Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats

Abstract

Rationale and Objectives Relapse to alcohol use during abstinence or maladaptive eating habits during dieting is often provoked by stress. The anxiogenic drug yohimbine, which causes stress-like responses in humans and nonhumans, reliably reinstates alcohol and food seeking in a rat relapse model. Yohimibine is a prototypical alpha-2 adrenoceptor antagonist but results from studies on noradrenaline's role in yohimbine-induced reinstatement of drug and food seeking are inconclusive. Here we further addressed this issue by studying the effect of the alpha-1 adrenoceptor antagonist prazosin and the alpha-2 adrenoceptor agonist guanfacine on yohimbine-induced reinstatement. Methods In Exp. 1, we trained rats to self-administer alcohol (12% w/v, 1-h/day) and after extinction of alcohol-reinforced lever-pressing, we tested prazosin's (0.5, 1.0, and 2.0 mg/kg, i.p.) or guanfacine's (0.125, 0.25, and 0.5 mg/kg, i.p.) effect on yohimbine (1.25 mg/kg, i.p.)-induced reinstatement; we also examined prazosin's effect on intermittent-footshock-stress-induced reinstatement. In Exp. 2, we trained food-restricted rats to self-administer 45 mg food pellets and first examined prazosin's or guanfacine's effects on food-reinforced responding, and then, after extinction of lever presses, on yohimibine-induced reinstatement. Results Prazosin (0.5-2.0 mg/kg) blocked yohimbine-induced reinstatement of food and alcohol seeking, as well as footshock-induced reinstatement of alcohol seeking. Guanfacine attenuated yohimbine-induced reinstatement of alcohol seeking at the highest dose (0.5 mg/kg) but its effect on yohimbine-induced reinstatement of food seeking was not significant. Neither prazosin nor guanfacine affected high rate food-reinforced responding. Conclusions Results demonstrate an important role of postsynaptic alpha-1 adrenoceptors in stress-induced reinstatement of alcohol and food seeking.

Low-dose prazosin alone and in combination with propranolol or naltrexone: effects on ethanol and sucrose seeking and self-administration in the P rat

“…With regard to prazosin, the high dose (1.0 mg/kg) consistently decreased ethanol-seeking and drinking in both Experiments, with lower doses showing efficacy varying by experiment. These findings are consistent with and extend that of Le et al (2011), in that prazosin was found to block stress-induced responding for ethanol at 0.5 and 1.0 mg/kg IP in Wistar rats. An examination of a purely consummatory response (i.e., home cage drinking) in P rats showed that acute prazosin at the 1.0 mg/kg IP dose decreased ethanol intake while 0.5 mg/kg IP prazosin only became effective after 3 consecutive days of drug treatment in that study (1.0 mg/kg remained effective throughout the treatment regimen; Rasmussen et al, 2009).…”

“…Prazosin, an α 1 -adrenergic antagonist, has been found to reduce ethanol drinking in home cage, limited access paradigms in P rats (Rasmussen et al 2009) and block operant responding for ethanol in dependent Wistar rats, with higher doses necessary to be effective in non-dependent animals in a fixed ratio (FR) paradigm (Walker et al 2008). Prazosin blocks stress-induced reinstatement of ethanol-seeking in Wistar rats (Le et al 2011), and reduces ethanol drinking throughout prolonged treatment in alcohol-experienced P rats and impedes acquisition of ethanol drinking in naïve P rats (Froehlich et al 2013b). In the same paradigm used in the present investigation, prazosin attenuated ethanol- and sucrose-seeking and consumption in P rats (Verplaetse et al 2012).…”

“…However, the dose range used in experiments to date produces non-specific reductions in sucrose and food consumption in Wistar and P rats (Le et al 2011; Verplaetse et al 2012), and naltrexone decreases saccharin and sucrose intake in Wistar, Long Evans, and P rats (Goodwin et al 2001; Henderson-Redmond and Czachowski 2014), suggesting possible adverse secondary effects of these medications. Subthreshold dosing combinations may be an important next step in providing new treatment strategies for AUDs.…”

β-Adrenergic Receptor Mediation of Stress-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Roles for β1 and β2 Adrenergic Receptors

“…A preliminary experiment suggested the involvement of ␤ 2 adrenergic receptors in reinstatement in response to forced swim (Mantsch et al, 2010). It is noteworthy that although these findings are indicative of a selective role for ␤-adrenergic receptors in stress-induced reinstatement, it has been reported that prazosin can block yohimbine-or foot shock stress-induced reinstatement of extinguished food or alcohol seeking in rats (Lê et al, 2011). In the present study we further investigate the role of ␤-adrenergic receptors in stress-induced relapse by testing for reinstatement of extinguished cocaine-induced conditioned place preference in ␤-adrenergic receptor-deficient mice.…”

Investigation of allyphenyline efficacy in the treatment of alcohol withdrawal symptoms

“…These compounds are beneficial not only in the treatment of alcohol withdrawal symptoms but also in preventing recidivism to drug use associated with stress or cue exposure in animal models and in humans (Fox et al, 2014;Smith and Aston-Jones, 2011;Erb et al, 2000;Lê et al, 2011). Nevertheless, the major problems associated with the use of non subtype selective α 2 -adrenoceptor agonists are hypotension and sedation side effects.…”