κ Opioid receptors in the nucleus accumbens shell mediate escalation of methamphetamine intake

Abstract

Given that the κ opioid receptor (KOR) system has been implicated in psychostimulant abuse, we evaluated whether the selective KOR antagonist norbinaltorphimine dihydrochloride (nor-BNI) would attenuate the escalation of methamphetamine (METH) intake in an extended-access self-administration model. Systemic nor-BNI decreased the escalation of intake of long-access (LgA) but not short-access (ShA) self-administration. nor-BNI also decreased elevated progressive-ratio (PR) breakpoints in rats in the LgA condition and continued to decrease intake after 17 d of abstinence, demonstrating that the effects of a nor-BNI injection are long lasting. Rats with an ShA history showed an increase in prodynorphin immunoreactivity in both the nucleus accumbens (NAc) core and shell, but LgA animals showed a selective increase in the NAc shell. Other cohorts of rats received nor-BNI directly into the NAc shell or core and entered into ShA or LgA. nor-BNI infusion in the NAc shell, but not NAc core, attenuated escalation of intake and PR responding for METH in LgA rats. These data indicate that the development and/or expression of compulsive-like responding for METH under LgA conditions depends on activation of the KOR system in the NAc shell and suggest that the dynorphin-KOR system is a central component of the neuroplasticity associated with negative reinforcement systems that drive the dark side of addiction.

Keywords: dynorphin; escalation; kappa opioid receptors; methamphetamine; nucleus accumbens; substances of abuse.

Conflict of interest statement

The authors have no financial conflicts to disclose.

Copyright © 2015 the authors 0270-6474/15/354296-10$15.00/0.

Figures

Figure 1.

Schematic representation of experimental procedures used in Experiments 1–3.

Figure 2.

A, Rats that received pretreatment with nor-BNI showed an attenuation of METH intake and a significant blockade of escalation of METH intake during the first hour of self-administration during the escalation phase of the experiment. Pairwise comparison tests determined that vehicle-pretreated rats significantly escalated their intake by session 9 and maintained escalated intake until the final session (session 1 compared with session 9, 10, or 11, ***p < 0.001). nor-BNI-treated rats failed to demonstrate significant escalation of intake over 11 consecutive sessions. B, Pretreatment with nor-BNI decreased initial METH intake and significantly blocked the escalation of METH intake during LgA sessions. Pairwise comparison tests indicated that vehicle-treated rats escalated intake by session 5 (session 1 compared with session 5, *p < 0.05) and continued to escalate their intake until the final session (session 1 compared with session 9, 10, or 11, ***p < 0.001), but nor-BNI-treated rats failed to demonstrate escalation of intake over 11 consecutive sessions. Systemic administration of the KOR antagonist nor-BNI attenuated the elevated PR breakpoints associated with extended-access self-administration. nor-BNI-treated (30 mg/kg) rats were tested under a PR schedule after escalation (C) and after abstinence (D) to evaluate their motivation to work for METH injections. C, During PR1, rats with a history of extended access showed increased PR breakpoints, whereas nor-BNI decreased PR breakpoints. Pairwise comparison tests indicated that both nor-BNI-treated and vehicle-treated rats with a history of LgA exhibited increased PR breakpoints compared with ShA rats (#p < 0.05, ##p < 0.01), and nor-BNI decreased the motivation for METH in both ShA and LgA conditions (**p < 0.01, ***p < 0.001). D, In PR2, nor-BNI decreased the motivation for METH only in the LgA condition, demonstrating a selective effect in rats with an escalated PR breakpoint. Pairwise comparison tests indicated that only vehicle-treated rats with a history of LgA demonstrated increased PR breakpoints compared with ShA rats (##p < 0.01), and nor-BNI decreased the motivation for METH only in the LgA condition (***p < 0.001, n = 5–6 per group).

Figure 3.

Extended access to METH self-administration increases prodynorphin immunoreactivity in both the core and shell subdivisions of the NAc. A, Rats with a history of extended access exhibited escalation of METH intake during the first hour of self-administration. Post hoc tests indicated that LgA rats escalated intake by session 11 (***p < 0.0001) and continued to escalate their intake until the final session. B, Rats with a history of extended access exhibited escalation of METH intake during the entire 6 h sessions. Post hoc tests indicated that LgA rats escalated intake by session 9 (***p < 0.0001) and continued to escalate their intake until the final session. C, Representative photographs of prodynorphin immunoreactivity in the ventral striatum. D, Representative illustration that shows the designated boundaries used for the analysis of immunoreactivity in striatal subregions as determined by Paxinos and Watson (2005). E, Photograph that shows a high-resolution representative image of prodynorphin immunoreactivity in the dorsal NAc shell subregion for the LgA condition. F, Rats with a history of either ShA or LgA showed an elevation in prodynorphin immunoreactivity (IR) in the NAc core (*p < 0.05, **p < 0.01), whereas only extended access to METH self-administration selectively increased prodynorphin immunoreactivity in the NAc shell (*p < 0.05, n = 6 per group). aca, anterior part of anterior commissure; CPu, caudate–putamen; Ctx, cortex; LNAcSh, lateral nucleus accumbens shell subregion for the LgA condition; LV, lateral ventricle; NAcSh, NAc shell subregion; PDYN, prodynorphin.

Figure 4.

Intra-NAc shell administration of nor-BNI attenuated the escalation of METH intake associated with extended-access self-administration. A, Pretreatment with intra-NAc shell nor-BNI (4 μg/0.5 μl per side) blocked the escalation of METH intake during the first hour of self-administration in LgA rats during escalation. Pairwise comparison tests indicated that aCSF-infused rats escalated intake by session 7 (**p < 0.001) and continued to escalate their intake until the final session (**p < 0.01), but nor-BNI-pretreated rats failed to exhibit escalation of intake over 10 consecutive sessions. B, Pretreatment with intra-NAc shell nor-BNI blocked the escalation of METH intake during the 6 h sessions. Pairwise comparison tests indicated that aCSF-infused rats escalated intake by session 8 and continued to escalate their intake until the final session (**p < 0.01), but nor-BNI-pretreated rats failed to exhibit escalation of intake over 10 consecutive sessions. Intra-NAc shell administration of nor-BNI attenuated the elevated PR breakpoints associated with extended-access self-administration. nor-BNI-pretreated (4 μg/0.5 μl per side) rats were tested on a PR schedule after escalation (C) and after abstinence to evaluate their motivation to work for METH injections. C, During PR1, rats with a history of extended access showed increased PR breakpoints, whereas nor-BNI decreased PR breakpoints. Pairwise comparison tests indicated that aCSF-infused rats with a history of LgA exhibited increased PR breakpoints compared with ShA rats (###p < 0.001), and nor-BNI decreased the motivation for METH selectively in the LgA condition (***p < 0.001). D, In PR2, nor-BNI decreased the motivation for METH only in the LgA condition, exhibiting a selective effect in rats with an escalated PR breakpoint. Pairwise comparison tests indicated that aCSF-infused rats with a history of LgA demonstrated increased PR breakpoints compared with ShA rats (###p < 0.001), and nor-BNI decreased the motivation for METH only in the LgA condition (***p < 0.001, n = 5–6 per group). E, Illustration shows cannula placements for Experiment 3, in which black lines represent successful placements within the NAc shell subregion, and black × symbols represent missed placements outside the region of interest (range, +1.70–1.60 mm relative to bregma).

Figure 5.

Intra-NAc core administration of nor-BNI did not alter the escalation of METH intake associated with extended-access self-administration. A, Pretreatment with intra-NAc core nor-BNI (4 μg/0.5 μl per side) failed to alter the escalation of METH intake during 6 h of self-administration in LgA rats. B, Illustration shows cannulae placement. Black lines represent successful placements within the NAc core subregion, and black × symbols represent missed placements outside the region of interest (range, +1.70–1.60 mm relative to bregma).