Prazosin + Naltrexone Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone in P Rats with a Protracted History of Extensive Voluntary Alcohol Drinking, Dependence, and Multiple Withdrawals

Abstract

Background: Prazosin (PRZ; an α1 -adrenergic receptor antagonist) and naltrexone (NTX; a nonspecific opioid receptor antagonist) each decrease alcohol drinking when administered to rats selectively bred for high voluntary alcohol drinking (alcohol-preferring or "P"), and the combination of PRZ + NTX decreases alcohol drinking more effectively than does either drug alone. As drug responsiveness can depend on history of alcohol drinking and dependence, we investigated whether various schedules of PRZ and NTX administration, alone or in combination, are effective in decreasing alcohol drinking in male P rats with a history of protracted voluntary alcohol drinking, dependence, and repeated withdrawals closely resembling human alcoholism.

Methods: Male P rats became alcohol-dependent during 1 year of ad libitum 24 h/d access to food, water, and 20% alcohol with repetitive temporary alcohol withdrawals. Four sequential studies then addressed effects of oral PRZ (2 mg/kg) and NTX (10 mg/kg), alone or together, on alcohol drinking during: (i) daily alcohol access with daily drug treatment, (ii) intermittent alcohol access with daily drug treatment, (iii) intermittent alcohol access with occasional drug treatment, and (iv) postdeprivation reinstatement of alcohol access.

Results: The combination of PRZ + NTX consistently suppressed alcohol drinking during daily or intermittent alcohol access conditions and when drug treatment was either daily or occasional. PRZ + NTX was consistently more effective than either drug alone. The reduction in alcohol drinking was not due to sedation, motor effects, or malaise.

Conclusions: Both daily and "as-needed" treatment with PRZ + NTX are highly effective in suppressing daily, intermittent, and postdeprivation alcohol drinking in male P rats with a protracted history of alcohol dependence and repeated withdrawals. This drug combination may be especially effective for treating individuals with long histories of heavy alcohol abuse, dependence, and repeated relapse, as commonly encountered in clinical practice.

Keywords: Alcohol; Alcoholism Treatment; Naltrexone; Noradrenergic; Opioid; Prazosin.

Figure 1

Timeline of sequential studies. These studies were conducted after 1 year of ad libitum access to food, water and 20% alcohol, with repetitive temporary alcohol withdrawals, that produced alcohol dependence.

Figure 2

Effects of oral prazosin (PRZ, 2 mg/kg) and naltrexone (NTX, 10 mg/kg), alone or in combination, on alcohol intake during daily 2-h alcohol access with daily drug treatment (Expt. 1, treatment weeks 1-3). Each bar represents data from 12-13 rats. *** p<0.001, ** p<0.01, * p<0.05, independent of day. Veh: vehicle.

Figure 3

Effects of oral prazosin (PRZ, 2 mg/kg) and naltrexone (NTX, 10 mg/kg), alone or in combination, on alcohol intake during intermittent 2-h alcohol access with daily drug treatments (Expt. 2; treatment weeks 4-5). A, B and C indicate tests of PRZ and NTX effects on 1 h, 5 min or 2 min intake of a solution of [3% sucrose + 0.125% saccharin] on days with no alcohol access (results presented in Fig. 4). Each bar represents data from 12-13 rats. *** p<0.001, PRZ+NTX vs vehicle (VEH), independent of day.

Figure 4

Effects of oral prazosin (PRZ, 2 mg/kg) and naltrexone (NTX, 10 mg/kg), alone or in combination, on intake of a solution of [3% sucrose + 0.125% saccharin] during 1-h, 5-min or 2-min access in Expt. 2 (as noted in Fig. 3). Each bar represents data from 12-13 rats. *** p<0.001, ** p<0.01, * p<0.05 vs vehicle (VEH).

Figure 5

Effects of oral prazosin (PRZ, 2 mg/kg) and naltrexone (NTX, 10 mg/kg), alone or in combination, on alcohol intake during intermittent 2-h alcohol access with intermittent drug treatments (Expt. 3, treatment weeks 6-8). Solid black boxes (██) indicate days on which drug treatment was administered. Each bar represents data from 12-13 rats. *** p<0.001, ** p<0.01, * p<0.05 vs vehicle (VEH).

Figure 6

Weekly average alcohol and water intakes during all 3 sequential experiments spanning drug treatment weeks 1-8. PRE: pretreatment week. Each bar represents data from 12-13 rats. *** p<0.001, ** p<0.01, * p<0.05 vs VEH. PRZ: prazosin, NTX: naltrexone, VEH: vehicle.

Figure 7

Effects of the combined oral prazosin (PRZ, 2 mg/kg) + naltrexone (NTX, 10 mg/kg) treatment on alcohol intake during post-deprivation reinstatement of alcohol access (Expt. 4). Rats that had previously received only vehicle (VEH) control treatments in Experiments 1-3 were restored to unlimited 24-h alcohol access for 4 weeks, followed by 2 weeks of alcohol deprivation. The rats received either PRZ+NTX or VEH on the final 2 days of alcohol deprivation and on 2 days reinstatement of 2-h/day alcohol access. Each bar represents data from 6 rats. ** p<0.01, independent of day.