The long-lasting effects of JDTic, a kappa opioid receptor antagonist, on the expression of ethanol-seeking behavior and the relapse drinking of female alcohol-preferring (P) rats

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Abstract

The current study assessed the effects of the selective kappa opioid antagonist JDTic on alcohol (EtOH) -seeking behavior, EtOH relapse, and maintenance responding for EtOH. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) on a fixed-ratio 5 (FR-5) and water on a FR-1 schedule of reinforcement during 1-hr sessions. After 10 weeks, rats underwent extinction training for seven sessions. Rats were then maintained in their home cages for 3 weeks without EtOH access. All rats received an injection (s.c.) of 0, 1, 3, or 10 mg/kg JDTic (n = 11–14/group) after the first week of the home cage period. Rats were then tested using the Pavlovian Spontaneous Recovery paradigm (PSR; an animal model of alcohol-seeking) for four sessions during which, responses on the EtOH and water levers were recorded but did not produce their respective reinforcer. Following PSR testing rats were returned to their home cages without access to EtOH for one week prior to the start of EtOH relapse testing. To examine EtOH relapse responding, rats were returned to the operant chambers and the EtOH (FR5) and water (FR1) levers were active. Finally, rats were then tested over 17 operant sessions to assess the effects of JDTic on maintenance responding for EtOH. Rats received 0, 1, 3, or 10 mg/kg JDTic (counterbalanced from the initial experiment) 30 minutes prior to the initial maintenance session. JDTic administered 14 and 25 days prior to testing dose-dependently reduced the expression of an EtOH PSR and relapse responding. In contrast, JDTic did not alter EtOH responding under maintenance conditions. Overall, the results of this study indicate that different mechanisms mediate EtOH self-administration under relapse and maintenance conditions and kappa opioid receptors are involved in mediating EtOH-seeking behavior and relapse responding but not on-going EtOH self-administration.

Highlights

► The Kappa opioid receptor mediates some alcohol related behaviors. ► We investigated the effect of JDTic on alcohol related behaviors. ► JDTic decreased alcohol seeking and relapse but not maintenance responding. ► The Kappa opioid receptor mediates alcohol seeking and relapse but not maintenance. ► Kappa opioid receptors represent therapeutic targets for the treatment of alcoholism.

Introduction

The neurological mechanisms that underlie the dysfunctional behaviors associated with alcohol (EtOH) abuse and alcoholism are complex. Despite extensive preclinical research that has evaluated numerous neurotransmitter systems and proof-of-concept clinical trials to determine the efficacy of putative treatments in high EtOH drinking populations, relatively few pharmacological treatments for EtOH dependence have been approved for use in the United States and throughout the world (Johnson and Ait-Daoud, 2000). Among the most studied approved pharmacotherapeutic agents for alcohol addiction is the non-selective opioid antagonist naltrexone which, has been reported to improve abstinence rates, decrease the impulse to initiate drinking, reduce the hedonic effects of alcohol, and reduce alcohol-induced positive mood (O'Malley et al., 1992, Volpicelli et al., 1992, Davidson et al., 1996). Although effect sizes relative to placebo responses in clinical trials have been modest, the therapeutic utility of naltrexone has consistently been demonstrated. For instance, recent data from the COMBINE study found that naltrexone significantly increased the length of abstinence in EtOH-dependent individuals (Anton et al., 2006) and reduced the probability that participants would fall into the consistent heavy drinking trajectory (Gueorguieva et al., 2010).

Preclinical data indicate that non-selective opioid antagonists robustly decrease free-choice EtOH consumption and/or the operant self-administration of EtOH in several alcohol-preferring rodent lines. For instance, Sable et al. (2006) reported that naltrexone was efficacious at reducing the expression of EtOH-seeking, relapse drinking, and maintenance EtOH self-administration during operant testing in both adolescent and adult alcohol-preferring (P) rats. Similarly, naloxone reduced EtOH intake in high-alcohol-drinking (Froehlich et al., 1990), P (Badia-Elder et al., 1999, Overstreet et al., 1999) and Alko-Alcoholic (Sinclair, 1990) rats. Naloxone also reduced EtOH intake in P rats under relapse conditions (i.e., after 2-weeks of EtOH deprivation; Badia-Elder et al., 1999). Naltrexone treatment has also been shown to reduce operant responding for EtOH (Middaugh et al., 1999, Middaugh et al., 2000), the consumption of EtOH (Middaugh and Bandy, 2000, Middaugh et al., 2003), as well as the expression of EtOH place conditioning (Middaugh and Bandy, 2000) in the EtOH-preferring C57BL/6 mouse line. Both naltrexone and naloxone bind to the three main opioid receptors (Mu: MOR, Delta: DOR, and kappa: KOR) and are believed to decrease EtOH intake by blocking EtOH-stimulated increases in endogenous opioid activity within the brain (for review see Gianoulakis, 2001). Although both naltrexone and naloxone possess a higher affinity for the MOR, studies utilizing selective opioid receptor subtype ligands have identified a significant contribution of each opioid receptor with regard to EtOH intake and reward (Di Chiara et al., 1996, Koob et al., 2003, Walker et al., 2011).

Recently, the KOR system has gained attention for its role in addiction to several drugs of abuse including EtOH (Shippenberg et al., 2007, Wee and Koob, 2010). The KOR system is believed to function in the rewarding properties of EtOH, mainly through the mediation of DA signaling in the reward pathway. Specifically, KORs are located pre-synaptically on dopamine (DA) neurons in the nucleus accumbens (ACB) near the DA transporter, and serve to regulate the release and uptake of DA (Svingos et al., 2001). KORs are selectively sensitive to the dynorphin class of opioid peptides and studies have shown that acute EtOH exposure produces an enduring increase in dynorphin levels and an increased sensitivity of KORs within the ACB (Lindholm et al., 2000, Lindholm et al., 2007). Manipulation of the KOR system, via local or systemic administration of KOR agonists, reduces basal levels of extracellular DA in the ACB (Spanagel et al., 1990) and inhibits cocaine- or morphine-evoked DA release in the ACB (Maisonneuve et al., 1994, Spanagel et al., 1994). Conversely, selective KOR antagonists, such as nor-BNI, increase extracellular DA levels in the ACB (Spanagel et al., 1992) and decrease EtOH self-administration in EtOH-dependent rats (Walker and Koob, 2008, Walker et al., 2011). Rats that are not EtOH-dependent fail to exhibit similar decreases in EtOH self-administration when administered KOR antagonists (Doyon et al., 2006, Walker and Koob, 2008) which suggests that the DYN and KOR systems become functionally unregulated during the development of EtOH-dependence (Przewlocka et al., 1997, Lindholm et al., 2000, Lindholm et al., 2007, Walker and Koob, 2008). Interestingly, rodents genetically predisposed to consume EtOH exhibit differences in the expression of opioid receptors, as well as brain tissue levels of opioid peptides, which, have been postulated to contribute to their high EtOH intake and preference (Fadda et al., 1999, McBride and Li, 1998, Murphy et al., 2002). However, relatively little attention has focused on the effect of selective KOR antagonism on EtOH self-administration in the P line of rats.

JDTic is the first potent, selective KOR antagonist not derived from naltrexone or opiate compounds (c.f., Carroll et al., 2004). JDTic has subnanomolar affinity for the KOR and is functionally selective for the KOR at levels over 500-fold and 16,000-fold than the MOR and the DOR respectively (Thomas et al., 2001). In vivo studies have shown that JDTic blocks KOR agonist-induced diuresis and antinociception for 2–4 weeks depending on the species and assay used (Carroll et al., 2004). In addition to the long-lasting pharmacological properties, JDTic exhibits antidepressant and anxiolytic-like effects, and has demonstrated efficacy in substance abuse and relapse models in male rats (Beardsley et al., 2005, Beardsley et al., 2010, Carroll et al., 2005, Knoll et al., 2007, Jackson et al., 2010).

The intent of this study was to examine the effects JDTic on operant EtOH self-administration, relapse, and EtOH-seeking behavior of P rats. Specifically, alcohol-seeking was tested through Pavlovian Spontaneous Recovery (PSR), the recovery of responding, in the absence of the previously trained reward, which, is observed following a period of rest after extinction (Domjan and Burkhard, 1982, Macintosh, 1977). PSR is a measure of the relative strength of reinforcer-seeking behavior. In P rats, the expression of an EtOH PSR is enhanced following periadolescent alcohol drinking, exposure to EtOH odor during PSR testing, and EtOH priming (Rodd-Henricks et al., 2002a, Rodd-Henricks et al., 2002b). Thus, the PSR model is an established animal model of craving-like behavior (c.f., Rodd et al., 2004). In addition, EtOH relapse responding, as well as maintenance responding, for EtOH were assessed. It was hypothesized that JDTic would act to decrease EtOH-seeking behavior, EtOH relapse responding, as well as the EtOH maintenance responding of P rats.

Section snippets

Animals

Adult female P rats from the 55th–57th generations weighing 250–325 g at the start of the experiment were used (n = 49). Rats were maintained on a 12-h reversed light–dark cycle (lights off at 0900 h). Food and water were available ad libitum throughout the experiment, except during operant testing. The animals used in these experiments were maintained in facilities fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC). All research protocols

Effects of JDTic administration on EtOH lever responding in the PSR test — under relapse conditions

P rats were self-administering on average 2.4 ml of 15% EtOH (estimated 1.1 ± 0.1 g/kg/session) prior to the start of extinction training. JDTic administered 14 days prior to testing, dose-dependently reduced responding on the EtOH lever during PSR testing. Examining the number of responses on the lever previously associated with the delivery of EtOH (Fig. 1a) indicated a significant effect of Session (F4, 42 = 25.5; p < 0.001), Dose (F3, 45 = 6.9; p < 0.001), and a Session by Dose interaction (F12, 132 = 

Discussion

The data indicate selective effects of JDTic on different aspects of EtOH self-administration behavior. A single injection of JDTic (all doses tested) 14 days prior to testing reduced the expression of EtOH-seeking in P rats, as measured in the PSR test. Additionally, the same single injection of JDTic (given 25 days before) suppressed responding on the EtOH lever under relapse conditions. To our knowledge, this is the first example of JDTic demonstrating a long-lasting effect on EtOH-seeking or

Acknowledgements

This research was supported by the National Institutes of Health grants AA07611, AA07462, and AA10721 from the National Institute on Alcohol Abuse and Alcoholism, and DA09045 from the National Institute on Drug Abuse. The authors would like to thank the Research Triangle Institute (Research Triangle Park, North Carolina) and Eli Lilly for generously supplying the JDTic to be used in this research. The authors would also like to thank Tylene Pommer for her expert technical assistance with the

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