Prazosin Reduces Alcohol Intake in an Animal Model of Alcohol Relapse

Alcoholism is the most prevalent and widespread of all addictive diseases in the world and development of effective treatments is a high priority. Alcoholism is a chronic illness (Duka et al, 2002; Heinz et al, 2003) and alcoholics often find it difficult to maintain abstinence once it is achieved (Dawson et al, 2007; Hunt et al, 1971; Schuckit et al, 1997). Relapse to heavy drinking, after both short and prolonged periods of alcohol abstinence, is a common feature of alcoholism (American Psychiatric Association, 2000; Barrick and Connors, 2002). Depending on the definition of alcohol relapse used (Chiauzzi, 1991; Hunt et al, 1971), relapse rates over a 12-month period post-treatment can range from 50%, if relapse is defined as a return to pretreatment drinking levels (Armor et al, 1978), to as high as 90% if consumption of a single drink is used to define relapse (Orford and Edwards, 1977). Alcohol dependent individuals often repeatedly attempt to achieve abstinence without permanent success and hence undergo multiple alcohol withdrawal/detoxification episodes (Schuckit et al, 1997; Barrick and Connors, 2002). Multiple previous detoxifications are associated with heavier alcohol drinking during alcohol relapse (Malcolm et al, 2000). Because relapse to alcohol drinking is a hallmark of alcoholism, animal models that exhibit this characteristic are useful for developing behavioral and pharmacological approaches that have the potential to attenuate or prevent alcohol relapse. Just like humans, rats also exhibit an increase in alcohol drinking when given reaccess to alcohol after a period of imposed “abstinence” (Sinclair and Senter, 1967; Heyser et al, 1997; Spanagel et al, 1996; Wolffgramm and Heyne, 1995). This increased alcohol intake that occurs when access to alcohol is reinstated following a period of alcohol deprivation in rodents is termed the “alcohol deprivation effect” or “ADE” (Sinclair and Senter, 1967; Heyser et al, 1997; Wolffgramm and Heyne, 1995). The ADE is thought to reflect an increase in the reinforcing value of alcohol (Heyser et al, 1997; McKinzie et al, 1998; Rodd-Henricks et al, 2000b; Spanagel et al, 1996; Wolffgramm and Heyne, 1995) and is not thought to be merely a consequence of physiological withdrawal since it is evident long after obvious withdrawal symptoms have disappeared which usually occurs within 1 week following termination of drinking in rats (Cicero et al., 1971). Instead, the ADE has been attributed to increased motivation to obtain alcohol due to increased alcohol craving during periods of alcohol withdrawal and abstinence (Heyser et al, 1997; Holter et al, 2000; Sinclair and Li, 1989). Because the ADE in rats is characterized by increased motivation to obtain alcohol (Sinclair and Li, 1989), is present even after prolonged periods of alcohol deprivation (McKinzie et al, 1998; Sinclair and Li, 1989; Sinclair et al, 1973) and is hardly modified by external stimuli such as taste adulterations (Spanagel et al, 1996), it is regarded by many as a good animal model of alcohol relapse in alcoholics (Froehlich and Li, 1991; Holter et al, 1998; 2000; McKinzie et al, 1998; Spanagel et al, 1996). Rats selectively bred for alcohol preference and high voluntary alcohol drinking (alcohol preferring or P rats) demonstrate a robust ADE in a variety of alcohol deprivation (imposed abstinence) conditions (McBride et al, 2002; McKinzie et al, 1998; Rodd-Henricks et al, 2000a; 2000b; 2001; Sinclair and Li, 1989) and are regarded by many as an appropriate animal analog of alcohol relapse in humans (Holter et al, 1998; 2000; McKinzie et al, 1998; Spanagel et al, 1996). To date, only three medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol dependence and relapse: disulfiram (Antabuse) approved in 1949, naltrexone (Trexan) approved in 1994 and acamprosate (Campral) approved in 2004. Only about 20% of eligible patients receive these medications and, even when medications are given, not all alcohol dependent subjects respond well to them regardless of which medication is used. Clearly, a need exists for other agents to treat populations of alcohol dependent individuals who do not respond to the FDA approved medications that are currently available. One goal of our research program is to increase the number of pharmacotherapeutic agents available for the treatment of alcohol abuse, dependence and relapse. The physiologic processes and pathways that underlie alcohol relapse in humans and the alcohol deprivation effect in rats are not yet well understood but classic symptoms such as hyperactivity and anxiety have been noted during periods of alcohol deprivation in humans and rats and are thought to reflect central nervous system (CNS) hyperexcitability (Rasmussen et al, 2001). Alcohol, which is both anxiolytic and sympatho-suppressive (Koob and Le Moal, 1997; Kushner et al, 1990; Kushner et al, 1999), alleviates these symptoms and hence alcohol relapse in alcoholics is often viewed as an attempt to self-medicate (American Psychiatric Association, 2000; Cappell and LeBlanc, 1979; Koob, 2003). One mechanism that underlies both anxiety and hyperexcitability in humans and rats is sympathetic activation and considerable evidence suggests that noradrenergic activation promotes and maintains alcohol drinking in rodents and humans. Prazosin is a postsynaptic α1-adrenergic receptor antagonist that blocks brain α1-adrenergic receptors that mediate central noradrenergic signaling (Menkes, 1981). Prazosin blocks noradrenergic excitation of the mesolimbic dopaminergic system (Sommermeyer et al, 1995) which plays a role in mediating the reinforcing properties of drugs of abuse, including alcohol (Weiss et al, 1992). Unlike other clinically available α1-adrenergic receptor antagonists, prazosin crosses the blood-brain barrier and is centrally active when administered systemically in clinically relevant doses. Prazosin was introduced in 1973 under the trade name “Minipress” as an antihypertensive drug, and has been used chronically by millions of people for hypertension (Lund-Johansen et al, 1993) and for urinary symptoms associated with benign prostatic hypertrophy (Hieble and Ruffolo, 1996). It has a long safety and clinical compliance record, and it is not associated with significant adverse side effects (Graham, 1984). As part of our long-standing research program on the identification and characterization of potential pharmacotherapeutic agents for the treatment of alcoholism using a rodent model of alcoholism (Froehlich et al, 2003; Froehlich, 2010; Froehlich and Li, 1991), we have become interested in prazosin. Anxiolyic agents, such as prazosin, may substitute for the anxiolytic effects of alcohol and thereby reduce motivation to drink and reduce alcohol intake. In a series of preclinical studies we have found that prazosin decreased alcohol drinking/self-administration in many experimental conditions: in rats selectively bred for high voluntary alcohol drinking during both acute (Rasmussen et al, 2009) and prolonged (Froehlich et al, 2013a) treatment; when administered alone or in combination with naltrexone (Froehlich et al, 2013b); when administered during reaccess to alcohol following periods of alcohol deprivation (Rasmussen et al, 2009); and when administered during acute alcohol withdrawal (Walker et al, 2008). In humans, prazosin has been used to treat posttraumatic stress disorder (PTSD) where it reduces hyperarousal, overall PTSD severity (Raskind et al, 2003) and, parenthetically, alcohol drinking (Raskind et al, 2009). Prazosin also decreases relapse drinking in alcohol-dependent men without PTSD (Simpson et al, 2009) and a preliminary study reports that prazosin decreases stress- and cue-induced alcohol craving in alcohol-dependent individuals (Fox et al, 2012). In the current study we examine the potential link between CNS hyperexcitability and alcohol relapse (“ADE” in rats) by determining whether a reduction of sympathetic activation, via prazosin treatment, might reduce the magnitude of, or even eliminate, the ADE in P rats. Such a finding would suggest that prazosin might be useful for reducing alcohol relapse in alcoholics and heavy drinkers.