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Indiana University-Purdue University Indianapolis (IUPUI) / Background: Previous studies show that prazosin, an α1-adrenergic receptor antagonist, decreases alcohol drinking in animal models of alcohol use and dependence and in alcohol-dependent men. These studies extended previous findings by using a paradigm that allows for separate assessment of prazosin on motivation to seek versus consume ethanol or sucrose in selectively bred rats given acute or chronic prazosin treatment. Methods: Alcohol-preferring P rats were trained to complete an operant response that resulted in access to either 2% (Exp. 1) or 1% (Exp.2) sucrose or 10% ethanol. In Experiment 1, a 4-week consummatory testing phase consisted of rats bar-pressing to “pay” a specified amount up front to gain access to unlimited ethanol (or sucrose) for a 20-minute period. A 4-week appetitive testing phase examined how much the rats would bar-press for ethanol in an extinction session when no reinforcer could be obtained. In Experiment 2, during testing, the response requirement was dropped to a 1 and daily session cycles of drug (3 weeks/ 14 sessions from Tues to Fri) or vehicle (2 weeks/ 9 sessions from Tues to Fri) treatment were alternated per drug dose for a total of 3 drug doses (3 cycles) per rat. After each drug cycle, a single non-reinforced extinction session was conducted with no drug ‘on board’ and no reinforcer access. On test days, rats were given IP injections of either vehicle or one of three doses of prazosin (Exp 1: 0.5, 1.0, 1.5 mg/kg; Exp 2: 0.25, 0.5, 1.0 mg/kg; balanced design; -30 min). Results: In Experiment 1, prazosin significantly decreased ethanol-seeking at all doses tested. The highest dose decreased ethanol intake and increased the latency to first lever-press and first lick. Sucrose-seeking and intake were decreased by the same doses of prazosin. In Experiment 2, prazosin significantly decreased reinforcer-seeking at the lowest and highest doses while ethanol intake was not decreased by prazosin. Conversely, sucrose-seeking was decreased at the highest dose of prazosin tested while sucrose consumption was decreased by all doses. Latency to lever-press for sucrose was increased by the lowest dose of prazosin compared to vehicle. Conclusions: These findings extend previous research and indicate that prazosin decreases motivation to seek ethanol and sucrose. The specificity of prazosin on different behaviors and over different reinforcers suggests that these findings are not due to prazosin-induced motor-impairment or malaise. These data suggest that prazosin may work by decreasing the reinforcing properties of reinforcers in general.