intoxication stage (Figure 9.2), withdrawal/negative affect stage (Figure 9.3), and preoccupation/anticipation stage (Figure 9.4). From a broad perspective, none of these targets are completely new or novel (GABA, glutamate, or CRF), but they all have the potential for providing novel medications from the validation framework elaborated here. Finally, in this section, the innovative drug vaccine approach will be elaborated, which largely involves pharmacokinetically limiting the reinstatement of drug taking.

TABLE 9.5

Targets for Medications Development Derived from Preclinical Basic Research.

Class

Target

Dopamine receptor partial agonists

D2 receptor partial agonist (aripiprazole)
D3 receptor partial agonist

Modulators of _-aminobutyric acid

GABA modulators

Modulators of brain stress systems

CRF1 receptor antagonist
_ opioid receptor anatagonist
neurokinin-1 receptor antagonist

Modulators of glutamate

AMPA receptor antagonist
NMDA receptor antagonist
metabotropic glutamate receptor agonist
glutamate-5 receptor antagonist
topiramate

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