The α₁ adrenergic receptor antagonist prazosin reduces heroin self-administration in rats with extended access to heroin administration

Abstract

Previous studies have reported that noradrenergic antagonists alleviate some of the symptoms of opiate withdrawal and dependence. Clinical studies also have shown that modification of the noradrenergic system may help protect patients from relapse. The present study tested the hypothesis that a dysregulated noradrenergic system has motivational significance in heroin self-administration of dependent rats. Prazosin, an α₁-adrenergic antagonist (0.5, 1.0, 1.5 and 2.0 mg/kg, i.p.), was administered to adult male Wistar rats with a history of limited (1 h/day; short access) or extended (12 h/day; long access) access to intravenous heroin self-administration. Prazosin dose-dependently reduced heroin self-administration in long-access rats but not short-access rats, with 2 mg/kg of systemic prazosin significantly decreasing 1 h and 2 h heroin intake. Prazosin also reversed some changes in meal pattern associated with extended heroin access, including the taking of smaller and briefer meals (at 3 h), while also increasing total food intake and slowing the eating rate within meals (both 3 h and 12 h). Thus, prazosin appears to stimulate food intake in extended access rats by restoring meals to the normal size and duration. The data suggest that the α₁ adrenergic system may contribute to mechanisms that promote dependence in rats with extended access.

Introduction

To understand better the mechanisms underlying heroin addiction, animal models relevant to components of heroin dependence have been sought. Such models of dependence have involved opiate exposure/withdrawal paradigms (e.g., chronic morphine pellet implantation and multiple morphine injections), reinstatement of heroin-seeking, and operant self-administration in limited access sessions (Young et al., 1977, Bozarth and Wise, 1985, Shaham et al., 1998, Carrera et al., 1999, Erb and Stewart, 1999, Hutcheson et al., 2001, Azar et al., 2003). However, only recently have models studying extended drug access in rats been modified to incorporate the excessive and increasing drug intake associated with human addiction.

Heroin and cocaine are both self-administered in increasing quantities when animals are allowed extended, as opposed to limited, access, a finding termed “escalation” (Ahmed and Koob, 1998, Ahmed et al., 2000). Extended access to heroin consumption (11 h/day) increased intake and persistently increased the motivation to take heroin, reflected by the increased responding for heroin after footshock stress, more lever responding for heroin, and slower extinction of heroin-seeking behavior compared with short-access controls (Ahmed et al., 2000). Rats allowed 23 h access to a fixed unit dose of heroin showed even more dramatic, spontaneous escalation in intravenous self-administration of heroin (Chen et al., 2006). These “escalation” models of heroin self-administration have face and predictive validity for modeling the compulsive drug intake associated with heroin dependence in humans (Ahmed and Koob, 1998, Ahmed et al., 2000, Koob et al., 2004, Chen et al., 2006). Short-access rats, in contrast, limit consumption to lower, more stable levels, and show significantly decreased extinction responding, a faster extinction rate, and are less prone to footshock-induced reinstatement than long-access rats (Ahmed et al., 2000). Thus, the short- vs. long-access models of intake offer further predictive validity via the inclusion of controls that, while having experience with opioid self-administration, differ in heroin intake, helping to discern the effects of treatments directed toward opioid use vs. excessive use.

Additionally, rat models of extended heroin access have been useful particularly when comparing the behavioral profiles associated with different stages in the development of heroin dependence, such as circadian and meal pattern measures of food intake (Chen et al., 2006). Previous research has shown that changes in the amount and pattern of food intake may be valuable as a sensitive indicator of the effects of heroin (Thornhill et al., 1976) and the development of heroin dependence (Chen et al., 2006). Meal pattern analysis revealed that smaller and briefer, but more, meals of food were taken within 7 days of daily extended (23 h) access to heroin (Chen et al., 2006). Thus, neuroadaptive mechanisms contributing to dependence also may be reflected not only in increased heroin self-administration, but also in changes in homeostatic processes measured by meal pattern analysis.

The challenge now is to identify the neuroadaptive mechanisms that mediate the change in motivation for heroin that occurs during the transition to dependence. Neurochemical systems implicated include γ-aminobutyric acid (GABA), dopamine, corticotropin-releasing factor (CRF), neuropeptide Y, and norepinephrine (Koob, 1992). An interaction between opioidergic and noradrenergic systems has been proposed (Aghajanian, 1978), and α₂- and β-adrenergic receptors have been targeted for alleviating opioid withdrawal (Redmond and Huang, 1982, Funada et al., 1994). Clonidine, an α₂-adrenergic receptor agonist, has been reported to be effective in reducing opiate withdrawal symptoms in humans and animals (Gold et al., 1978, Katz, 1986). Recently, studies have noted the importance of noradrenergic signaling in mediating not only opiate withdrawal (for review, see Maldonado 1997), but also opiate reward (Olson et al., 2006).

Furthermore, data suggest that α₁ receptor modulation of the effects of opioids may be more important than previously hypothesized. Prazosin, an α₁ adrenergic receptor antagonist, binds all three α₁ receptor subtypes with high affinity (Nicholas et al., 1996). Prazosin was found to block acquisition of morphine-induced conditioned place preference in mice (Zarrindast et al., 2002). Mice lacking α_1b receptors had decreased locomotor hyperactivity and an attenuated conditioned place preference in response to morphine administration (Drouin et al., 2002). Prazosin also reversed tolerance to morphine analgesia and attenuated morphine withdrawal-induced weight loss in mice (Ozdogan et al., 2003, Zarrindast et al., 2002, Drouin et al., 2002). Therefore, the α₁ receptor appears to have a role in opiate reward, tolerance, and withdrawal, and thus was hypothesized to have a role in the increased heroin self-administration that develops with prolonged drug access.

The present study tested the hypothesis that administration of prazosin would decrease drug self-administration in long-access (12 h) rats compared with limited access (1 h) control rats and determined whether prazosin would reverse some additional measures associated with dependence, such as the meal pattern changes observed in rats with extended access to heroin (Chen et al., 2006).