alpha1-noradrenergic receptor antagonism blocks dependence-induced increases in responding for ethanol

Abstract

The purpose of this study was to test the hypothesis that blockade of alpha1-adrenergic receptors may suppress the excessive ethanol consumption associated with acute withdrawal in ethanol-dependent rats. Following the acquisition and stabilization of operant ethanol self-administration in male Wistar rats, dependence was induced in half the animals by subjecting them to a 4-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14h/day. Subsequent to dependence induction, the effect of alpha1-noradrenergic receptor antagonist prazosin (0.0, 0.25, 0.5, 1, 1.5, and 2.0mg/kg IP) was tested on operant responding for ethanol in vapor-exposed and control rats during acute withdrawal. In ethanol-dependent animals, prazosin significantly suppressed responding at the 1.5 and 2.0mg/kg doses, whereas only the 2.0mg/kg dose was effective in nondependent animals, identifying an increase in the sensitivity to prazosin in dependent animals. Conversely, at the lowest dose tested (0.25mg/kg), prazosin increased responding in nondependent animals, which is consistent with the effect of anxiolytics on ethanol self-administration in nondependent animals. None of the doses tested reliably affected concurrent water self-administration. These results suggest the involvement of the noradrenergic system in the excessive alcohol drinking seen during acute withdrawal in ethanol-dependent rats.

Figure 1

Left panel: Daily mean (±S.E.M) responses during 30 minutes sessions for ethanol and water prior to dependence induction for the ethanol vapor-exposed and air-exposed groups. Right panel: Mean (± S.E.M.) responses for ethanol and water during 30 minute sessions (occurring twice weekly) at a time-point corresponding to 6 h into withdrawal (i.e., acute withdrawal) following dependence induction. The vapor-exposed animals display escalated responding compared to the air-exposed controls.

Figure 2

Mean (+S.E.M.) responses for ethanol during 30 minute sessions that occurred twice weekly following prazosin (0.0 – 2.0 mg/kg) administration in nondependent and ethanol-dependent animals during acute withdrawal. At higher doses, prazosin decreased ethanol self-administration in both nondependent and ethanol-dependent animals (*p<0.05 compared to air-exposed vehicle dose; # p<0.01 and ## p<0.001 compared to vapor-exposed vehicle dose). Water self-administration was unaffected by prazosin.

Figure 3

Mean (+S.E.M.) responses for water during 30 minute sessions that occurred twice weekly following prazosin (0.0 – 2.0 mg/kg) administration in nondependent and ethanol-dependent animals during acute withdrawal. There was no effect of prazosin on water self-administration in ethanol-dependent or nondependent rats.

Figure 4

Mean (±S.E.M.) responses for ethanol during 30 minutes sessions in nondependent and ethanol-dependent animals following 0.0 and 1.5 mg/kg prazosin. Prazosin (1.5 mg/kg) attenuated ethanol self-administration in ethanol-dependent animals (*** p<0.001), leaving nondependent self-administration intact.