Modafinil restores methamphetamine induced object-in-place memory deficits in rats independent of glutamate N-methyl-d-aspartate receptor expression
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.
References (73)
- et al.
Persistent increase in the motivation to take heroin in rats with a history of drug escalation
Neuropsychopharmacology
(2000) - et al.
Modafinil for the treatment of methamphetamine dependence
Drug Alcohol Depend.
(2012) - et al.
A sensitizing regimen of methamphetamine causes impairments in a novelty preference task of object recognition
Behav. Brain Res.
(2006) - et al.
Short toxic methamphetamine schedule impairs object recognition task in male rats
Brain Res.
(2002) - et al.
Time-course of methamphetamine-induced neurotoxicity in rat caudate-putamen after single-dose treatment
Brain Res.
(2000) - et al.
Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study
Drug Alcohol Depend.
(2003) One-trial object recognition in rats and mice: methodological and theoretical issues
Behav. Brain Res.
(2010)- et al.
A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data
Behav. Brain Res.
(1988) - et al.
The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission
Neurosci. Lett.
(1998) - et al.
Extended access to methamphetamine self-administration affects sensorimotor gating in rats
Behav. Brain Res.
(2011)
Randomized, double-blind, placebo-controlled trial of modafinil for the treatment of methamphetamine dependence
Drug Alcohol Depend.
Reinstatement of methamphetamine seeking in male and female rats treated with modafinil and allopregnanolone
Drug Alcohol Depend.
Action of modafinil through histaminergic and orexinergic neurons
Vitam. Horm.
Varied access to intravenous methamphetamine self-administration differentially alters adult hippocampal neurogenesis
Biol. Psychiatry
Long-term depression: multiple forms and implications for brain function
Trends Neurosci.
A neurotoxic regimen of methamphetamine impairs novelty recognition as measured by a social odor-based task
Behav. Brain Res.
Methamphetamine self-administration produces attentional set-shifting deficits and alters prefrontal cortical neurophysiology in rats
Biol. Psychiatry
Methamphetamine-induced changes in the object recognition memory circuit
Neuropharmacology
Glutamate receptor function in learning and memory
Behav. Brain Res.
The effect of relapse on cognition in abstinent methamphetamine abusers
J. Subst. Abuse Treat.
Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder
Biol. Psychiatry
Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine
Brain Res.
NMDA receptor plasticity in the perirhinal and prefrontal cortices Is crucial for the acquisition of long-term object-in-place associative memory
J. Neurosci.
Recognition memory for objects, place, and temporal order: a disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex
J. Neurosci.
When is the hippocampus involved in recognition memory?
J. Neurosci.
The different effects on recognition memory of perirhinal kainate and NMDA glutamate receptor antagonism: implications for underlying plasticity mechanisms
J. Neurosci.
Impaired object recognition memory following methamphetamine, but not p-chloroamphetamine- or d-amphetamine-induced neurotoxicity
Neuropsychopharmacology
Methamphetamine influences on recognition memory: comparison of escalating and single-day dosing regimens
Neuropsychopharmacology
Novelty and curiosity as determinants of exploratory behaviour
Br. J. Psychol.
Medial frontal cortex mediates perceptual attentional set shifting in the rat
J. Neurosci.
A new form of long-term depression in the perirhinal cortex
Nat. Neurosci.
Enduring deficits in sustained visual attention during withdrawal of intravenous methylenedioxymethamphetamine self-administration in rats: results from a comparative study with d-amphetamine and methamphetamine
Neuropsychopharmacology
Evaluation of modafinil effects on cardiovascular, subjective, and reinforcing effects of methamphetamine in methamphetamine-dependent volunteers
Drug Alcohol Depend.
Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans
J. Stud. Alcohol Drugs
A meta-analytic review of the sensitivity of the Wisconsin card sorting test to frontal and lateralized frontal brain damage
Neuropsychology
The episodic memory system: neurocircuitry and disorders
Neuropsychopharmacology
Cited by (23)
Perirhinal to prefrontal circuit in methamphetamine induced recognition memory deficits
2023, NeuropharmacologyNeurotoxicity of methamphetamine: Main effects and mechanisms
2021, Experimental NeurologyCitation Excerpt :Importantly, there is a suggestion that recovery of cognitive functions can occur in conjunction with improvement in impulsivity and self-regulation after a psychological intervention with working memory training during in-patient treatment for methamphetamine use disorder (Brooks et al., 2016). These observations are supported by pre-clinical studies that have reported improvement in cognitive functions after administration of pharmacological compounds such as ZSET1446, a T-type calcium channel activator (Ito et al., 2007), silibinin, a natural polyphenolic flavonoid (Lu et al., 2010), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) a mGluR5 allosteric modulator (Reichel et al., 2011) and modafinil, a dopamine uptake blocker (Kalechstein et al., 2010; González et al., 2014; Reichel et al., 2014). The ameliorating effect of ZSET1446 (azaindolizinone derivative, a T-type calcium channel activator) and modafinil (2-[(diphenylmethyl) sulfinyl] acetamide) on METH-induced impairment of recognition memory is mediated via activation of ERK cascade (Ito et al., 2007; González et al., 2014).
Neural mechanisms underlying incubation of methamphetamine craving: A mini-review
2020, Pharmacology Biochemistry and BehaviorCitation Excerpt :It is of note that Schwendt et al. (2012) also demonstrated that extinction training after Meth self-administration reverses the decrease of mGlu2/3 in NAc and DS as described above, which supports the notion that dissociable neural mechanisms underlie extinction training versus abstinence after drug self-administration (Wolf, 2016; Reiner et al., 2019; Sutton et al., 2003; Knackstedt et al., 2010; Shaham and Hope, 2005). In addition, Reichel et al. (2014) and Scofield et al. (2015) reported that PRH, on withdrawal day 7, exhibits decreased GluN2B expression in crude membrane fraction, decreased GluN2B surface expression and inability for LTD induction, an effect reversed by an NMDA receptor agonist. Furthermore, on withdrawal day 8, Mishra et al. (2017) demonstrated decreased AMPA/NMDA ratio in mPFC, possibly contributed by increased NMDA-mediated currents and increased GluN2B surface expression.
Extended access self-administration of methamphetamine is associated with age- and sex-dependent differences in drug taking behavior and recognition memory in rats
2020, Behavioural Brain ResearchCitation Excerpt :These discrepancies may be explained by the region(s) of mPFC that were assessed. The regions of mPFC collected by Mishra and colleagues [68] were not specified, whereas the study by Reichel and colleagues [69] and the current report analyzed the prelimbic and infralimbic subregions of the mPFC together in a single homogenate. We chose not to separately analyze these subregions because of our lab’s previous work showing no difference between them following adolescent or adult AMPH exposure [23].
Glutamate Signalling in Object Novelty Recognition Memory Tests
2018, Handbook of Behavioral Neuroscience