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. 2023 Dec 12;49(6):953–960. doi: 10.1038/s41386-023-01777-z

Methylphenidate with or without fluoxetine triggers reinstatement of cocaine seeking behavior in rats

Lorissa Lamoureux 1,2, Joel Beverley 1, Heinz Steiner 1,3, Michela Marinelli 1,4,5,6,✉
PMCID: PMC11039773  PMID: 38086900

Abstract

Methylphenidate (MP) is commonly prescribed to treat attention-deficit hyperactivity disorder (ADHD). MP is also taken for non-medical purposes as a recreational drug or “cognitive enhancer”. Combined exposure to MP and selective serotonin reuptake inhibitors such as fluoxetine (FLX) can also occur, such as in the treatment of ADHD with depression comorbidity or when patients taking FLX use MP for non-medical purposes. It is unclear if such exposure could subsequently increase the risk for relapse in former cocaine users. We investigated if an acute challenge with MP, FLX, or the combination of MP + FLX could trigger reinstatement of cocaine seeking behavior in a model for relapse in rats. Juvenile rats self-administered cocaine (600 µg/kg/infusion, 1–2 h/day, 7–8 days) and then underwent extinction and withdrawal during late adolescence-early adulthood. Reinstatement was tested at a low dose of MP (2 mg/kg, I.P., comparable to doses used therapeutically) or a high dose of MP (5 mg/kg, comparable to doses used recreationally or as a cognitive enhancer), with or without FLX (2.5–5 mg/kg, I.P.). An acute challenge with the high dose of MP (5 mg/kg), with or without FLX, reinstated cocaine seeking behavior to levels comparable to those seen after an acute challenge with cocaine (15 mg/kg, I.P.). The low dose of MP (2 mg/kg) with or without FLX did not reinstate cocaine seeking behavior. Our results suggest that acute exposure to a high dose of MP, with or without FLX, may increase the risk for relapse in individuals who used cocaine during the juvenile period.

Subject terms: Addiction, Behavioural methods, Motivation

Introduction

Relapse to drug taking can be triggered by brief re-exposure to drugs. For example, an acute (single) exposure to psychostimulant drugs can trigger relapse and craving in persons with former substance use disorder, a phenomenon often referred to as “priming” [1, 2]. However, the effects of priming vary across categories of psychostimulant drugs. For example, cocaine priming can trigger relapse in former cocaine users, but the same is not as clear for methylphenidate (MP) [3, 4].

MP is generally used for medical purposes, most often to treat attention-deficit hyperactivity disorder (ADHD); this occurs more frequently in males, who have a greater prevalence of this condition [5]. MP is also taken by people without ADHD, for recreational purposes [6–9]. The use of MP as a cognitive enhancer is another particularly uncontrolled form of exposure, which happens often in students who use this drug to improve concentration or to stay awake to study [10, 11]. Misuse of prescription stimulants is more prevalent in males than females [12]. Such non-medical use of MP has reached 5–35% in college-age students [8, 13, 14] and even higher percentages in some other studies [13].

Administration of MP has also been proposed as a treatment for subjects with cocaine addiction; however, data on its effectiveness are inconclusive [15–19]. For example, while MP could be a good substitute for cocaine and alleviate cocaine addiction, especially in patients with ADHD [20], it may also trigger cocaine craving thereby promoting relapse, similar to cocaine itself [21]. In fact, outside medical applications, MP is often used illegally, possibly as cocaine substitute in those taking cocaine [22, 23]. However, we lack clear data on the potential relapse-provoking effects of MP in former psychostimulant users.

In addition to having limited data on the potential risks produced by medical and non-medical use of MP alone, this psychostimulant is sometimes combined with other psychotropic drugs, especially selective serotonin reuptake inhibitor (SSRI) antidepressants, and even less is known regarding the potential risks of such combination treatments. For example, MP plus SSRI combinations are indicated in the treatment of comorbid ADHD and depression [24–26]. Moreover, it is estimated that 25–50% of those who seek counseling in college-aged youth are prescribed SSRIs – most commonly fluoxetine (FLX) [27]. Therefore, accidental co-exposure to these drugs can occur in patients on SSRIs who then use MP recreationally or as a cognitive enhancer [28–30].

Due to their neurochemical profiles, co-exposure of MP and SSRIs is of concern. The addition of FLX to MP could make the combination more “cocaine-like” (for review, see [31]). MP elevates extracellular levels of the neurotransmitters dopamine and norepinephrine, but unlike cocaine, MP does not affect serotonin [32, 33]. Elevation of serotonin levels, however, is a consequence of FLX treatment [34]. The emergence of “cocaine-like” properties for MP plus SSRI combinations is supported by recent molecular findings demonstrating that adding FLX to MP potentiates addiction-related gene regulation in the forebrain and alters the regional profile of these molecular changes to resemble those induced by cocaine [31]. For example, FLX potentiates MP-induced changes in the expression of various transcription factors and other signaling molecules in the striatum and shifts the most affected functional domains from the dorsomedial (associative) to the dorsolateral (sensorimotor) striatum, mimicking the effects of cocaine [31]. Therefore, it is possible that this “cocaine-like” drug combination could increase the risk of triggering relapse in former psychostimulant users.

In the present study, we investigated if a single challenge exposure to MP or the combination of MP + FLX, using dosing regimens that induced molecular changes in our previous studies [31], can trigger relapse of cocaine seeking behavior in rats that had previously established cocaine self-administration behavior.

Materials and methods

Subjects

We used male Sprague Dawley rats (Harlan Sprague Dawley, Indianapolis, IN). Rat were housed 2–3 per cage, with ad libitum access to food and water at all times, with a 12/12 h dark/light cycle, and under constant temperature (~22 °C) and humidity (35–65%). Experiments were carried out after at least one week of acclimation to the vivarium, and 2–6 h prior to lights off. All experiments were approved by the institutional animal care and use committee (IACUC).

Drugs

Cocaine HCl was generously provided by the National Institute on Drug Abuse or purchased from Sigma-Aldrich (St. Louis, MO). Cocaine was dissolved in 0.9% saline solution (Henry Schein, Piedmont, MO), and its pH was adjusted to 6.5–7.0 with 0.1 N NaOH if necessary. Fluoxetine HCl (FLX) was purchased from Sigma-Aldrich or from Enzo Life Sciences (Farmingdale, NY). Methylphenidate HCl (MP) was purchased from Sigma-Aldrich. These drugs were dissolved in vehicle made of 0.02% ascorbic acid (Sigma-Aldrich). Isoflurane and sodium methohexital were purchased from Henry Schein. Flunixin meglumine was from Merck Animal Health (Whitehouse Station, NJ).

Self-administration

Surgeries to implant intravenous catheters for self-administration

Rats received the analgesic flunixin meglumine (2.5 mg/kg, subcutaneously) immediately prior to surgery. Then, they were anesthetized with isoflurane gas (5% induction, 2–3% maintenance), and surgically implanted with a Silastic catheter (10–12 µL dead volume) in the right external jugular vein. The catheter was secured to the jugular vein and passed subcutaneously to exit from the back (2 cm caudally from to the mid-scapular region). Rats received the antibiotic gentamycin (2 mg/kg/0.5 mL, intravenously) or cefazolin (50 mg/kg/0.5 mL, intravenously) on surgery day and two days after. During the post-operative period of at least 6 days, catheters were flushed daily with 0.9% sterile saline (100 µL) to maintain catheter patency.

Self-administration procedures

The day before the start of self-administration experiments, rats were acclimated to the self-administration chamber, to prevent exploratory behaviors from interfering with subsequent self-administration behavior [35]. To this end, each rat was placed in the self-administration chambers for 2 h, but the operant devices (holes for nose poking) were covered. Self-administration began the following day in custom-sized operant chambers (41 × 24 cm floor area, 21 cm high; MED Associates), each fitted in a sound-attenuating cubicle. Chambers were equipped with two nose poke holes on opposite walls, located 2 cm above the floor of the chamber. A nose poke in the hole designated “active” (active hole) delivered one infusion (Fixed Ratio 1 schedule of reinforcement; FR1) unless otherwise noted. Nose poking in the hole designated “inactive” (inactive hole) was recorded but had no consequences. Each infusion was signaled by illumination of a light inside the active hole and was followed by a timeout period (10 s for the first 10 infusions, 20 s for the next 10, and 30 s for the rest of the infusions), during which nose pokes were recorded but had no consequences. Infusions were delivered by a syringe pump at the rate of ~12 µL/s and a volume of 200 µL/kg. One-to-four days after the last self-administration session, rats were tested for catheter patency by administering sodium methohexital (5 mg/kg/0.5 mL intravenously). Rats that did not respond to the anesthetic immediately were eliminated from the study.

Extinction and reinstatement

We tested if a single challenge injection of MP, FLX, the combination of MP + FLX, or cocaine produced reinstatement of cocaine seeking behavior in rats that previously self-administered cocaine (600 µg/kg/infusion) during the juvenile period (P37-54) and then underwent extinction and/or withdrawal until late adolescence-early adulthood. The juvenile period was chosen for cocaine self-administration because onset of cocaine use typically occurs during adolescence in humans [36, 37].

Juvenile rats were trained to self-administer cocaine (600 µg/kg/infusion) as described above. Then, rats took a break from self-administration, after which they were tested for reinstatement of seeking behavior following extinction. Extinction consisted of placing rats in the self-administration chamber with identical conditions as for cocaine self-administration, except that cocaine was not available. During this time, responding (i.e., “seeking” for the drug) decreased over time (i.e., “extinguished”). We then tested if seeking behavior increased (i.e., if there was “reinstatement”), after an acute challenge I.P. injection of Vehicle (1 mL/kg), FLX at 2.5 or 5 mg/kg (FLX2.5 or FLX5), MP at 2 or 5 mg/kg (MP2 or MP5), MP + FLX (with different dose-combinations, according to the experiment), or cocaine 15 mg/kg (COC15), given immediately prior to the reinstatement test. The doses of MP mimic what is used therapeutically (2 mg/kg) or what could be reached recreationally or as cognitive enhancer (5 mg/kg) [38]. The doses of FLX reduce behavioral markers of depression [39] and, in combination with MP (i.e., MP + FLX), they potentiate the effects of MP on gene expression and behavioral responses [31, 40]. For the extinction/reinstatement tests, the light-cue in the previously active nose poke hole was presented randomly every 2–4 min, for 5 s [41]. We used two procedures: within-session extinction/reinstatement, in which reinstatement is tested immediately after a single extinction session (Experiment 1) and between-sessions extinction/reinstatement in which reinstatement is tested after repeated daily extinction sessions (Experiments 2 and 3). Reinstatement with different drugs was tested either in different subjects (Experiments 1 and 3) or in the same ones sequentially (Experiment 2). Conducting the same experiment in different settings/conditions increases external validity, as it validates results obtained in different circumstances.

Procedures

Experiment 1: within-session extinction/reinstatement

Juvenile rats (P39-40 at the start) were trained to self-administer cocaine at 600 µg/kg/infusion for 7 days (1 h/day). Rats then underwent 13–16 days of break from the self-administration chambers, after which (at P60-62) they were placed back in the chambers for one hour of extinction, immediately followed by one hour of reinstatement produced by a challenge injection of Vehicle (n = 9), MP2 (n = 6) or MP5 (n = 8).

Experiment 2: between-sessions extinction/reinstatement (sequential testing)

A separate cohort of juvenile rats (P47 at the start, n = 6) were trained to self-administer cocaine at 600 µg/kg/infusion for 8 days (2 h/day). Then, they were exposed to repeated extinction sessions across days. On day 16 of extinction, rats were tested for reinstatement of seeking behavior after a 3–5 min exposure to cold swim, as a pilot experiment to establish conditions for a different study [42]. After four additional days of extinction, the same rats were tested sequentially for reinstatement of cocaine seeking behavior induced by different drugs, with a 2-day break after each reinstatement test. Tested drugs were: Vehicle (day 23, P77), MP5 + FLX5 (day 25, P79), COC15 (day 32, P86), MP5 (day 39, P93), and FLX5 (day 46, P100). Seeking during extinction and reinstatement was tested over 2 h.

Experiment 3: between-sessions extinction/reinstatement

We repeated the same experiment as the one above in a separate cohort of juvenile rats (P37-40 at the start), but administered the drug treatments in separate groups of rats, instead of sequentially in the same rats. Rats were trained to self-administer cocaine at 600 µg/kg/infusion for 8 days (2 h/day). Then, they were exposed to repeated extinction sessions across days, for 10–11 days. On days 11 or 12, rats were tested for reinstatement after Vehicle (P57-59). After one to two additional extinction days (P59-61) they were tested for reinstatement after a challenge injection with either FLX2.5 (n = 6), FLX5 (n = 7), MP2 (n = 13), MP2 + FLX2.5 (n = 9), MP2 + FLX5 (n = 11), MP5 (n = 11), MP5 + FLX2.5 (n = 9), MP5 + FLX5 (n = 6), or COC15 (n = 10). Seeking during extinction was tested over 2 h and for reinstatement over 1.5 h.

Statistics

All data were analyzed with analysis of variance (ANOVA) followed by post-hoc comparisons: Duncan’s test (for between-subject comparisons) and Tukey’s test (for within-subject comparisons).

To ensure similar intake of cocaine across groups that would later be tested for reinstatement of seeking behavior, we stratified rats according to their intake and responding and distributed them evenly across experimental groups. Even distribution across group was assessed by comparing intake (i.e., the number of infusions) and responses in the active and inactive holes; responses in the active and inactive hole were also analyzed separately and as within-subject factors, to assess discrimination between the two holes (i.e., ascertain that rats acquired self-administration behavior). Days were analyzed as within-subject factor.

For the reinstatement tests, we compared groups for the number of responses in the active hole and inactive hole as well as for the discrimination between the two holes, analyzed as within-subjects factor. We used MP (doses 0 or 2 or 5 mg/kg) and FLX (doses 0 or 2.5 or 5 mg/kg) as between-subject factors when both drugs were used. When this was not possible because not all groups were present, or when we also had a group treated with cocaine (COC) we used group (Vehicle, MP, FLX, MP + FLX, COC or combinations of these) as between-subjects factor. Reinstatement was considered to have occurred if seeking (responding in the previously active hole) induced by the challenge injection of drug was higher than seeking produced by the challenge injection of Vehicle. This was examined as within-subjects factor when Vehicle and drugs were administered sequentially and as between-subjects factor when Vehicle and drugs were administered in different subjects.

Results

Experiment 1: within-session extinction/reinstatement

During the self-administration phase, rats learned self-administration behavior and discriminated between the active and inactive holes (Fig. 1a) (Hole effect F1,20 = 20.68, P < 0.001), and this occurred to a similar extent across groups that would later receive treatment with Vehicle, MP2, or MP5 (Treatment effect F2,20 = 0.12, P = 0.890, Treatment x Hole interaction F2,20 = 0.54, P = 0.587). Average cocaine intake (600 µg/kg/infusion) over the last three days of self-administration was 24.6 ± 1.3 infusions/1 h. Intake was comparable across groups that would later receive treatment with Vehicle, MP2, or MP5 (Treatment effect F2,20 = 0.77, P = 0.493). Similar results were seen during the extinction phase (Fig. 1b).

Fig. 1. Effects of Vehicle (n = 9), MP2 (n = 6), or MP5 (n = 8) on seeking behavior during a within-session extinction/reinstatement test.

Fig. 1

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The timeline is shown above the figure. a Responses in the active and inactive hole during self-administration of cocaine (600 µg/kg/infusion, 1 h/day) over 7 days prior to any treatment; rats showed good discrimination between holes. b Seeking behavior (non-rewarded responses) during the extinction phase, prior to any treatment; responding decreased over time. c Seeking behavior during the reinstatement phase, after rats received a challenge injection of Vehicle, MP2, or MP5 (each administered in a separate group of rats). MP5 produced reinstatement of seeking behavior, i.e., it increased responding in the previously active hole (solid bars) without modifying responding in the inactive hole (hashed bars). *p < 0.05 compared with the previously active hole in the Vehicle group and the MP2 group, and with the inactive hole in all groups. Data are mean and SEM for each group.

After extinction, treatments produced different levels of reinstatement of cocaine seeking (Fig. 1c), as measured by responding in the previously active hole (Treatment effect F2,20 = 3.66, P = 0.044). Only the high dose of MP produced reinstatement of cocaine seeking. Thus, MP5 showed higher levels of responding in the previously active hole compared with Vehicle (post-hoc comparison P = 0.044) and MP2 (post-hoc comparison P = 0.030). The Vehicle group and MP2 group showed similar levels of responding (post-hoc comparison P = 0.763). Reinstatement was also measured as levels of discrimination between the previously active hole and the inactive hole. Treatments showed different discrimination (Treatment effect F2,20 = 3.66, P = 0.044) with only the MP5 group discriminating between holes (post-hoc comparison previously active hole vs. inactive hole for MP5 P = 0.012; for Vehicle P = 0.139; for MP2 P = 0.302; post-hoc comparison for MP5 group vs. Vehicle group P = 0.038 and vs. MP2 group P = 0.034).

Experiment 2: between-sessions extinction/reinstatement (sequential testing)

During the self-administration phase, rats learned self-administration behavior and discriminated between the active and inactive holes (Fig. 2a) (Hole effect F1,5 = 92.89, P < 0.001). Average cocaine intake over the last three days of self-administration was 46.1 ± 3.1 infusions/2 h.

Fig. 2. Effects of Vehicle, FLX5, MP5, FLX5 + MP5, or COC15 administered sequentially in the same rats on seeking behavior during a between-session extinction/reinstatement test (n = 6).

Fig. 2

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The timeline is shown above the figure. a Responses in the active and inactive hole during self-administration of cocaine (600 µg/kg/infusion, 2 h/day, 8 days) prior to any treatment; rats showed good discrimination between holes. b Seeking behavior (non-rewarded responses) during the extinction phase, prior to any treatment followed by sequential challenge injections of Vehicle, FLX5, MP5, MP5 + FLX5, or COC15. MP5, MP5 + FLX5, and COC15 all produced reinstatement of seeking behavior, i.e., they increased responding in the previously active hole and showed higher responding than the group challenged with Vehicle. FLX5 did not produce reinstatement. *p < 0.05 compared with the previously active hole in the Vehicle group and ##p < 0.01 compared with responding in the inactive hole. Data are mean and SEM for each group.

After extinction, MP5 and MP5 + FLX5, but not FLX5, produced reinstatement of cocaine seeking (Fig. 2b), as measured by increased responding in the previously active hole (MP5 effect F1,8 = 58.72, P < 0.001, FLX5 effect F1,8 = 0.22, P = 0.651). These effects of MP5 were not modified by adding FLX5 (MP5 x FLX5 interaction F1,8 = 0.03, P = 0.867). Reinstatement was also measured as different levels of discrimination between the previously active hole and the inactive hole. The MP5 treatment produced discrimination between the two holes and this was not modified by adding FLX5 (MP5 x Hole interaction F1,8 = 23.10, P = 0.001, FLX x Hole interaction F1,8 = 0.54, P = 0.482, MP5 x FLX5 x Hole interaction F1,8 = 0.94, P = 0.360, post-hoc comparison MP5 active hole vs. all other groups Ps < 0.001; all other comparisons Ps = 0.214–0.730).

We also analyzed the groups together with the COC15 group. Results were similar. Treatments produced different levels of reinstatement, as measured by responding in the previously active hole (Treatment effect F4,32 = 8.45, P < 0.001). MP5, MP5 + FLX5, and COC15 showed similar levels of responding (post-hoc comparisons Ps = 0.466–0.933), which were all greater than those produced by Vehicle and FLX5 (post-hoc comparisons Ps < 0.01). Vehicle and FLX5 showed similar levels of responding (post-hoc comparison P = 0.860). Reinstatement was also measured as different levels of discrimination between the previously active and inactive holes. Treatments produced different levels of responding across holes (Treatment effect F4,32 = 8.07, P < 0.001, Treatment x Hole interaction F4,32 = 6.18, P < 0.001). MP5, MP5 + FLX5, and COC15, all discriminated between the previously active hole and the inactive hole (post-hoc comparisons Active vs. Inactive Holes, Ps < 0.01–0.001), whereas Vehicle and FLX5 did not (post-hoc comparison Active vs. Inactive Holes, both Ps > 0.877).

Experiment 3: between-sessions extinction/reinstatement

During the self-administration phase, rats learned self-administration behavior and discriminated between the active and inactive holes (Fig. 3a) (Hole effect F1,73 = 96.55, P < 0.001), and this occurred to a similar extent across groups that would later receive treatment with MP, FLX, or COC (Treatment effect F8,73 = 0.61, P = 0.765, Treatment x Hole interaction F8,73 = 0.90, P = 0.518). Average cocaine intake over the last three days of self-administration was 42.6 ± 1.2 infusions/2 h. Intake was comparable across groups that would later receive a challenge injection of MP, FLX, or COC (Treatment effect F8,73 = 0.38, P = 0.926).

Fig. 3. Effects of Vehicle, FLX2.5 (n = 6), FLX5 (n = 7), MP2 (n = 13), MP2 + FLX2.5 (n = 9), MP2 + FLX5 (n = 11), MP5 (n = 11), MP5 + FLX.2.5 (n = 9), MP5 + FLX5 (n = 6), or COC15 (n = 10) on seeking behavior during a between-sessions extinction/reinstatement test.

Fig. 3

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The timeline is shown above the figure. a Responses in the active and inactive hole during self-administration of cocaine (600 µg/kg/infusion, 2 h/day, 8 days) prior to any treatment; rats showed good discrimination between holes. b Seeking behavior (non-rewarded responses) during the extinction phase, prior to any treatment; responding decreased over time. c Seeking behavior during the reinstatement phase, after rats received a challenge injection of Vehicle, and 1–2 days later, one of the drugs listed above (each administered in a separate group of rats). MP5, with or without FLX, and COC15 produced reinstatement of seeking behavior, i.e., increased responding in the previously active hole, without modifying responding in the inactive hole (inset bars).***p < 0.001 compared with the previously active hole on the day they received Vehicle and with the inactive hole. Data are mean and SEM for each group.

After extinction, treatments produced different levels of reinstatement of cocaine seeking (Fig. 3b), as measured by responding in the previously active hole during the drug day vs. the Vehicle day (Treatment effect F8,73 = 5.57, P < 0.001, Treatment x Day interaction F8,73 = 6.16, P < 0.001). Cocaine and the high dose of MP produced reinstatement of cocaine seeking, and this was independent of FLX treatment. Thus MP5, MP5 + FLX2.5, MP5 + FLX5, and COC15 showed similar levels of responding in the previously active hole (post-hoc comparisons between these groups Ps = 0.454–0.999), which were greater than responding produced by FLX2.5, FLX5, MP2, MP2 + FLX2.5, or MP2 + FLX5 (post-hoc comparisons of COC15 or MP5-containing groups with other groups Ps = 0.050–0.001) and greater than responding produced by the prior administration of Vehicle (Ps < 0.001). Groups not treated with MP5 or COC15 showed similar levels of responding (post-hoc comparison Ps = 0.982–0.999). Reinstatement was also measured as different levels of discrimination between the previously active and inactive holes, which yielded similar results (Treatment effect F8,73 = 5.50, P < 0.001, Treatment x Hole interaction F8,73 = 5.05, P < 0.001). Thus, MP5, MP5 + FLX2.5, MP5 + FLX5, and COC15, all discriminated between the active and inactive holes (post-hoc comparisons Active vs. Inactive Holes, Ps < 0.001), whereas the other groups did not (post-hoc comparison Active vs. Inactive Holes, Ps = 0.496–0.988).

Discussion

Our main finding is that rats that self-administered cocaine during the juvenile period and then underwent withdrawal and extinction of cocaine seeking behavior showed reinstatement of cocaine seeking behavior after a challenge injection of MP or MP + FLX, at levels comparable to those seen after a challenge injection of cocaine.

In the present study, we chose to expose rats to self-administration of cocaine during the juvenile period (P35-54), because onset of cocaine use typically occurs during adolescence in humans [36, 37]. Rats then underwent withdrawal and extinction of cocaine seeking behavior for 2–3 weeks until young adulthood, and a single challenge injection of MP or MP + FLX produced reinstatement of seeking behavior. Reinstatement was seen both using a between-sessions extinction/reinstatement procedure and a within-session extinction/reinstatement procedure, as well as with sequential or single challenge injections of MP and MP + FLX. Obtaining the same outcome under these different experimental conditions enhances the external validity of these results, on the effects of MP and MP + FLX on reinstatement of seeking behavior.

We only investigated male rats. Males are more likely to be exposed to MP, both for medical and recreational purposes [12, 43]. However, conceivably, females may respond differently to MP with or without FLX (e.g., [44]), and future studies will be needed to determine potential sex differences in reinstatement.

Our doses of MP and FLX were informed by our recent molecular studies showing that adding FLX (5 mg/kg) to MP (2–5 mg/kg) potentiates MP-induced gene regulation in the striatum in adolescent male rats [31]. These molecular adaptations induced by MP + FLX include altered gene regulation by a subsequent cocaine challenge [45, 46]. While most of these previous studies used the higher dose of MP (5 mg/kg, I.P.), which may be more relevant for MP abuse [31], borderline potentiated effects were also seen with the clinically relevant dose of MP (2 mg/kg) [47].

In our present study, only the high dose of MP (5 mg/kg) but not the low dose (2 mg/kg) produced reinstatement of seeking behavior, with or without FLX (2.5 or 5 mg/kg). Our findings with MP-only challenges are consistent with results in the literature. For example, one study found that a slightly higher dose of MP (6.3 mg/kg) also produced reinstatement of cocaine seeking behavior in rats; however, this was found following cocaine self-administration in adulthood [48]. In another study, MP (0.3–3 mg/kg) did not influence cocaine seeking during a second order schedule of reinforcement [49]. It was unclear if having cocaine “on board”, as in second order schedules of reinforcement, might have prevented MP from increasing seeking, and that seeking is only increased in a cocaine-free state. In our study, cocaine was not present during the MP challenge test, and a low dose of MP (2 mg/kg) also did not increase seeking, emphasizing the importance of dose, rather than being in a cocaine-free state, in MP-induced seeking behavior.

To our knowledge, interactions between an SSRI such as FLX and MP in cocaine seeking behavior have not been investigated. Our results show that acute treatment (i.e. a single challenge injection) with FLX did not alter the propensity of acute MP to elicit reinstatement. This outcome can be seen as surprising, as several previous studies revealed interactions between FLX and MP in a number of behavioral tests. For example, in one early study, FLX increased acute MP-induced locomotor activity [50]. Moreover, one of our previous studies, using the same doses for MP and FLX as in the present study (5 mg/kg each, I.P.), showed that repeated treatment with FLX potentiated MP-induced stereotypies and facilitated subsequent cocaine self-administration [51]. Similarly, increased cocaine self-administration after MP + FLX pretreatment (vs. MP-alone) [52] as well as various other MP + FLX-induced behavioral changes [53], were also demonstrated after prolonged oral treatment. Importantly, these latter effects were found after chronic (daily, 6–30 days) MP + FLX vs. MP exposure (with chronic FLX-alone having no effect) [51, 53, 54], while the present findings were seen after a single MP + FLX challenge. Future studies will thus have to clarify whether or not chronic FLX exposure in conjunction with MP may impact reinstatement of cocaine seeking. However, in contrast to this lack of effect of acute FLX, acute MP (5 mg/kg), with or without FLX, was able to reinstate cocaine seeking under various experimental conditions.

In humans, cocaine addiction lacks a reliable treatment. It has been suggested that substituting cocaine with less “harmful” psychostimulants such as MP could help curb craving for cocaine, similar to substitution therapies for opioids or nicotine (for review, see [55]). This notion is supported by the fact that MP normalizes some neurochemical effects produced by chronic cocaine use [56]. Preliminary studies suggest that under controlled conditions, chronic treatment with MP could indeed be useful in reducing cocaine intake in some cases, but results are conflicting in humans. For example, it was found that MP (45 mg per day) did not reduce cocaine intake nor craving in cocaine-dependent patients [15, 57]. In patients with ADHD, MP (doses up to 90 mg/day) either had no effects [58] or reduced cocaine intake and craving [20]. Overall, results have been deemed inconclusive, perhaps because of low dosage and different experimental designs [17, 59].

In contrast, our present preclinical study demonstrates that a single exposure to a high dose of MP, with or without FLX reliably triggers reinstatement of cocaine seeking behavior. Such an exposure might mimic what happens with single-use of MP, either recreationally or as cognitive enhancer. Our results therefore advocate for caution regarding the use of MP in persons with prior cocaine use, as MP could have the potential of triggering cocaine seeking behavior.

Neurochemically, MP elevates extracellular levels of both norepinephrine and dopamine but not serotonin. Our findings therefore support a major role for dopamine and/or norepinephrine in reinstatement of cocaine seeking and relapse [60, 61]. In contrast, increasing serotonin by adding FLX in combination with MP did not modify the effects of MP on reinstatement, suggesting no major involvement of serotonin in reinstatement of cocaine seeking. The use SSRI antidepressants in recovering cocaine users, therefore, may not be of major concern (but see caveat above for potential effects of repeated FLX treatment), whereas acute administration of a high, recreational dose of MP could be of concern.

In conclusion, our findings show that a single exposure to a high dose MP, with or without FLX, can be sufficient to trigger reinstatement of cocaine seeking behavior, making both MP and the combination of MP + FLX “at risk” drugs for relapse in former cocaine users.

Author contributions

Conception and design of the study: MM and HS. Acquisition of the work: LL, JB and MM. Analysis of the data: MM and HS. Drafting and revising of the manuscript: MM and HS.

Funding

This work was supported by National Institute on Drug Abuse Grants R21 DA031916 to MM and R01 DA046794 to HS.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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