Elsevier

Drug and Alcohol Dependence

Volume 134, 1 January 2014, Pages 115-122
Drug and Alcohol Dependence

Modafinil restores methamphetamine induced object-in-place memory deficits in rats independent of glutamate N-methyl-d-aspartate receptor expression

https://doi.org/10.1016/j.drugalcdep.2013.09.018Get rights and content

Abstract

Background

Chronic methamphetamine (meth) abuse in humans can lead to various cognitive deficits, including memory loss. We previously showed that chronic meth self-administration impairs memory for objects relative to their location and surrounding objects. Here, we demonstrate that the cognitive enhancer, modafinil, reversed this cognitive impairment independent of glutamate N-methyl-d-aspartate (GluN) receptor expression

Methods

Male, Long-Evans rats underwent a noncontingent (Experiment 1) or contingent (Experiment 2) meth regimen. After one week of abstinence, rats were tested for object-in-place recognition memory. Half the rats received either vehicle or modafinil (100 mg/kg) immediately after object familiarization. Rats (Experiment 2) were sacrificed immediately after the test and brain areas that comprise the key circuitry for object in place performance were manually dissected. Subsequently, glutamate receptor expression was measured from a crude membrane fraction using Western blot procedures.

Results

Saline-treated rats spent more time interacting with the objects in changed locations, while meth-treated rats distributed their time equally among all objects. Meth-treated rats that received modafinil showed a reversal in the deficit, whereby they spent more time exploring the objects in the new locations. GluN2B receptor subtype was decreased in the perirhinal cortex, yet remained unaffected in the prefrontal cortex and hippocampus of meth rats. This meth-induced down regulation occurred whether or not meth experienced rats received vehicle or modafinil.

Conclusions

These data support the use of modafinil for memory impairment in meth addiction. Further studies are needed to elucidate the neural mechanisms of modafinil reversal of cognitive impairments.

Introduction

Abstinence from prolonged methamphetamine (meth) abuse is associated with persistent cognitive deficits, even after cessation of drug use. In humans, chronic meth abuse can lead to some deficits in executive function, information processing, and memory (Scott et al., 2007). When cognitive impairments do occur, memory deficits are among the most prominent and recurrent problems with human meth addicts (Ersche et al., 2006, Scott et al., 2007). Further, meth addiction is characterized as a chronically relapsing disorder, and memory impairments can exacerbate relapse episodes (Simon et al., 2004). Ideally, pharmacological treatments that target meth addiction will address both the cognitive and motivational factors driving relapse.

Modafinil is a cognitive enhancing drug approved for narcolepsy treatment and chronic excessive sleepiness during waking hours. Modafinil also alleviated meth-induced cognitive impairments during withdrawal (Ling et al., 2006, Minzenberg and Carter, 2008, Vocci and Appel, 2007), improved memory (Ghahremani et al., 2011, Kalechstein et al., 2010), and increased attention (Dean et al., 2011) in meth dependent participants. Of additional importance, modafinil did not result in euphoria, craving, or medical risks when given to meth addicts (Dackis et al., 2003, De La Garza et al., 2009, McGaugh et al., 2009). Abstinence rates generally increased in meth users treated with modafinil. Nevertheless, the full efficacy of modafinil as an anti-relapse medication remains inconclusive due to compliance issues in one study (Anderson et al., 2012) and sample size in others (Heinzerling et al., 2010, Lee et al., 2013, Shearer et al., 2009).

In preclinical animal models of relapse, we have collectively demonstrated that both acute and chronic modafinil decreased meth seeking in rats (Reichel and See, 2010, Reichel and See, 2012). Encouraged by this corroboration between clinical and preclinical findings, we also tested whether modafinil would ameliorate meth-induced memory impairments in a rat model of episodic memory. While not all components (i.e., what, where, and/or when) of episodic memory are testable in rats (Ennaceur, 2010), object recognition tasks can assess some elements depending on specific task parameters (Dickerson and Eichenbaum, 2010, Ennaceur, 2010, Warburton and Brown, 2009). These one trial tasks rely on the innate tendency of rodents to explore environmental novelty (Berlyne, 1950), rather than heuristic learning or changes in the motivational state of the subject (Ennaceur and Delacour, 1988). An object-in-place (OIP) task requires subjects to concurrently remember object and place information and incorporates elements of “what” and “where” of episodic memory (Ennaceur, 2010). As such, this task is ideally suited to study meth-induced episodic memory changes in rats, which incidentally are particularly compromised in human meth addicts (Iudicello et al., 2011, Kalechstein et al., 2003, Simon et al., 2004). We recently demonstrated that experimenter administered and extended (6 h) access to self-administered meth impaired performance on the OIP tasks in both male and female rats (Reichel et al., 2012a, Reichel et al., 2012b).

The extended access self-administration model emulates several characteristics of drug addiction, including the escalation of drug intake over time (Ahmed et al., 2000, Kitamura et al., 2006), compulsive drug seeking (Vanderschuren and Everitt, 2004), and increased motivation (Paterson and Markou, 2003). Further, this procedure also impacts other cognitive domains compromised in meth addicts, such as impulsivity (Dalley et al., 2007), attention (Parsegian et al., 2011), and sensory motor gating (Hadamitzky et al., 2011). Therefore, one purpose of this study was to determine whether modafinil would reverse meth-induced cognitive deficits in OIP recognition memory using both experimenter and contingent meth delivery.

The neural circuitry for OIP memory relies on interactions between the perirhinal cortex, prefrontal cortex, and hippocampus (Barker et al., 2007), but the neurochemical bases for this memory process have not been clearly defined. Glutamatergic neurotransmission may be a key factor, as it has been extensively implicated in a variety of memory processes (Riedel et al., 2003). Glutamate receptors are divided into ionotropic and metabotropic subtypes. Of particular interest are glutamate N-methyl-d-aspartate (GluN) receptors, as blockade of GluN receptors in the prefrontal and perirhinal cortices before sampling objects impaired object-in-place associative memory following a 1-h retention interval (Barker and Warburton, 2008). Further, selective antagonism of the GluN receptor subtype 2B blocked perirhinal long-term depression (Massey et al., 2004), which is essential for novelty recognition (Massey and Bashir, 2007).

As an initial step in determining the potential glutamatergic mechanisms underlying meth-induced OIP memory deficits, we used Western blotting techniques to quantify the GluN receptor subtypes, GluN1, GluN2A, and GluN2B in the OIP circuitry in rats following withdrawal from extended access to self-administered meth. Modafinil does not directly bind to GluN receptors (Nguyen et al., 2011), but does modify GluN receptor complexes (Sase et al., 2012). Thus, we also determined whether modafinil would affect the expression of GluN receptors in the prefrontal cortex, perirhinal cortex, and hippocampus.

Section snippets

Subjects

One hundred male Long-Evans rats (Charles-River) weighing 250–300 g at the time of delivery were individually housed in a temperature- and humidity-controlled vivarium on a reversed 12:12 light-dark cycle. Rats received ad libitum water throughout the study and 25 g of standard rat chow (Harlan, Indianapolis, IN, USA) daily until self-administration stabilized, at which time animals were maintained ad libitum. Procedures were conducted in accordance with the “Guide for the Care and Use of

Noncontingent meth-induced deficits in OIP recognition memory

Fig. 1 shows recognition indices for rats given noncontingent administration of meth (4 × 4 mg/kg, IP) or saline and then tested with either modafinil (100 mg/kg, IP) or vehicle. Prior to initial testing, exploration values for all groups were equivalent on the familiarization sessions (saline/vehicle, 0.51 ± 0.03; saline/modafinil, 0.48 ± 0.05; meth/vehicle, 0.51 ± 0.05; meth/modafinil, 0.55 ± 0.04). Further, these values did not differ from chance exploration of the objects. On the OIP test (Fig. 1),

Discussion

A single day, experimenter delivered meth regimen and a chronic escalating meth self-administration procedure impaired memory for objects in a particular place (Reichel et al., 2012b and current report). Here, we further demonstrated that modafinil could restore memory function during abstinence from either meth regimen. Restoration of memory function may be a crucial component for treatment of meth addiction, as human meth addicts often report prominent and recurrent memory problems (Ersche et

Author disclosure

Role of the funding sources: The National Institutes of Health (NIH) provided funding for this study. The NIH had no involvement in study design, data collection, analysis, and interpretation. Further the funding source did not have a role in writing the research report or the decision to submit the paper for publication.

Contributors: Author CMR designed the experiments, assisted in conducting the behavioral and neurochemical experiments, and writing the manuscript. Author MGG conducted the

Acknowledgements

This research was supported by National Institute on Drug Abuse grants DA022658, DA033049, and F32DA02934, and NIH grant C06 RR015455. MGG and LAR were supported by the Summer Undergraduate Research Program (SURP) at MUSC. The authors thank Stacey Sigmon, Weilun Sun, Marek Schwendt, Rebecca Mendel, and Shannon Ghee for technical assistance.

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