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. Author manuscript; available in PMC: 2013 Jun 1.
Published in final edited form as: Pharmacol Biochem Behav. 2012 Mar 10;101(4):581–587. doi: 10.1016/j.pbb.2012.03.006

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

Gerald A Deehan Jr 1, David L McKinzie 2, F Ivy Carroll 3, William J McBride 1, Zachary A Rodd 1
PMCID: PMC3327789  NIHMSID: NIHMS363479  PMID: 22429993

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.

Keywords: ethanol self-administration, ethanol relapse, ethanol-seeking, Pavlovian Spontaneous Recovery, JDTic, kappa opioid receptor

1. 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 & Bandy, 2000 Middaugh et al., 2003), as well as the expression of EtOH place conditioning (Middaugh & 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 & 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 & 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 & 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 & 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 & 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, 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 Burkard, 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, b). 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.

2. Materials and Methods

2.1 Animals

Adult female P rats from the 55th – 57th generations weighing 250–325g at the start of the experiment were used (n = 49). Rats were maintained on a 12-hr reversed light-dark cycle (lights off at 0900 hr). 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 were approved by the Indiana University Institutional Animal Care and Use Committee and are in accordance with the guidelines of the Institutional Care and Use Committee of the National Institute on Drug Abuse, National Institutes of Health, and the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council 1996).

Female rats were used in the current study because of availability. Past studies have indicated that male and female P rats express comparable levels of EtOH-seeking in the PSR model, and in response to cannabinoid agents of EtOH-seeking (Getachew, 2010). Estrus cycle determination was not tested in the current experiment. Vaginal smear testing is stressful to female rats during the initial days of estrus testing (Sfikakis et al., 1996). Vaginal smears in P rats can alter numerous alcohol-related behaviors (Rodd unpublished findings). Females in estrus may display greater drug –seeking behavior (Kippin et al., 2005), but testing for estrus also enhances drug-seeking behaviors in unselected rats (Nofrey et al., 2008). Therefore, estrus cycle was allowed to be a random factor that acted to increase within group variance.

2.2 Operant Procedures

Ethanol self-administration was conducted in standard two-lever operant chambers (Coulbourn Instruments) that were contained within ventilated, sound-attenuated environmental boxes. Within each chamber, two levers were located on the same wall 15 cm above a metal grid floor and 13 cm apart. A dipper trough was located immediately below each lever where a 0.1 ml dipper cup was presented to deliver response-contingent fluid. A small dipper trough light illuminated for the 4 s period while the dipper was raised. All operant chamber functions were controlled by a personal computer which, also recorded all lever responses and dipper presentations. Levers associated with 15% (v/v) EtOH or water were counterbalanced among rats but remained constant for each animal. Operant sessions were 60 min in duration and were conducted daily. Without any prior training, exposure to the experimental set-up, or access to EtOH, rats were placed into the operant chambers. The EtOH and water levers were maintained on a fixed-ratio 1 (FR1) schedule of reinforcement for the first 5 weeks. Subsequently, the reinforcement schedule on the EtOH lever was increased to FR3 in weeks 6 and 7 and to FR5 in weeks 8–10. Water was always reinforced on an FR1 schedule. The number of responses on the EtOH and water levers and the number of EtOH and water reinforcements were recorded. Following approximately 10 weeks of EtOH self-administration, P rats underwent extinction training whereby responses on. Rats were exposed to extinction training for 7 sessions. After extinction training, rats were maintained in the home cages for 21 days (imposed abstinence period). All rats were then returned to the operant chambers for PSR testing whereby both levers and dippers were once again active but EtOH and water remained absent. Rats were exposed to the PSR testing for 4 sessions.

2.3 The Effects of JDTic on responding for EtOH during the PSR test and during relapse and maintenance self-administration

JDTic was provided by Research Triangle Institute (Research Triangle Park, North Carolina). The drug was dissolved in saline. Seven days after the final extinction session (14 days prior to PSR testing), rats received a single s.c. injection of 0, 1, 3, or 10 mg/kg JDTic (n = 11–14/group) and were returned to their home cages and left undisturbed, except for normal husbandry activities, for the next 2 weeks. Rats then underwent 4 PSR test sessions after which, they were maintained in their home cages for an additional 7 days. Rats were then transferred to the operant chambers with both EtOH and water available for 60-min sessions to examine EtOH self-administration under relapse conditions. Note that the first EtOH relapse session occurred 25 days after the single JDTic administration.

Following EtOH relapse testing and an additional 16 consecutive daily sessions of operant access to EtOH and water, the effects of JDTic on EtOH maintenance responding was tested. Rats were administered a second dose of JDTic (0, 1, 3, or 10 mg/kg s.c.) 30 min prior to the first maintenance operant test session. Operant responding data were recorded for 17 consecutive sessions (days) following JDTic administration. Drug treatment groups for the second JDTic injection were counterbalanced based upon initial drug assignment. For example, rats receiving the 1 mg/kg JDTic dose at the first administration were equally divided between all 4 dose groups during maintenance testing.

2.4 Statistical Analyses

Operant responding (60 min) data were analyzed with a mixed factorial ANOVA with a between-subject factor of Dose and a repeated-measure of Session. For the PSR experiments, the baseline measure for the factor of Session was the average number of responses on the EtOH lever for the last 3 extinction sessions. For the deprivation studies, the baseline measure for the factor of Session was the average number of responses on the EtOH lever for the 3 sessions immediately prior to deprivation. Baseline measure for the maintenance experiment was the 3 sessions immediately prior to JDTic testing. When appropriate, Tukey’s b post-hoc comparisons were performed to determine individual differences.

3. Results

3.1 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 = 3.1; p < 0.001). Decomposing the interaction term by performing individual ANOVAs on each session indicated that there was a significant effect of Dose during the initial PSR session (F3, 45 = 13.5; p < 0.001). Post-hoc comparisons indicated that rats administered saline responded more during the initial PSR test session compared to rats administered 1, 3, or 10 mg/kg JDTic. There were no significant effects of dose during the other 3 PSR test sessions (p values > 0.37). Rats administered saline or 1 mg/kg JDTic exhibited significantly higher levels of responding on the EtOH lever during the initial PSR test session compared to extinction baseline levels (p values < 0.047). The low levels of responding on the water lever was significantly altered during PSR testing (Fig. 1b; Session (F4, 42 = 3.7; p = 0.01), Dose (F3, 45 = 1.3; p = 0.27), Session by Dose interaction (F12, 132 = 2.1; p = 0.023). However, these effects were observed because of an increase in responding on the water lever during the 2nd PSR session by rats administered 10 mg/kg JDTic, but t-tests revealed that this level of responding was not significantly different from baseline (p > 0.52).

Fig. 1.

Fig. 1

Fig. 1

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a. Depicts the mean (± SEM) responses/session on the lever previously associated with the delivery of EtOH in P rats (n = 11–14/group) given 0, 1, 3 or 10 mg/kg JDTic 14 days prior to the four PSR session. * indicates that vehicle treated rats responded significantly more on the EtOH lever during the 1st PSR session compared to extinction baseline levels and from all other groups.

b. Depicts the mean (± SEM) responses/session on the lever previously associated with the delivery of water in P rats (n = 11–14/group) given 0, 1, 3 or 10 mg/kg JDTic 14 days prior to the four PSR session.

JDTic administered 25 days prior to relapse testing reduced responding on the EtOH lever during the first relapse session (Fig. 2a). Examining the number of responses on the EtOH lever indicated a significant effect of Session (F4, 42 = 8.1; p < 0.001) and a Session by Dose interaction (F12, 132 = 3.4; p < 0.001). Decomposing the interaction term by performing individual ANOVAs on each session indicated that there was a significant effect of Dose during the initial two relapse sessions (p values < 0.05). Post-hoc comparisons indicated that rats administered saline responded more during the initial relapse test session compared to rats administered 1, 3, or 10 mg/kg JDTic. Post-hoc comparisons indicated that there were no significant differences between groups during the 2nd reinstatement session. There were no significant differences during the 3rd and 4th reinstatement sessions (p values > 0.31). In saline treated rats, the estimated EtOH intake during the 1st reinstatement session was greater than that observed prior to deprivation (1.7 ± 0.2 vs. 1.1 ± 0.1 g/kg). In the JDTic treated rats, the estimated EtOH intake during the 1st reinstatement session was reduced compared to that observed prior to deprivation (0.7 ± 0.2 vs. 1.1 ± 0.1 g/kg). Statistically, an analysis performed on estimated g/kg paralleled the findings observed for EtOH level responding.

Fig. 2.

Fig. 2

Fig. 2

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a. Depicts the mean (± SEM) responses/session by P rats on the EtOH lever under relapse conditions (n = 8/group) (n = 11–14/group) given 0, 1, 3 or 10 mg/kg JDTic 25 days prior to the first reinstatement session. * indicates that rats administered vehicle responded significantly more on the EtOH lever during the 1st reinstatement session compared to baseline levels and significantly more than all other rats.

b. Depicts the mean (± SEM) responses/session on the water lever during reinstatement of EtOH and water in P rats (n = 11–14/group) given 0, 1, 3 or 10 mg/kg JDTic 25 days prior to the first reinstatement session. * indicates that rats administered 10 mg/kg JDTic responded significantly more on the water lever during the 3rd and 4th reinstatement session compared to baseline levels and significantly more than all other rats.

With respect to the low water lever responding (Fig. 2b), there were significant effects of Session (F4, 42 = 6.5; p < 0.001) and a Session by Dose interaction (F12, 132 = 1.8; p = 0.049) under relapse conditions. The significant differences observed were based upon an increase in water responding, primarily during sessions 4 and 5, in rats administered 10 mg/kg JDTic. However, responding for water was low and this late experimental effect is most likely a spurious result produced by a floor effect. To date, reports have consistently indicated that administration of KOR agents do not alter water self-administration (June et al., 1998; 2004; Walker and Koob, 2008; Nealey et al., 2011).

3.2 Effects of JDTic Administration on EtOH Maintenance Responding

Administration of JDTic did not alter EtOH self-administration during maintenance testing. Examining the number of responses on the EtOH lever (Fig. 3a) for 17 consecutive sessions following the single administration of JDTic revealed no significant effect of Session (F17, 19 = 1.25; p = 0.32) Dose (F3, 35 = 1.0.; p = 0.39), or a Session by Dose interaction (F51, 63 = 1.2; p = 0.18). During this time period, administration of JDTic did not alter water responding (Fig. 3b; all p values > 0.14). The estimated intake prior to JDTic administration (estimated 1.2 ± 0.1 g/kg/session) did not differ from the estimated intake following JDTic treatment (estimated 1.3 ± 0.3 g/kg/session; all p values > 0.44).

Fig. 3.

Fig. 3

Fig. 3

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a. Depicts the mean (± SEM) responses/session on the EtOH lever during reinstatement of EtOH and water in P rats (n = 11–14/group) given 0, 1, 3 or 10 mg/kg JDTic 30 min prior to the first test session. JDTic did not alter EtOH self-administration during the 17 consecutive days of testing.

b. Depicts the mean (± SEM) responses/session on the water lever during reinstatement of EtOH and water in P rats (n = 11–14/group) given 0, 1, 3 or 10 mg/kg JDTic 30 min prior to the first test session. JDTic did not alter water self-administration during the 17 consecutive days of testing.

4. 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 EtOH relapse behavior. Previous research demonstrated that JDTic is pharmacologically active for greater than 21 days following a single subcutaneous injection (Beardsley et al., 2005) and up to 28 days following intra-gastric administration (Caroll et al., 2004). However, for the current research, it is uncertain whether the single administration of JDTic reduced EtOH-seeking and EtOH relapse behavior by preventing the development of the biological basis of these two phenomena, reducing the expression of these behaviors through a reduction in lever responding, or a combination of the two (development/expression). Given that JDTic did not significantly decrease operant responding on the water lever during both PSR and relapse testing nor did it produce a significant decrease in responding on the EtOH or water levers during maintenance responding, it would seem that the effect of JDTic on EtOH-seeking and EtOH-relapse is altering the biological basis of these two phenomena.

The lack of an effect of JDTic, at any dose, on maintenance responding for EtOH is similar to past findings that the KOR antagonist nor-binaltorphimine (nor-BNI) failed to alter operant responding for EtOH in rats and monkeys that were in a non-dependent state (Doyon et al., 2006; Williams and Woods, 1998). However, research has shown that nor-BNI does reduce operant responding for EtOH in dependent animals (Walker & Koob, 2008; Walker et al., 2011). The selective efficacy of nor-BNI was in contrast to that of naltrexone which, also reduced EtOH intake in non-dependent rats (Walker & Koob, 2008). Further, microinjections of KOR agents into the nucleus accumbens shell reduced EtOH consumption in rats with prior vapor chamber exposure to EtOH (Nealey et al., 2011). Thus, it has been hypothesized that the KOR system may not be integral to all processes associated with EtOH reward, but rather undergoes alterations as part of the neuroadaptations underlying EtOH dependence (Walker & Koob, 2008). It is not known if P rats under the current operant conditions developed EtOH dependence. However, ongoing research has made progress in elucidating the distinct neurochemical system(s) that contribute to EtOH-seeking and/or EtOH relapse. For instance, Rodd et al. (2006) reported that activation of the metabotropic glutamate (mGlu) 2/3 receptors inhibited the expression of EtOH-seeking as well as EtOH relapse behavior but did not alter maintenance EtOH self-administration (Rodd et al., 2006). This finding relates directly to the current research as KORs mediate the release of excitatory glutamate in the shell region of the ACB (Hjelmstad and Fields, 2001). On the other hand, exposure to an orexin-1 receptor antagonist selectively decreased EtOH relapse behavior immediately following abstinence but did not affect EtOH-seeking (Dhaher et al., 2010). Thus, the mechanisms underlying EtOH-seeking behavior and EtOH relapse behavior appear to be separable, and support the idea that different mechanisms may mediate relapse and ongoing alcohol drinking. Further research will be needed to tease apart the complex interaction between contributory neurochemical systems.

Alcohol-seeking (i.e., craving) and relapse possess a significant motivational learning component (Heinz et al., 2009). Several studies have shown that neutral discrete and contextual stimuli that have been previously associated with alcohol, serve to enact behaviors that were associated with alcohol consumption (i.e. operant responding) without alcohol being present or available (for review see: Heinz et al., 2009). Research attempting to correlate such learned associations with neurological functioning has shown motivational drug learning/associations to be heavily dependent on neural signaling within the extended mesolimbic DA reward pathway (Spanagel & Weiss, 1999). Within the mesolimbic pathway, there are several secondary neurochemical/receptor systems that have been shown to alter DA release, in turn altering drug related behaviors (for review see: McBride et al., 1999). For instance, KORs have been found to regulate the release of DA within the ACB. KOR agonists have been found to decrease DA efflux in the ACB (DiChiara & Imperato, 1988; Donzanti et al., 1992; Spanagel et al., 1992) whereas a limited amount of research suggests that KOR antagonists, such as nor-BNI, increase basal DA levels in the ACB (Maisonneuve et al., 1994; Spanagel et al., 1992). Furthermore, animals repeatedly exposed to EtOH exhibit an enduring increase in DYN tissue levels (Lindholm et al., 2000) as well as a greater sensitivity to nor-BNI compared to control animals (Lindholm et al., 2007). With respect to the current data, it is possible that JDTic reduced EtOH-seeking and -relapse by altering the mesolimbic DA system via KOR functioning, which, in turn altered learned EtOH associations/behaviors. However, it is unlikely that mediation of DA signaling by the KOR is solely responsible for the decrease in both EtOH-relapse and -seeking observed in the current study.

The KOR system has been hypothesized to oppose the action of the MOR system in a modulatory manner (Nealy et al., 2011; Walker & Koob, 2008; Wee & Koob, 2010). The action of KOR agonists in inhibiting DA release within the ACB is in direct contrast to the action of MOR agonists which increase accumbal DA levels through direct action within the ACB (Di Chiara & Imperato, 1998) as well as the disinhibition of DA neurons in the VTA (Johnson & North, 1992). This concept of KOR functioning opposing MOR functioning is an important focus in the field of addiction research as it is theorized that the primary reinforcement of virtually every major drug of abuse within the opioid system occurs, either directly or indirectly, through the MOR system (for review see: Contet et al., 2004). Much like major drugs of abuse, MOR agonists produce reinforcing effects and are readily self-administered directly into the VTA (Devine & Wise, 1994) and produce conditioned place preferences in rodents (for review see: Shippenberg et al., 1992). On the other hand, KOR agonists reduce the rewarding properties of intra-cranial self-stimulation (Todtenkopf et al., 2004) and produce place aversions (Mucha & Herz, 1985). However, recent research suggests that the KOR system does possess a therapeutic benefit beyond modulating the activity of the MOR system on DA release. Clinical research has found that the combined pharmacotherapy of buprenorphine (partial MOR agonist/KOR antagonist) and naltrexone is more efficacious in patients suffering from opiate addiction than naltrexone alone (Gerra et al., 2006). The combination of naltrexone and buprenorphine significantly decreases the MOR activity while maintaining KOR antagonism (Gerra et al., 2006) further supporting a role for selective KOR antagonism in drug addiction treatment.

The current study showed that JDTic was effective at decreasing EtOH-seeking and EtOH relapse in an animal model for alcoholism. While this effect did not carry over to EtOH maintenance responding, it is believed that JDTic may represent a novel pharmacological compound that will aid in the development of treatments for individuals that are EtOH-dependent and/or suffering from alcoholism. A large majority of individuals suffering from alcoholism, that attempt abstinence, suffer relapse while attempting detoxification (Heinz et al., 2009). The profile of a KOR antagonist such as JDTic would be efficacious in the population of human alcoholics in many ways. Both stress and depression contribute to EtOH craving as well as relapse rates in human alcoholics (Farren & McElroy, 2010; Sinha, 2007). Given the anxiolytic and antidepressive properties of KOR antagonists (Knoll & Carlezon, 2010), such a pharmacological profile would be advantageous for treating comorbid dysphoric states associated with alcohol depencence and perhaps prevent stress-precipitated alcohol relapse. Additionally, since JDTic, as well as other KOR antagonists possess an extended period of action and are in some cases additive in nature, the compliance of individuals taking the drug may be higher due to the fewer number of doses needed. Thus, the development of a pharmacotherapy based on the profile of JDTic/KOR antagonists might possess a greater ability to decrease relapse rates in individuals suffering from alcoholism/alcohol abuse.

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.

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 completion of this research.

Footnotes

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