Effects of Known Medications on Animal Models of Addiction – Reverse Validity (Rosetta Stone Approach)
Drugs Currently on the Market for the Treatment of Addiction – Preclinical Background
• Disulfiram (Antabuse). Disulfiram is an inhibitor of aldehyde dehydrogenase and is used in the treatment of alcoholism to suppress drinking and prevent relapse. Disulfiram has a variable therapeutic effect, but it can be effective under conditions of compliance. In animal studies, disulfiram decreases alcohol intake, but tolerance develops to the suppression with chronic intake. Disulfiram also has anxiogenic-like effects. Both characteristics are possibly relevant for its therapeutic use.
• Acamprosate (Campral). Acamprosate is a modulator of hyperglutamatergic function either through an action on N-methyl-D-aspartate (NMDA) receptors or through an action on metabotropic glutamate receptors. The preclinical data that led to the clinical studies on acamprosate began with a series of studies in Europe on the effects of acamprosate on excessive drinking in rats. Acamprosate injected chronically decreased alcohol drinking in rats that were selectively bred for excessive drinking and decreased alcohol drinking in dependent rats. Acamprosate also reverses the hyperglutamatergic state produced by alcohol withdrawal. Acamprosate was then shown to selectively block the increased alcohol drinking associated with withdrawal and alcohol deprivation. Although at high doses acamprosate had effects on baseline drinking in general, the excessive drinking associated with dependence and withdrawal was much more sensitive to the effects of acamprosate (for further reading, see Littleton et al., 2007).
• Nalmefene (Selincro). Nalmefene is an orally active opioid antagonist with high affinity for both μ and κ opioid receptors. It was shown to decrease heavy drinking in individuals with alcoholism in a double-blind, placebo-controlled clinical trial. It is now marketed in parts of Europe for the treatment of alcoholism. Moreover, the efficacy of nalmefene led to preclinical studies that showed greater efficacy in dependent than nondependent animals, thus increasing interest in dynorphin/κ opioid targets for the treatment of alcoholism (see dynorphin discussion below). In human studies, nalmefene has been tested on patients who were instructed to take their pills only on days they felt like they were going to drink; thus, treatment was aimed at curbing heavy drinking on an “as needed basis.” Nalmefene received approval for reducing alcohol consumption in alcohol dependence in the European Union in 2013 and is already marketed in some countries in Europe, including Norway, Finland, and Poland. Nalmefene has not been approved for use in the United States.
• Baclofen (Lioresal). Preclinical studies show that baclofen can block alcohol self-administration and alcohol seeking in animal models. Baclofen has also been shown to block cocaine and heroin seeking in animals and block nicotine, cocaine, and morphine-induced dopamine release in the shell of the nucleus accumbens. Baclofen is a γ-aminobutyric acid-B (GABAB) receptor agonist that blocks the increase in alcohol self-administration during acute withdrawal in dependent rats at lower doses than those that block alcohol self-administration in nondependent rats, suggesting the increased sensitivity of this system during the development of dependence. Baclofen, a GABAB agonist, was shown to reduce alcohol craving and intake in some double-blind, placebo-controlled clinical trials but not in others (for further reading, see Ameisen, 2008). Baclofen was recently approved for the treatment of alcoholism in France only. It has not yet been approved for the treatment of alcoholism in Europe as a whole or in the United States. Direct GABAB receptor agonists such as baclofen are also currently in therapeutic use for the relief of flexor spasms in multiple sclerosis, but they have substantial sedative effects at therapeutic dose ranges.