Opiate reinforcement and naloxone aversion, as revealed by place preference paradigm, in two strains of rats

Abstract

Two strains of rats--LC2-Hi and LC2-Lo--selected for high and low self-stimulation rates, respectively, were tested for responses to opiates and to naloxone using conditioned place preference paradigm. In the two experiments which used opiates as UCS, conditioning was carried out in the non-preferred compartment while in the experiment which used naloxone, conditioning was performed in the preferred compartment. The preference changes were determined on the basis of times spent in the compartments before and after conditioning with drugs. LC2-Hi rats showed positive changes in the preference to the initially non-preferred side when morphine or heroin (5 mg/kg and 1 mg/kg, respectively) were used; no such effect was observed with LC2-Lo rats. Both lines exhibited aversive reactions to naloxone by diminishing the time spent in the environment paired with this drug, but again the response of LC2-Hi animals was significantly larger than the response of LC2-Lo rats. Chronic intake of a sweet solution (3 mM saccharin for 4 weeks) tended to amplify the aversive reaction to naloxone in both lines. It may be inferred from the present findings that there exists a common genetic factor, as revealed by the conditioned place preference paradigm, underlying positive reinforcing properties of opiates and aversive effects of naloxone.

Measuring the incentive value of escalating doses of heroin in heroin-dependent Fischer rats during acute spontaneous withdrawal

“…Rats learned to associate escalating doses of heroin with a unique chamber while receiving chronic exposure to escalating doses of heroin in their homecages and, when tested during acute spontaneous withdrawal, preferred the heroin-paired chamber. Although conditioned place aversion has been used to examine the aversive state of withdrawal (Azar et al 2003; Dymshitz and Lieblich 1987; Harris and Aston-Jones 1993; Rothwell et al 2009; Spanagel et al 1994), few studies have used conditioned place preference to measure heroin’s incentive value across this relapse-prone period. Paired with chronic homecage exposure to heroin, the present place preference study offers insight into the incentive-motivational value attributed to heroin by a dependent rat, once heroin is discontinued and withdrawal begins.…”

“…While the magnitude of heroin preference did not correspond to patterns of somatic withdrawal signs, extending limited self-administration analyses (Hellemans et al 2002), it is likely that negative emotional and stress states of withdrawal contributed to heroin preference. In rodents, withdrawal has been associated with increased anxiety- and depression-like behavior (Goeldner et al 2011; Grasing et al 1996; Harris and Aston-Jones 1993; Rothwell et al 2009; Zhang and Schulteis 2008), conditioned place aversions (Dymshitz and Lieblich 1987; Harris and Aston-Jones 1993; Mucha 1987; Rothwell et al 2009; Spanagel et al 1994) elevated self-stimulation thresholds (Schaefer and Michael 1985), and elevated and persistent heroin-seeking behavior (Hutcheson et al 2001; Lenoir and Ahmed 2007; Gerak et al 2009; Negus 2006; Negus and Rice 2009). We speculate that heroin place preference reported here was not driven by avoidance of withdrawal but rather the value attributed to heroin across cycles of withdrawal and re-exposure.…”

“…Continued drug use and high rates of relapse are thought to be motivated by the aversive state of withdrawal and/or the positive incentive-motivational value of the drug itself (Frenois et al 2005; Jaffe 1992; Koob 2009; Koob and Kreek 2007; Koob and Le Moal 2001, 2008; Robinson and Berridge 1993, 2000; Hutcheson et al 2001). While the aversive state of opiate withdrawal is well characterized (Azar et al 2003; Dymshitz and Lieblich 1987; Harris and Aston-Jones 1993; Rothwell et al 2009; Spanagel et al 1994), little is known about the positive incentive-motivational value of heroin during withdrawal. An important goal of current psychopharmacology research is to identify how the incentive value attributed to heroin by a dependent individual contributes to heroin-seeking behavior that can persist across withdrawal and prolonged abstinence.…”

The selective dopamine D3 receptor antagonist, SR 21502, reduces cue-induced reinstatement of heroin seeking and heroin conditioned place preference in rats

“…In heroin addicts, drug-related cues can support compulsive drug taking, elicit drug-associated physiological responses, prompt craving and trigger relapse (Childress et al, 1988; O’Brien et al, 1992, 1984; Sherman et al, 1989; Sideroff and Jarvik, 1980; Wikler, 1973). In animal models of addiction, opiate-associated cues can reinforce intravenous drug self-administration (Davis and Smith, 1976; Di Ciano and Everitt, 2004; Dymshitz and Lieblich, 1987), enhance locomotor activity (Mucha et al, 1981), facilitate the acquisition of opiate tolerance (Siegel, 1975), elicit conditioned place preference (Bardo et al, 1984; Bardo and Neisewander, 1986; Schenk et al, 1983) and reinstate drug seeking (McFarland and Ettenberg, 1997; Peck and Ranaldi, 2014; Schuster and Woods, 1968). …”

The effects of continuous naltrexone infusions on diet preferences are modulated by adaptation to the diets

“…In addition to their ability to establish conditioned taste aversions, opioid antagonists have been shown to be effective unconditioned stimuli for the establishment of conditioned place aversions (10,25). We do not believe such conditioning played a significant role in the present experiment because cage positions of the two diets were reversed daily.…”