Investigating the therapeutic range of prazosin alone and in combination with propranolol and naltrexone: Is combination pharmacotherapy more effective than monotherapy in reducing ethanol-seeking and self-administration in the P rat?
Abstract
Evidence suggests that the noradrenergic system plays a key role in mediating ethanol-motivated behaviors in both alcohol-dependent and non-dependent humans and rats. However, preclinical studies indicate that noradrenergic antagonists block the reinforcing properties of other palatable, oral reinforcers. Combination therapy is one such strategy that could be utilized to possibly avoid unwanted side effects and still attenuate ethanol seeking and self-administration. The present study examined the effects of low-dose combinations of prazosin and propranolol or prazosin and naltrexone using an operant behavioral paradigm that separately assesses seeking and intake. Methods: 40 male alcohol-preferring (P) rats (n=20/experiment) were trained to complete an operant response requirement that resulted in access to 1% sucrose (sucrose group; n=10/experiment) or 10% ethanol (ethanol group; n=10/experiment) for 20 min. Upon stable responding, rats were tested on Tuesdays (intake tests) and Fridays (seeking tests) over 10 weeks in the sipper tube model. On test days, rats received an IP injection (-30 min; balanced design) of vehicle, prazosin alone (0.125, 0.25, 0.5, 1.0 mg/kg), or prazosin (same doses) in combination with propranolol (5 mg/kg) for Experiment 1 or vehicle, prazosin alone, or prazosin in combination with naltrexone (0.03 mg/kg; SC) for Experiment 2. Results: For Experiment 1, baseline reinforcer seeking was comparable for sucrose and ethanol. Mean baseline ethanol intake was 1.26 g/kg, consistent with 'binge-like' ethanol consumption. Prazosin alone was more effective at decreasing sucrose versus ethanol seeking, but was more effective at decreasing ethanol intake with no effects on sucrose intake. Propranolol alone was more effective at decreasing ethanol versus sucrose seeking and decreased ethanol intake with no effect on sucrose intake. The effectiveness of propranolol at a dose not expected to affect ethanol responding made it difficult to observe any possible synergistic effects, but there were additive effects of prazosin+propranolol on ethanol and sucrose seeking and intake. For Experiment 2, prazosin alone was more effective at decreasing ethanol-seeking and intake with no effect on sucrose-seeking. Naltrexone alone was more effective at decreasing ethanol intake and seeking with no effect on sucrose intake or seeking. There were additive effects of prazosin+naltrexone on ethanol-seeking and intake as well as on sucrose self-administration, but not seeking. Conclusions: Low-dose combination treatment was effective at decreasing high ethanol intake and seeking in P rats. Noradrenergic drugs with different mechanisms of action may target different aspects of ethanol-motivated behavior and thus, in combination, may be good candidates for novel pharmacotherapeutic treatments for problem drinking. Support: NIAAA T32AA07462, P60AA007611
Degree
Ph.D.
Advisors
Czachowski, Purdue University.
Subject Area
Psychobiology|Pharmacy sciences
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