Preclinical evaluation of riluzole: assessments of ethanol self-administration and ethanol withdrawal symptoms.

Alcoholism is a complex neurobehavioral disorder that is characterized in part by excessive consumption of ethanol and by the development of physical dependence. Many of the neurobiological and behavioral effects of ethanol are mediated by excitatory NMDA and inhibitory GABAA receptor systems (for reviews see Davis and Wu, 2001; Grant and Lovinger, 1995; Koob et al., 1998; Nevo and Hamon, 1995). For example, preclinical studies have shown that GABAA and NMDA receptor systems modulate ethanol drinking (Bienkowski et al., 2001; June et al., 1992), reinforcement (Hodge et al., 1996), reward (Chester and Cunningham, 1999), drug discrimination (Besheer et al., 2003; Grant et al., 1991; Hodge and Cox, 1998), tolerance (Khanna et al., 1991; Mihic et al., 1992), dependence (Morrisett et al., 1990; Morrow et al., 1994), and relapse (Nie and Janak, 2003). Given the involvement of GABAergic and NMDA/glutamatergic systems in a variety of ethanol's neurobiological and behavioral effects, there is growing interest in these systems as potential therapeutic targets in the pharmacological treatment of problems associated with alcoholism (Anton, 2001; Davis and Wu, 2001; Nevo and Hamon, 1995). One efficient strategy that might be used to identify candidate medications for treatment of alcoholism is to use preclinical animal models to evaluate the potential of FDA approved medications with mechanism(s) of action that are known to underlie the neurobehavioral effects of ethanol. The drug riluzole (2-amino-6-trifluoromethoxy benzothiazole), which is presently an approved medication for the treatment of amyotrophic lateral sclerosis (ALS) (Wagner and Landis, 1997), appears to be one such candidate. That is, riluzole inhibits the presynaptic release of glutamate (Jehle et al., 2000; Martin et al., 1993) and may act postsynaptically to interfere with NMDA receptor function (reviewed by Doble, 1996). Evidence also indicates that riluzole decreases GABA uptake (Mantz et al., 1994) and potentiates function of postsynaptic GABAA receptors (He et al., 2002). In vivo, riluzole has neuroprotective (Debono et al., 1993; Malgouris et al., 1989; Pratt et al., 1992), anticonvulsant (Mizoule et al., 1985; Romettino et al., 1991), anxiolytic-like (Munro et al., 2007), and sedative properties (Mantz et al., 1992) that are consistent with a decrease in CNS excitability via inhibition of NMDA and enhancement of GABAA receptor activity. Riluzole also appears to have another mechanism of action which may indirectly result in inhibition of CNS excitation. Noh and colleagues (2000) found riluzole to be an effective and direct inhibitor of protein kinase C (PKC). PKC is a family of kinases that regulates a variety of neuronal functions including ion channel activity, neurotransmitter release, receptor desensitization, and differentiation (Tanaka and Nishizuka, 1994). PKC has been shown to positively modulate glutamate channels, as well as sodium and chloride channels (Shearman et al., 1989). Moreover, the finding that riluzole inhibits PKC presents the possibility that riluzole-induced suppression of glutamate release may occur via an indirect mechanism. Previous work from our laboratory has shown that mice lacking the epsilon isoform of PKC (PKCe) show decreased ethanol self-administration (Hodge et al., 1999; Olive et al., 2000), greater sensitivity to ethanol's sedative effects (Hodge et al., 1999), reduced anxiety-like behavior (Hodge et al., 2002), and exhibit diminished ethanol-induced withdrawal seizures (Olive et al., 2001). Given that riluzole influences glutamate and GABA functioning, and inhibits PKC, the effects of riluzole on ethanol self-administration were tested in inbred C57BL/6J mice, with the prediction that riluzole pretreatment would reduce ethanol self-administration. The pattern of self-administration behavior across the 16-hour session was examined in 4-hour intervals in an effort to relate behavior with the known kinetics of riluzole after IP administration in mice, which shows a dual peak in brain levels at 20 and 80 minutes and is then significantly reduced by 4 hours (Hockly et al., 2006). Further, given riluzole's general suppressant effect on the central nervous system and anticonvulsant properties, suppression of ethanol withdrawal seizures was also predicted. Because riluzole is already approved for human use, reductions in ethanol self-administration and withdrawal seizures may make this drug a viable therapeutic for the treatment of alcohol use disorders.