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Chronic modafinil effects on drug-seeking following methamphetamine self-administration in rats

Carmela M. Reichel , Ronald E. See
DOI: http://dx.doi.org/10.1017/S1461145711000988 919-929 First published online: 1 August 2012

Abstract

Acute administration of the cognitive enhancing drug, modafinil (Provigil®), reduces methamphetamine (Meth) seeking following withdrawal from daily self-administration. However, the more clinically relevant effects of modafinil on Meth-seeking after chronic treatment have not been explored. Here, we determined the impact of modafinil on Meth-seeking after chronic daily treatment during extinction or abstinence following Meth self-administration. Rats self-administered intravenous Meth during daily 2-h sessions for 14 d, followed by extinction sessions or abstinence. During this period, rats received daily injections of vehicle, 30, or 100 mg/kg modafinil and were then tested for Meth-seeking via cue, Meth-primed, and context-induced reinstatement at early and late withdrawal time-points. We found that chronic modafinil attenuated relapse to a Meth-paired context, decreased conditioned cue-induced and Meth-primed reinstatement, and resulted in enduring reductions in Meth-seeking even after discontinuation of treatment. Additionally, we determined that only a very high dose of modafinil (300 mg/kg) during maintenance of self-administration had an impact on Meth intake. These results validate and extend clinical and preclinical findings that modafinil may be a viable treatment option for Meth addiction.

Key words
  • Abstinence
  • methamphetamine
  • modafinil
  • reinstatement
  • relapse

Introduction

Methamphetamine (Meth) addiction is a chronic relapsing disorder that is highly treatment resistant. To date, no approved medications exist for Meth dependence, although multiple compounds have been suggested (Karila et al. 2010; Ling et al. 2006; Rose & Grant, 2008; Vocci & Appel, 2007). Of these drugs, modafinil shows good potential as a pharmacotherapy for Meth addiction (McGaugh et al. 2009; Shearer et al. 2009). Modafinil is currently approved for the treatment of narcolepsy and excessive sleepiness during waking hours (Keating & Raffin, 2005). In regards to Meth addiction, modafinil has been found to alleviate withdrawal symptoms such as impaired cognition, poor impulse control, and altered mood (Ling et al. 2006; Minzenberg & Carter, 2008; Vocci & Appel, 2007). Clinical findings have determined that modafinil is safe to use in Meth addicts and does not result in medical risks, craving, or euphoria (Dackis et al. 2003; De La Garza et al. 2009; McGaugh et al. 2009). In Meth addicts, modafinil produces a trend towards more negative urine samples (McGaugh et al. 2009; Shearer et al. 2009). Specifically, Shearer and colleagues (2009) reported that modafinil reduced positive urine samples and self-reported incidences of use relative to placebo during a 4-wk period of assessment (Shearer et al. 2009); however, this reduction was transient and not replicated by others (McGaugh et al. 2009). Additionally, modafinil improves memory in Meth-dependent participants, indicating efficacy as a cognitive-enhancing drug for Meth addicts (Ghahremani et al. 2011; Kalechstein et al. 2010).

Although modafinil acts on multiple neurotransmitter systems, the exact mechanisms remain unclear (Minzenberg & Carter, 2008). Modafinil does bind to dopamine transporters, consequently inhibiting dopamine uptake (Madras et al. 2006; Mignot et al. 1994; Volkow et al. 2009; Zolkowska et al. 2009). However, modafinil's binding affinity is weak relative to other reuptake inhibitors such as cocaine, GRB12909, methylphenidate, and benztropine (Madras et al. 2006; Zolkowska et al. 2009). Additionally, clinical data have shown that the abuse liability and reinforcing effects of modafinil are low (Malcolm et al. 2002; Rush et al. 2002; Vosburg et al. 2009). The preclinical data also indicate little abuse liability, as modafinil does not lead to a conditioned place preference or maintain self-administration in rats (Deroche-Gamonet et al. 2002).

Encouraged by these clinical studies with modafinil, we recently tested the effects of acute modafinil on reinstatement of Meth-seeking in a rat model of relapse (Reichel & See, 2010). Modafinil blocked Meth-primed reinstatement following extinction and failed to reinstate Meth-seeking when administered alone. However, the ability of modafinil to modify Meth-taking was not addressed. Acute injections of modafinil failed to alter cocaine self-administration in rats (Deroche-Gamonet et al. 2002), but modafinil did maintain self-administration in cocaine-experienced primates (Gold & Balster, 1996). As such, one purpose of the current study was to determine whether modafinil alters the reinforcing effects of Meth during maintenance of Meth self-administration and to compare Meth-seeking after administration of modafinil, Meth, and cocaine during reinstatement tests.

Reinstatement tests occur following extinction of a conditioned response or instrumental action. That is, the Pavlovian signal or instrumental response is repeatedly presented without its associated reinforcer. The traditional extinction-reinstatement model of relapse is the most commonly used in rodents (Shaham et al. 2003). Most treatment options in humans do not explicitly extinguish drug-associated cues; thus, to increase the translational usefulness of rodent models, abstinence-relapse models have been tested (Reichel & Bevins, 2009). Both models require study, since the incorporation of extinction training into a withdrawal period changes the behavioural profile (Neisewander et al. 2000; Reichel et al. 2011; Zavala et al. 2007) and neuroadaptations related to relapse (Fuchs et al. 2006; Knackstedt et al. 2010; Schmidt et al. 2001; Self, 2004; Sutton et al. 2003). Both models involve a period of maintained drug self-administration for intravenous (i.v.) infusions. In the extinction-reinstatement model, self-administration is followed by extinction trials, whereby operant responding decreases in the drug-associated context when lever pressing no longer results in reinforcement. Drug-seeking is reinstated by exposure to a priming injection of drug, stress, or previously drug-associated cues. In the abstinence-relapse model, the operant behaviour (e.g. lever pressing) is not extinguished; rather subjects are kept away from the self-administration environment for a predetermined interval. The drug-reinforced associations (i.e. lever presses, environmental context, and conditioned cues) are fully intact at the time of relapse testing, having never been experienced in the absence of the drug. Indeed, acute administration of modafinil also reduced relapse in an abstinence-relapse model (Reichel & See, 2010).

While single-injection protocols provide potential insight into pharmacological treatment options for addiction (Yahyavi-Firouz-Abadi & See, 2009), treatment programmes typically administer anti-relapse medications on a repeated basis, rather than acute injections as used in most preclinical rodent models. In fact, modafinil has typically been given to Meth addicts daily for 4–12 wk when treatment outcomes are the primary measures (Heinzerling et al. 2010; McGaugh et al. 2009; Shearer et al. 2009). Therefore, to more closely emulate human treatment conditions, we used chronic modafinil treatment protocols during withdrawal from self-administered Meth. Specifically, we compared the impact of chronic modafinil treatment during extinction and abstinence on subsequent Meth-seeking at early and late withdrawal points. Based on prior clinical trials and the ability of acute modafinil to reduce reinstatement and relapse, we predicted that chronic modafinil should have a more pronounced and lasting effect on Meth-seeking. Further, because modafinil is a cognitive enhancing drug, protection from relapse should be more evident in combination with extinction, since extinction involves new learning of an altered contingency (Bouton, 2002; Quirk & Mueller, 2008).

Methods

Subjects

Seventy-four male Long-Evans rats (Charles River, USA) weighing 250–300 g at the time of delivery were housed on a reversed 12-h light/dark cycle (lights on 06:00 hours) in a temperature- and humidity-controlled vivarium. Rats were individually housed and received ad libitum water throughout the study and 25 g of standard rat chow (Harlan, 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 Laboratory Rats’ (Institute of Laboratory Animal Resources on Life Sciences, National Research Council) and approved by the IACUC of the Medical University of South Carolina.

Surgery

Anaesthesia consisted of intraperitoneal (i.p.) injections of ketamine (66 mg/kg; Vedco Inc., USA), xylazine (1.3 mg/kg; Lloyd Laboratories, USA), and equithesin (0.5 ml/kg; sodium pentobarbital 4 mg/kg, chloral hydrate 17 mg/kg, and 21.3 mg/kg magnesium sulfate heptahydrate dissolved in 44% propylene glycol, 10% ethanol solution). Ketorolac (2.0 mg/kg i.p.; Sigma, USA) was given just prior to surgery as an analgesic. One end of a silastic catheter was inserted 33 mm into the external right jugular and secured with 4.0 silk sutures. The other end ran subcutaneously and exited from a small incision just below the scapula. This end attached to an infusion harness (Instech Solomon, USA) that provided access to an external port for i.v. drug delivery. An antibiotic solution of cefazolin (10 mg/0.1 ml; Schein Pharmaceuticals, USA) was given post-surgery and during recovery along with 0.1 ml 70 U/ml heparinized saline. During self-administration, rats received an i.v. infusion (0.1 ml) of 10 U/ml heparinized saline (Elkins-Sinn, USA) before each session. After each session, catheters were flushed with cefazolin and 0.1 ml 70 U/ml heparinized saline. Catheter patency was periodically verified with methohexital sodium (10 mg/ml dissolved in 0.9% physiological saline; Eli Lilly, USA), a short-acting barbiturate that produces a rapid loss of muscle tone when administered i.v.

Meth self-administration

Meth self-administration was conducted in standard self-administration chambers (30×20×20 cm, Med Associates, USA) housed inside sound-attenuating cubicles fitted with a fan for airflow and masking noise. Each chamber contained two retractable levers, two stimulus lights, a speaker for tone delivery, and a house-light to provide general illumination. Additionally, each chamber was equipped with a balanced metal arm and spring leash attached to a swivel (Instech). Tygon® tubing extended through the leash and was connected to a 10 ml syringe mounted on an infusion pump located outside the sound-attenuating cubicle.

Following at least 5 d of recovery, rats were given daily 2-h sessions to self-administer methamphetamine hydrochloride (Sigma) on a fixed ratio 1 (FR1) schedule of reinforcement. The house-light always signalled the beginning of a session and remained on throughout the session. During the sessions, a response on the active lever resulted in activation of the pump for a 2-s infusion (20 µg/50 µl bolus infusion) and presentation of a stimulus complex consisting of a 5-s tone (78 dB, 4.5 kHz) and a white stimulus light over the active lever, followed by an un-signalled 20-s timeout. Responses occurring during the timeout and on the inactive lever were recorded, but had no scheduled consequences. All sessions took place during the dark cycle between 09:00 and 13:00 hours. Sessions were conducted 6 d/wk until the rat reached a criterion of more than 10 infusions during a session for 14 cumulative days. All ensuing experiments featured the same self-administration procedures; schematic representations of abstinence, extinction, and reinstatement testing for each experiment are depicted in Figs 1–3.

Fig. 1

Acute modafinil effects during and after Meth self-administration. (a) Time-course for expt 1. Modafinil or vehicle treatment occurred 90 min before self-administration sessions in a counterbalanced order, followed by extinction and reinstatement tests. (b) Meth intake (mg/kg) and (c) active lever responding after modafinil injection (* p<0.05: lower intake relative to all other doses; † p<0.05: reduced responding relative to 30 mg/kg modafinil). (d) Responding during self-administration (SA), extinction (Ext) and reinstatement of Meth-seeking after modafinil (Mod), Meth, and cocaine (Coc) injections (* p<0.05: lower responding relative to Meth and cocaine reinstatement).

Fig. 2

Chronic modafinil during extinction. (a) Time-course for expt 2. Modafinil (0, 30, or 100 mg/kg) treatment occurred during daily extinction sessions and on the first conditioned cue-induced and Meth-primed reinstatement tests. Rats were retested following 2 wk of abstinence without modafinil. (b) Active lever presses during the last 3 d of self-administration. (c) Lever responding over the 10 d of extinction. (d) Reinstatement of Meth-seeking by cues or Meth during continuous modafinil treatment (* p<0.05: difference in responding relative to vehicle on the same test). (e) Meth-seeking 2 wk after discontinuation of modafinil treatment (* p<0.05: reduced responding relative to vehicle).

Fig. 3

Chronic modafinil during abstinence. (a) Time-course for expt 3. Modafinil (30 mg/kg) treatment occurred daily during abstinence, but not on tests or during extinction. Rats were tested for context relapse, followed by daily extinction and subsequent reinstatement testing. (b) Active lever presses during the last 3 d of self-administration. (c) Relapse to Meth-seeking in the Meth context after abstinence (* p<0.05: reduced responding by prior modafinil treatment relative to vehicle treatment). (d) Lever responding over the 10 d of extinction. (e) Reinstatement of Meth-seeking by cues or Meth.

Abstinence, extinction, and reinstatement

The term ‘reinstatement’ connotes responding subsequent to daily extinction of the lever press response (Bouton, 2002). Adhering to the traditional extinction-reinstatement model (Shaham et al. 2003), tests conducted after extinction are termed ‘reinstatement tests’, while tests that occur following abstinence in the absence of daily extinction are referred to as ‘relapse’ (Reichel et al. 2011). Following Meth self-administration, rats were placed into abstinence and/or extinction before reinstatement testing. During abstinence, rats were transported from the colony room, handled, weighed, and fed, but not placed in the self-administration chamber. During extinction, rats were placed in the self-administration chamber for daily 2-h sessions; responding on either lever had no scheduled consequences. To have met extinction criterion, responses on the active (i.e. drug-seeking) lever needed to be ≤25 presses for two consecutive days. When this criterion was met, rats were tested for Meth-primed or cue-induced reinstatement. During the Meth-prime test, responding on either lever had no scheduled consequences. For cue-induced reinstatement, active lever presses resulted in presentation of the conditioned light+tone in the same manner as during self-administration. Further daily extinction sessions occurred between reinstatement tests until the criterion of ≤25 presses for two consecutive days was met.

Expt 1: modafinil dose response on Meth intake during self-administration and reinstatement to a drug-prime

Figure 1 a depicts the timeline for expt 1. In this experiment, self-administration occurred as described above. When responding stabilized, each rat (n=12) was tested with a unique order of vehicle, 30, 100, or 300 mg/kg modafinil [modafinil was purchased from Toronto Research Chemicals (Canada), suspended in 0.25% methylcellulose (Sigma), and injected i.p. at a volume of 1 ml/kg]. Each solution was administered i.p. 90 min before a regular self-administration session and each test was separated by at least 2 maintenance days of Meth self-administration without drug pretreatment. To meet test criteria, rats were required to have two consecutive days in which the number of infusions was within 20% of each other. Following completion of all tests, rats were given two maintenance self-administration days and then lever responding was extinguished and rats were tested for modafinil-, cocaine-, and Meth-primed reinstatement in a counterbalanced order. The 100 mg/kg modafinil dose was given 90 min before the session and was chosen because this dose blocks Meth-primed reinstatement, but does not reinstate Meth-seeking (Reichel & See, 2010). Doses for Meth-primed reinstatement (1 mg/kg) and cocaine-primed reinstatement (10 mg/kg) occurred immediately before the session and have been previously established as optimal doses in dose–response studies (Cornish & Kalivas, 2000; Schwendt et al. 2009).

Expt 2: chronic modafinil during extinction – effects on reinstatement

Figure 2 a depicts the timeline for expt 2. Rats had 14 d of 2-h daily Meth self-administration sessions, followed by at least 10 d of extinction. During extinction, rats received vehicle (n=15), 30 mg/kg (n=11), or 100 mg/kg (n=11) modafinil 90 min before the session began. When responding was extinguished, rats were tested with modafinil for cue-induced and Meth-primed reinstatement. Between tests, rats were re-extinguished to criteria and modafinil treatment continued. After two additional weeks of abstinence, rats were re-tested for cue-induced and Meth-primed drug-seeking in the absence of modafinil.

Expt 3: chronic modafinil during abstinence – effects on reinstatement of Meth-seeking

Figure 3 a depicts the timeline for expt 3. Rats underwent 14 daily Meth self-administration sessions followed by 10 d of abstinence. During abstinence, rats received vehicle (n=12) or 30 mg/kg (n=13) modafinil. Rats were tested for context relapse on day 11 of abstinence without modafinil (or vehicle). This test also served as the first day of a 10-d extinction period. Following extinction, rats were tested for cue-induced and Meth-primed reinstatement in the absence of any drug treatment.

Data analysis

The main dependent measures were Meth intake and lever presses (both active and inactive). To determine that groups did not differ before modafinil treatment, data from the last 3 d of self-administration were averaged for each variable and analysed with one-way analysis of variance (ANOVA). One-way within-subjects ANOVAs were used to determine the impact of modafinil on Meth intake and active lever presses during Meth self-administration. One-way between-subjects ANOVAs and planned comparisons were used to evaluate reinstatement and relapse tests, respectively. The effects of modafinil on extinction responding used a mixed ANOVA, with drug as the between-subjects factor and session as the within-subjects factor. Data points that were 2 standard deviations from the mean were excluded (Hill & Lewicki, 2007). Inactive lever presses were routinely very low and did not differ between groups (Supplementary Figs S1–S3, available online). All data are shown as mean±s.e.m. and alpha was set at p<0.05.

Results

Expt 1: modafinil effects on Meth intake and reinstatement

Figure 1 b depicts modafinil's impact on Meth intake and active lever presses during maintenance of Meth self-administration. Relative to all other groups, the highest dose of modafinil (300 mg/kg) significantly decreased Meth intake [F(3, 33)=13.25, p<0.01; Tukey, p<0.05] and decreased responses on the active lever [F(3, 33)=4.66, p<0.01]. The 300 mg/kg dose decreased lever presses relative to the 30 mg/kg group (Tukey, p<0.05). When tested for reinstatement of Meth-seeking (Fig. 1 c), a significant difference was seen between the three drugs [F(2, 20)=8.44, p<0.01], whereby modafinil failed to produce reinstatement, while Meth and cocaine both led to robust reinstatement (Tukey, p<0.05).

Expt 2: chronic modafinil effects on extinction and reinstatement

Rats treated with vehicle or modafinil (30 or 100 mg/kg) did not differ on daily Meth intake (control=1.71±0.14 mg/kg; 30 mg/kg modafinil=1.37±0.09; 100 mg/kg modafinil=1.73±0.07) or active lever presses before extinction training (Fig. 2 b). During extinction (Fig. 2 c), lever pressing decreased across the 10 sessions for all groups on the active lever [session main effect: F(9, 34)=14.02, p<0.01]. Although drug treatment did not significantly interact with session [F(18, 306)=1.59, p=0.06], there was a group main effect [F(2, 34)=6.95, p<0.01]. Tukey post-hoc comparisons on the marginal means showed that the 100 mg/kg group responded higher than both other groups during extinction (p<0.05). However, this transient increase in extinction disappeared by day 8 and all groups reached criteria by day 10.

Data from the first cue-induced and Meth-primed reinstatement tests are shown in Fig. 2 d, while rats were still receiving modafinil. The one-way ANOVA indicates that rats responded differently to presentation of the cue stimulus [F(2, 34)=4.93, p<0.05]. Vehicle and 30 mg/kg modafinil rats had similar levels of reinstatement; however, 100 mg/kg modafinil rats reinstated significantly higher than both other groups (Tukey, p<0.05). The Meth prime test (in the presence of available modafinil) also showed a significant group difference [F(2, 32)=4.06, p<0.05], in which 30 mg/kg was reduced relative to vehicle (Tukey, p<0.05). A second set of tests was conducted 2 wk after discontinuation of modafinil (Fig 2 e). On the cue test, rats that had received both 30 and 100 mg/kg modafinil during extinction showed significantly less responding than vehicle [F(2, 31)=6.83, p<0.01; Tukey, p<0.05]. Similarly, chronic 30 and 100 mg/kg modafinil during abstinence decreased Meth-primed reinstatement relative to vehicle [F(2, 31)=5.03, p<0.05; Tukey, p<0.05].

Expt 3: chronic modafinil effects on context relapse

Rats did not differ on Meth intake (control=1.66±0.13 mg/kg, modafinil=1.47±0.10 mg/kg) or active lever presses before the abstinence period (Fig. 3 b). Following 10 d of abstinence, rats that had received 30 mg/kg modafinil responded less on the Meth-paired lever than vehicle-treated rats [t(23)=1.97, p<0.05]. No differences were observed during daily extinction sessions or on subsequent cue-induced and Meth-primed tests.

Discussion

Chronic modafinil attenuated relapse to a Meth-paired context, decreased conditioned cue-induced and Meth-primed reinstatement, and resulted in enduring reductions in Meth-seeking even after discontinuation of treatment. These results support our earlier findings with acute modafinil treatment (Reichel & See, 2010), and provide important data on repeated modafinil dosing during conditions of both extinction and abstinence that are relevant for modafinil treatment in human Meth users. Collectively, these results corroborate clinical and preclinical findings that modafinil may be an effective anti-relapse medication (McGaugh et al. 2009; Reichel & See, 2010; Shearer et al. 2009).

Several differences emerged between single and repeated dosing schedules, suggesting that chronic treatment regimens in an animal model may provide better translational relevance for pharmacotherapy in human Meth addiction and relapse. Chronic dosing regimens revealed that the optimal doses used during single administration protocols do not have the same effect when repeatedly administered. For example, acute modafinil at 30 mg/kg did not impact Meth-intake (expt 1), conditioned cue-induced, Meth-primed, or modafinil-primed reinstatement (Reichel & See, 2010). In contrast, 30 mg/kg repeatedly administered during extinction (and on test) reduced Meth-primed reinstatement. Perhaps even more marked was the persistent reduction of both conditioned cue-induced and Meth-primed reinstatement 2 wk after modafinil treatment ceased. Thus, a seemingly ineffective dose given as an acute challenge (i.e. 30 mg/kg) resulted in long-term protection from Meth-seeking when given repeatedly in combination with new contingencies during extinction sessions.

At first glance, this reduction in reinstatement may be attributed to the combined effects of modafinil with extinction training, as chronic modafinil during abstinence did not provide enduring protection from relapse 2 wk after treatment was discontinued, although there was a recurring trend towards a reduction on both reinstatement tests. However, 30 mg/kg modafinil administered during abstinence reduced relapse in the Meth-associated context, indicating some efficacy without daily extinction experience. This reduction is important and notable, since most ‘treatment-as-usual’ protocols for human drug addicts do not explicitly extinguish drug-related cues, although extinction techniques are integral to intervention approaches such as guided imagery or cue-exposure therapy (Conklin, 2006; Lee et al. 2007). Further studies may implement techniques to enhance modafinil's effect during abstinence, such as the introduction of alternative rewards. We specifically only tested 30 mg/kg modafinil during abstinence due to the response patterns observed with chronic treatment of the higher dose (100 mg/kg) during extinction.

A single administration of 100 mg/kg modafinil did not impact Meth intake (expt 1), but has been shown to decrease contextual relapse and conditioned cue-induced and Meth-primed reinstatement, without reinstating Meth-seeking when given alone (Reichel & See, 2010). Unexpectedly, daily injections of 100 mg/kg modafinil transiently increased active lever pressing during extinction and increased conditioned cue-induced reinstatement when the drug was systemically available during testing. Even so, behaviour did extinguish to criteria for this group within 10 d. Similarly, in rhesus monkeys, chronic modafinil (32 and 56 mg/kg i.v.) during extinction caused a transient increase in responding, that decreased over three consecutive days (Newman et al. 2010). Active lever responding is indicative of drug-seeking behaviour, suggesting that repeated injections of 100 mg/kg modafinil increased Meth-seeking during extinction and in the presence of conditioned cues. It is unlikely that non-specific alterations in general motor activity impacted active lever responses because inactive lever responding was similarly very low in all groups. Furthermore, rats treated with repeated modafinil at 100 mg/kg actually showed lower responding during the Meth-primed reinstatement trial when modafinil was still being administered. More likely, the increased responding during extinction and cue-induced reinstatement may have resulted from modafinil substitution of drug effects experienced with repeated exposure, sensitized responding to the drug, or transient arousal effects of modafinil.

Substitution of drug effects results from shared stimulus properties between drugs. Meth shares stimulus properties with compounds affecting dopamine, histamine, norepinephrine, adenosine, γ-aminobutyric acid, and serotonin neurotransmitter systems (Gasior et al. 2004; Gatch et al. 2005; Munzar & Goldberg, 1999, 2000; Munzar et al. 1999, 2004), and modafinil also interacts with many of these neurotransmitter systems (Minzenberg & Carter, 2008). To date, the discriminative stimulus effects of Meth have not been tested with modafinil. However, 300 mg/kg modafinil fully substituted for the discriminative stimulus effects of cocaine in rats (Paterson et al. 2010), and cocaine substituted for Meth (Munzar & Goldberg, 2000; Reichel et al. 2007). Lower modafinil doses (100 mg/kg) produced only partial substitution or even saline-like responses to cocaine and D-amphetamine (Dopheide et al. 2007; Gold & Balster, 1996; Paterson et al. 2010), which is consistent with primate and human drug discrimination (Rush et al. 2002). Together, these studies indicate modafinil must be experienced at high doses to observe full substitution of stimulus drug effects.

Substitution tests are typically administered as acute injections, rather than as chronic treatment as in the current study. Chronic modafinil (75–150 mg/kg) results in expression of a sensitized response in a drug-paired environment (Paterson et al. 2010). Although speculative, repeated presentation of 100 mg/kg modafinil may have resulted in a sensitized drug effect within the drug-taking context, resulting in an increase of active lever responses on days 5–7 of extinction and the initial reinstatement to Meth-conditioned cues. This explanation does not account for the modafinil-induced reduction in Meth-primed reinstatement, so the exact mechanisms responsible for increased active lever presses remain unclear.

Some similarities between modafinil and other psychostimulant drugs merit caution about the possible reinforcing mechanism and abuse liability of modafinil (Bernardi et al. 2009; Volkow et al. 2009; Zolkowska et al. 2009). Although modafinil binds to dopamine transporters, affinity is markedly less than other psychostimulant drugs (Madras et al. 2006; Zolkowska et al. 2009) and clinical data demonstrate that modafinil is without potent reinforcing effects or abuse liability (Malcolm et al. 2002; Rush et al. 2002; Vosburg et al. 2009). Consistently, our results support little abuse liability, since moderate doses of modafinil (30 and 100 mg/kg) did not impact Meth intake, indicating that modafinil does not change the reinforcing value of Meth. Importantly, a single injection (i.p.) of modafinil (100 mg/kg) did not impact locomotor activity in drug-naive or Meth-experienced rats (Supplementary Fig. S4, online). Additionally, modafinil (30–300 mg/kg) does not reinstate Meth-seeking when experienced alone (Reichel & See, 2010). Thus, it is important to note that cocaine (10 mg/kg) reinstated Meth-seeking to the same extent as a Meth (1 mg/kg) prime, whereas modafinil (100 mg/kg) was equivalent to extinction levels, clearly indicating different effects between the three drugs on reinstatement. Although 300 mg/kg modafinil decreased Meth intake (expt 1), this dose did not reinstate Meth-seeking (Reichel & See, 2010). Recently, Zolkowska and colleagues (2009) reported that 60 mg/kg (i.v.) modafinil caused hyperactivity and stereotypy. As such, the possibility exists that 300 mg/kg modafinil (i.p.) may have prevented lever pressing for Meth due to non-specific changes in general activity or reduced drug-seeking via substitution of Meth effects at this high dose.

Even though repeated 100 mg/kg modafinil increased responding during extinction and cue-induced reinstatement when modafinil was systemically available, both modafinil doses reduced conditioned cue-induced and Meth-primed reinstatement relative to vehicle at 2 wk after discontinuation of the drug. Interestingly, rats treated with saline actually appeared to increase responding on these tests relative to tests conducted 2 wk earlier. This enhanced responding in controls is reminiscent of an ‘incubation’ effect, which is characterized as an increase in responding following a period of drug abstinence (Grimm et al. 2001). As such, modafinil may have attenuated this incubation of drug craving by reversing or compensating for Meth-induced neuroadaptations. The full extent of neuroadaptations caused by self-administered Meth has not been extensively characterized, so the exact mechanisms whereby chronic modafinil may restore function remain unknown. However, it is possible that chronic modafinil may restore N-acetyl aspartate (NAA) levels, a marker of neuronal integrity. Neuroimaging studies show that Meth addicts have lower NAA levels relative to controls (Salo et al. 2007). Neuroimaging results from a marmoset model of Parkinson's disease showed that chronic daily doses of modafinil (100 mg/kg) reversed the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) induced decrease in NAA (van Vliet et al. 2008). Modafinil also has agonist effects on group II metabotropic glutamate receptors (Tahsili-Fahadan et al. 2010) and enhances glutamate release (Ferraro et al. 1998). These glutamatergic actions of modafinil may act to restore changes in dysregulated corticostriatal glutamatergic function, which are altered after chronic cocaine self-administration (Kalivas, 2009).

Reduction in Meth-seeking after discontinuation of pharmacotherapy is a critical feature for successful development of anti-relapse medication. Indeed, the most important issue facing addiction treatment is prevention of relapse (O'Brien, 2006). Chronic modafinil demonstrated this ability under three different conditions of withdrawal and abstinence: (1) during reinstatement to conditioned cues, (2) during reinstatement to a Meth prime, and (3) during relapse to the Meth-paired context. The persisting anti-relapse effects of modafinil appeared to be enhanced by extinction training. Clinical techniques of cue-exposure therapy and guided imagery rely on extinction procedures and to date have shown moderate success (Childress, 1993; Conklin, 2006; Lee et al. 2007; Marissen et al. 2007). Several fields of psychiatry have incorporated medication-facilitated cue-exposure therapies to enhance success rates, with the most notable achievement seen in phobia treatment (Davis et al. 2006; Ressler et al. 2004). Addiction treatment may also benefit from such approaches (Otto et al. 2004), and modafinil may be a viable medication to use in conjunction with cue exposure or other extinction procedures for treatment of Meth and other drug addictions.

Acknowledgements

This research was supported by NIH grants DA022658 (R.E.S.), F32DA029344 (C.M.R.), and C06 RR015455. The authors thank Shannon Ghee, Clifford Chang, and Andrew Novak for technical assistance.

Note

Supplementary material accompanies this paper on the Journal's website.

Statement of Interest

None.

References

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