Intracranial self-stimulation reward thresholds during morphine withdrawal in rats bred for high (HiS) and low (LoS) saccharin intake

Abstract

Rational Sweet preference is a marker of vulnerability to substance use disorders, and rats selectively bred for high (HiS) vs. low saccharin (LoS) intake display potentiated drug-seeking behaviors. Recent work indicated that LoS rats were more responsive to the negative effects of drugs in several assays. Objective The current study used the intracranial self-stimulation (ICSS) procedure to investigate the anhedonic component of morphine withdrawal in male HiS and LoS rats. Methods Rats were administered morphine (10 mg/kg) or saline for 8 days. To evaluate withdrawal effects, reward thresholds were measured 24 and 28 h following the 8th morphine injection (spontaneous withdrawal) and again for 4 days following daily acute morphine and naloxone (1 mg/kg) administration (precipitated withdrawal). Results Twenty-four hr following the final morphine injection, reward thresholds in LoS rats were significantly elevated compared to reward thresholds in LoS controls, indicating spontaneous withdrawal. This effect was not observed in HiS rats. LoS rats also showed greater elevations of reward thresholds on several days during naloxone-precipitated withdrawal compared to their HiS counterparts. Conclusions LoS rats were more sensitive to morphine withdrawal-mediated elevations in ICSS thresholds than HiS rats. While these differences were generally modest, our data suggest that severity of the negative affective component of opiate withdrawal may be influenced by genotypes related to addiction vulnerability.

Cocaine-, caffeine-, and stress-evoked cocaine reinstatement in high vs. low impulsive rats: Treatment with allopregnanolone

“…In previous studies of individual differences in drug seeking, results demonstrated differential responding to the positive and negative aspects of drug taking in HiS and LoS rats. While HiS rats exceeded LoS rats in drug intake (Perry et al, 2006, Anker et al, 2012) and reinstatement of drug-seeking behavior (Perry et al, 2006), LoS rats (vs. HiS) revealed greater reactivity to negative events, such as food restriction (Carroll et al, 2012) and withdrawal from ethanol (Dess et al, 2005), glucose (Yakavenko et al, 2011) morphine (Holtz et al, 2014b), and cocaine (Radke et al, 2014). Given the previous finding that lower drug-seeking animals respond more to negative aspects of drugs compared to higher drug-seeking animals, one potential explanation for the results that ALLO reduced reinstatement more in LoI than HiI rats is that these pharmacological manipulations produced more of a stress response in LoI rats compared to HiI rats.…”

“…For example, animals selected for low impulsivity (LoI vs. HiI), low saccharin intake (LoS vs. HiS), as well as adults (vs. adolescents), and males (vs. females) not only exhibit less drug seeking than their counterparts, but they also exhibit more sensitivity to punishment by histamine, greater signs of withdrawal from drugs of abuse, greater taste aversion, greater response to anxiogenic stimuli, and greater acoustic startle (Carroll et al, 2009; Carroll and Holtz, 2014; Holtz et al, 2013, 2014b; Holtz and Carroll, 2014; McLaughlin et al, 2011; Radke et al, 2014, but see Radke et al, 2013), while their counterparts (HiI, HiS, adolescents, and females, respectively) have greater response to positive aspects of drugs (i.e., greater drug-seeking and drug-taking behaviors, see review by Carroll et al, 2009). This raises the question of to what extent are individual differences in drug seeking understood based on differential reactions to positive or negative aspects of drugs.…”

“…Female rats were selected for HiI vs. LoI impulsivity based on their performance on a delay-discounting task that was determined by their preference for a small-immediate (HiI) vs. large-delayed food reward (LoI) as described previously (Perry et al, 2005; Perry and Carroll, 2008). Allopregnanolone has been used in previous rat studies to reduce cocaine- (Anker et al, 2009; Anker and Carroll, 2010a) and methamphetamine- (Holtz et al, 2014b) induced reinstatement of drug seeking in rats. Since ALLO, progesterone, and their precursor, pregnenolone have been show to have anxiolytic effects (Anker and Carroll, 2010a, 2011; Anker et al, 2007; Concas et al, 2000; Llaneza and Frye, 2009; Schneider and Popik, 2007), it was hypothesized that it may produce a greater reduction of stress-induced (e.g., YOH and a high dose of CAFF priming injections) responding in LoI vs. HiI animals, since LoI rats may be more sensitive to anxiogenic stimuli or other negative aspects of drugs (Holtz et al, 2013; Holtz and Carroll, 2011, 2014).…”

Effects of Acute and Repeated Administration of Oxycodone and Naloxone-Precipitated Withdrawal on Intracranial Self-Stimulation in Rats

“…Although people may not always experience the full spectrum of the physical signs of oxycodone withdrawal, they still may be inflicted with those unpleasant enough to promote escalation of self-dosing, with the drug obtained either through legitimate or illegitimate channels. ICSS has been proposed as a preclinical model that can be used to model affective-like withdrawal symptoms, because many drugs, including morphine (Schaefer and Michael, 1986;Easterling et al, 2000;Liu and Schulteis, 2004;Altarifi and Negus, 2011;Holtz et al, 2015), nicotine (Epping-Jordan et al, 1998;Cryan et al, 2003;Kenny and Markou, 2005;Igari et al, 2014;Manbeck et al, 2014;Qi et al, 2015), ethanol (Schulteis et al, 1995;Chester et al, 2006;Rylkova et al, 2009;Boutros et al, 2014), and cocaine (Markou and Koob, 1991;Stoker and Markou, 2011), produce decreases in ICSS after either spontaneous or precipitated withdrawal. Furthermore, withdrawal from nicotine and morphine has been associated with decreased ventral tegmental area dopaminergic activity, which correlates with ICSS deficits (Liu and Jin, 2004;Kaufling and Aston-Jones, 2015).…”

Cocaine-induced reward enhancement measured with intracranial self-stimulation in rats bred for low versus high saccharin intake

“…HiS rats consume a variety of sweeteners more avidly (Dess 2000; Dess and Minor 1996; Dess et al 2005) and respond at higher rates than LoS rats in an operant conditioning paradigm for a sucrose reward (Gosnell et al 2010). HiS and LoS rats also display differences in measures of drug withdrawal (Radke et al 2013; 2015; Holtz et al 2015). On measures of cocaine-seeking, HiS rats are more vulnerable to acquisition, escalation, and reinstatement of drug seeking and maintain a higher level of drug intake (Carroll et al 2002; Perry et al 2006; Holtz and Carroll 2013) than their LoS counterparts.…”