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. Author manuscript; available in PMC: 2025 Dec 18.
Published in final edited form as: Behav Pharmacol. 2025 Dec 16;37(1):31–40. doi: 10.1097/FBP.0000000000000866

Limited effects of zolmitriptan maintenance on the pharmacodynamic profile of intravenous cocaine in humans

William W Stoops a,b,c,d,*, Joshua A Lile a,b,c, Joseph L Alcorn III a, Kevin W Hatton e, Lon R Hays b, Danielle M Anderson b, Janet L Neisewander f
PMCID: PMC12710779  NIHMSID: NIHMS2121915  PMID: 41401392

Abstract

Serotonin1b (5-HT1b) receptors play an important role in preclinical cocaine effects. Zolmitriptan, a commercially available 5-HT1b/1d agonist migraine medication, selectively attenuates the reinforcing and other abuse-related effects of cocaine. This project sought to advance these promising preclinical findings into humans, thereby demonstrating that the 5-HT1b/1d system plays a key role in the abuse-related effects of cocaine in people with cocaine use disorder (CUD). Twelve non-treatment seeking individuals (4 female human subjects) with CUD participated in this within-subject human laboratory study. Participants were maintained on 0, 2.5, 5 and 10 mg oral zolmitriptan/day in random order. After at least 3 days of maintenance on each target dose, participants completed experimental sessions in which the reinforcing, subjective, physiological and cognitive-behavioral effects of 0, 10 and 30 mg/70 kg of intravenous cocaine were determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g., increased ratings of "Stimulated" and heart rate). Zolmitriptan produced limited changes in oral temperature after 10 mg/70 kg cocaine. Cocaine administration improved working memory impairments observed under the 5 mg zolmitriptan condition. Zolmitriptan did not alter any other effects of cocaine. Data indicate that activating the 5-HT1b/1d systems through zolmitriptan maintenance produces limited changes in the pharmacodynamic effects of cocaine in humans, contrasting preclinical findings, suggesting this may not be a promising pharmacotherapeutic strategy for cocaine use disorder. Failing to translate from preclinical to clinical models could be due to methodological or species differences, suggesting the field needs to better address this translational gap.

Keywords: Humans, Self-Administration, Serotonin, Cocaine, Zolmitriptan

1. Introduction

Cocaine produces its effects by binding to monoamine transporters and preventing their reuptake back into the presynaptic terminal (Fleckenstein et al., 2000; Johanson and Fischman, 1989). The abuse-related effects of cocaine have largely been attributed to its interactions with the dopamine transporter (Heal et al., 2014; Ritz et al., 1987; 1988), but cocaine also potently inhibits serotonin (5-HT) reuptake, an effect that contributes to cocaine use and relapse in non-human animals and humans (reviewed in Filip et al., 2005; 2010; Taracha, 2021; Walsh and Cunningham, 1997). Increased synaptic 5-HT resulting from this reuptake inhibition activates multiple 5-HT receptor subtypes (reviewed in Filip et al., 2010). Some of these subtypes have been implicated in the abuse-related effects of cocaine, including its primary reinforcing effects and reinstatement of cocaine seeking behavior (reviewed in Filip et al., 2005; 2010; Neisewander et al., 2014; Walsh and Cunningham, 1997). 5-HT1b receptors are autoreceptors on 5-HT nerve endings that regulate 5-HT release. They are also heteroreceptors that mediate dopaminergic, GABAergic, glutamatergic and cholinergic release. These receptors play a particularly important role in cocaine effects, likely because they are highly expressed in the mesocorticolimbic system in non-human animals (reviewed in Miszkiel et al., 2011; Neisewander et al., 2014). For example, administration of the 5-HT1b agonist CP93129 to cocaine naïve rats increased cocaine induced dopamine efflux in the nucleus accumbens, an effect that was reversed by administration of the 5-HT1b antagonist, GR55562 (O’Dell and Parsons, 2004).

The 5-HT1b system is dysregulated by cocaine use (reviewed in Neisewander et al., 2014). Repeated cocaine dosing followed by a short abstinence period increased 5-HT1b mRNA and receptor binding in the mesolimbic and nigrostriatal pathways in rats (Hoplight et al., 2007; Przegaliński et al., 2003). After a longer abstinence period, though, 5-HT1b mRNA expression was decreased throughout the striatum in rats (Neumaier et al., 2009). Clinical neuroimaging research showed similar findings, with significantly decreased 5-HT1b receptor availability observed in the anterior cingulate and hypothalamus after cocaine abstinence in humans with histories of cocaine use relative to healthy controls, although it is worth noting that tobacco use was not well matched between the two groups, presenting a potential confound (Matuskey et al., 2014). These neuropharmacological adaptations are echoed by behavioral changes. Specifically, the 5-HT1b agonist RU24969 produced hypolocomotion in cocaine experienced rats during active cocaine self-administration periods, but hyperlocomotion after protracted abstinence in rats (O’Dell et al., 2006). Taken together, these data indicate functional interactions between cocaine use and the 5-HT1b system.

Rigorous preclinical research has evaluated the effects of selective 5-HT1b antagonists and agonists on the direct effects of cocaine. 5-HT1b antagonists generally did not change the abuse-related effects of cocaine during active administration in rodents (Castanon et al., 2000; Przegaliński et al., 2002; 2004; 2007). 5-HT1b agonists like RU24969, CP93129 and CP94253 increased reinforcing effects of cocaine in rats (e.g., Parsons et al., 1998; Pentkowski et al., 2009; Przegaliński et al., 2007). 5-HT1b agonists also increased the rewarding effects of cocaine in a conditioned place preference model (Cervo et al., 2002), discriminative-stimulus effects of cocaine (Filip et al., 2002; 2003) and locomotor sensitization to cocaine in rats (Przegaliński et al., 2001; 2002; 2004).

These findings must be considered in light of the fact that the studies cited above were conducted during active cocaine administration. Cocaine use disorder, like all other drug use disorders, consists of phases of use and nonuse (Koob and Volkow, 2016), so it is critical to evaluate 5-HT1b agonists during cocaine abstinence (for a review, see Neisewander et al., 2014; see also Tiger et al., 2018). Collectively, this work indicates that the effects of 5-HT1b agonists “switch” during cocaine abstinence relative to active cocaine use in rodents (Acosta et al., 2005; Kohtz et al., 2024; O’Dell et al., 2006; Pentkowski et al., 2009; 2012; 2014; Przegaliński et al., 2008; Scott et al., 2021).

In initial work, 5-HT1b agonists (e.g., RU24969, CP94253) reduced cue and cocaine primed reinstatement of cocaine seeking behavior after extinction of active cocaine self-administration, relative to placebo in rats (Acosta et al., 2005; Pentkowski et al., 2009; Przegaliński et al., 2008). These effects were reversed by administration of the 5-HT1b antagonist, GR127935, further implicating the 5-HT1b systems in reinstatement of cocaine use after extinction (Acosta et al., 2005). Later work demonstrated that activation of the 5-HT1b system during cocaine abstinence may prevent relapse in rats (Pentkowski et al., 2012). In that study, viral-vector-induced 5-HT1b receptor production reduced cue and cocaine primed cocaine seeking-behavior after 21 days of cocaine abstinence, relative to sham injection. That study also observed reductions in cocaine self-administration following abstinence in the virus treated group, relative to sham, suggesting that 5-HT1b receptor agonism reduces the reinforcing effects of cocaine during abstinence. Similar results were found in a later study wherein viral overexpression of 5-HT1b receptors in the nucleus accumbens shell reduced cocaine primed reinstatement, but did not change saccharin intake in rats (Nair et al., 2013). These viral vector findings were then replicated with the 5-HT1b agonist CP94253 (Pentkowski et al., 2014). This showed that preferential pharmacological stimulation, in addition to experimentally induced changes in 5-HT1b systems through viral manipulation, produced a downward shift in reinstatement of cocaine seeking behavior and self-administration after abstinence in rats.

Because all the experimental compounds tested in the preclinical research described above could not be given to humans, additional research was conducted to evaluate the influence of treatment with zolmitriptan, a clinically available, 5-HT1b/1d agonist used to treat migraines, on the effects of cocaine in rats (Garcia et al., 2020). In that study, acute zolmitriptan significantly reduced the number of cocaine infusions earned and overall cocaine intake. Zolmitriptan did not alter responding for sucrose, suggesting it had a specific effect on cocaine self-administration. Interestingly, this effect was observed even without the cocaine abstinence period imposed in the prior research described above.

The extant preclinical data support the premise that the 5-HT1b system plays a role in multiform abuse-related effects of cocaine. Although clinical research has shown that 5-HT1b receptors may be decreased following cocaine use (Matuskey et al., 2014), we are not aware of any studies that have directly translated the preclinical studies described above by evaluating how activating the 5-HT1b system influences the pharmacodynamic effects of cocaine in humans. The purpose of this experiment was to translate preclinical research to humans and determine how maintenance on placebo and zolmitriptan (2.5, 5 and 10 mg/day; doses within the therapeutic range up to the highest FDA approved daily dose) influenced self-administration of intravenous cocaine (0, 10 and 30 mg/70 kg; doses commonly tested in human laboratory studies, e.g., Lile et al., 2016; 2020) using a sophisticated human laboratory design. Subjective, physiological and cognitive-behavioral effects of cocaine were also evaluated as a function of zolmitriptan maintenance. We hypothesized zolmitriptan would attenuate motivation for cocaine on a concurrent progressive ratio drug versus money choice task, as well as other abuse-related effects of cocaine.

2. Materials and Methods

2.1. Subjects

To be eligible for the study, subjects had to be healthy and without contraindications to zolmitriptan. Subjects also had to report recent use of smoked or intravenous cocaine, meet diagnostic criteria for cocaine use disorder according to a computerized Structured Clinical Interview for DSM-5 (SCID) (Brodey et al., 2018) that was reviewed by a psychiatrist and provide a benzoylecgonine positive urine sample during screening to verify current cocaine use status. Screening procedures for all subjects included a medical history questionnaire, laboratory tests (i.e., blood chemistry screen, complete blood count and urinalysis), electrocardiogram and a brief psychiatric examination. Subjects were excluded from participation if a study physician deemed the screening results to be abnormal. Subjects were excluded if they had histories of serious physical disease (e.g., persistent hypertension, myocardial infarction, seizures), current physical disease or current or past histories of serious psychiatric disorder/substance use disorder (e.g., physiologic dependence on opioids, alcohol or benzodiazepines; schizophrenia; major depression; bipolar disorder), that in the opinion of a study physician would have interfered with study participation. Female subjects had to be using an effective form of birth control (e.g., birth control pills, IUD, condoms or abstinence) to participate.

A total of twelve human subjects (4 female subjects, 8 male subjects; 3 White, 8 Black, 1 Native American; 10 Non-Hispanic/Latino, 2 Hispanic/Latino) provided sober, written informed consent to participate and enrolled in this within-subject, placebo-controlled, inpatient study. Ten of these subjects completed the full study. Two subjects provided partial data sets that are included in the analysis but did not complete the study due to either violating study protocol drug use restrictions (n=1; only data collected prior to the violation of drug use restrictions are included) or experiencing an adverse event (i.e., a blood clot that ultimately resolved without further issue) that resulted in discharge from the study (n=1). Eleven additional subjects signed consent to enroll in the study. Of these, nine were not admitted to the inpatient unit and two were admitted to the inpatient unit but left before completing the study. For these two admitted subjects, one was discontinued due to elevated vital signs at the outset of the medical safety session and the other withdrew from the study after receiving the first dose (0 mg/70 kg cocaine) in the medical safety session, so they had no usable data for the present analysis.

Subjects weighed 81± 17 kg on average (± SD), had BMIs of 27 ± 4, were 47 ± 5 years of age at screening and had 12 ± 2 years of education. Drug Abuse Screening Test (Skinner, 1982) scores were 11 ± 7. Subjects reported using cocaine 18 ± 8 days in the month prior to screening. Subjects also reported experience with other drugs. Eight subjects smoked cigarettes daily (14 ± 13 cigarettes/day). Seven subjects reported weekly alcohol use (17 ± 8 standard drinks/week). In the month prior to screening, subjects reported amphetamine use (n=3), cannabis use (n=9) and opioid use (n=2). Aside from meeting criteria for cocaine use disorder, some subjects also met criteria for cannabis use disorder (n=3), alcohol use disorder (n=2; not physiologically dependent), amphetamine use disorder (n=2) and opioid use disorder (n=1; not physiologically dependent). All subjects were paid for their participation. The Medical Institutional Review Board of the University of Kentucky approved this study, which was conducted in accordance with all relevant guidelines, including the 1964 Declaration of Helsinki.

2.2. General Procedures

Subjects were enrolled as inpatients at the University of Kentucky Chandler Medical Center Inpatient Clinical Research Unit (CRU) for approximately one month and completed one drug-free practice, one medical safety and twelve experimental sessions. During inpatient admission, subjects received standard caffeine-free hospital meals. Urine samples were collected daily and expired breath samples were collected prior to each session to confirm drug and alcohol abstinence, respectively. Pregnancy tests were conducted daily on urine samples from the female subjects. All pregnancy tests were negative throughout their participation. When not in session, subjects could smoke cigarettes ad libitum if CRU staff was available to escort them to the designated smoking area.

During the medical safety session, subjects received each of the intravenous cocaine doses to be tested in subsequent experimental sessions (i.e., one infusion of 0, 10 and 30 mg/70kg cocaine) in ascending order, separated by 60 min. If predetermined cardiovascular parameters (see Lile et al., 2020) were exceeded during this session, the subject would have been discharged from the study, but only one subject was excluded as noted above.

2.2.1. Drug Maintenance Days.

Drug maintenance began on the day immediately after the medical safety session and continued throughout the protocol. Placebo or zolmitriptan was administered orally at 0700 and 1900 h in evenly divided doses. Subjects were maintained on placebo or zolmitriptan (2.5, 5 or 10 mg/day; the maximum daily dose of zolmitriptan is 10 mg) in random order, with the exception that the first five subjects received doses in ascending order as an initial demonstration of the safety and tolerability of the zolmitriptan/cocaine combinations. After at least three days of maintenance on the first assigned condition, subjects completed a block of three experimental sessions, described below. Maintenance on the assigned condition continued across experimental session days. Upon completion of these three experimental sessions, subjects underwent a drug washout period for at least three days (i.e., placebo capsules were administered at 0700 and 1900 h). Subjects then began maintenance on the next assigned condition, which also lasted at least three days before the second block of three experimental sessions was completed. This pattern continued twice more and after completing all twelve experimental sessions, subjects were discharged from the study.

2.2.2. Experimental Sessions.

Subjects who smoked cigarettes were allowed to smoke a cigarette between approximately 0730 and 0800 h prior to starting experimental sessions at 0900 h and were not allowed to smoke again until the session ended approximately 7.5 h later. Sessions consisted of a Sampling Phase and a Self-Administration Phase.

2.2.2.1. Sampling Phase.

Subjects completed a sampling phase in each experimental session to acquaint them with the effects of the cocaine dose available during that session. Baseline subjective and physiological measures were completed at approximately 0900 h. At approximately 1000 h, the intravenous cocaine dose (0, 10 or 30 mg/70 kg) was administered. Cocaine dosing order was random for each subject and zolmitriptan dose condition, with the exception that the first five subjects received doses in ascending order as an initial demonstration of safety and tolerability of the zolmitriptan/cocaine combinations. Immediately after dosing and at 15-min intervals for the next 60 min, subjective measures were completed. Physiological measures were collected at 15-min intervals after dosing. A Cognitive Battery was completed 20 min after administration of the sampling dose. The sampling phase ended at approximately 1100 h.

2.2.2.2. Self-Administration Phase.

The self-administration phase began at approximately 1100 h. During this phase, subjects were given five opportunities to choose between the cocaine dose administered during the sampling phase and USD $6.00 on a progressive ratio task (see below). At each of the five opportunities, subjects made a choice for either the cocaine dose or money and then completed the ratio requirement to earn that selection. The earned option was then administered, with subsequent choices separated by 60 min. Session ended at approximately 1600 h.

2.3. Experimental Session Measures

The reinforcing effects of intravenous cocaine were assessed using a progressive ratio task. Cocaine and money were available on concurrent, independent progressive ratio schedules as described previously (Stoops et al., 2012). The initial ratio to obtain a reinforcer was 400 clicks. The response requirement for each subsequent choice of that specific reinforcer increased by 200 (i.e., 600, 800, 1000 and 1200 responses if a subject responded exclusively for cocaine or money). The dependent measure for this task was number of drug choices, out of a maximum of five.

Subjective measures were an Adjective Rating Scale (Oliveto et al. 1992), a locally developed Drug-Effect Questionnaire (Rush et al. 2003) and the Cocaine Craving Questionnaire (Dudish-Poulsen and Hatsukami, 1997). Physiological measures (i.e., blood pressure and heart rate) were recorded using a digital monitor. Temperature was measured using a digital oral thermometer.

Subjects completed a battery of cognitive-behavioral tasks 20 min after the cocaine sampling dose in each experimental session. These included the:

1) n-Back, which measured working memory and working memory capacity (Jaeggi et al. 2010). In this task, subjects were presented with a sequence of numbers and asked to indicate when the current stimulus matched the one from “n” steps earlier. Two settings were used in this study, the 1-back and the 2-back (i.e., matching 1 and 2 stimuli back, respectively). The primary outcome of this task was proportion of correct responses for the 1- and 2-back conditions 20 min after receiving the cocaine dose, subtracting proportion correct at baseline.

2) 5-Trial Adjusting Delay Discounting Task, which assessed discounting rates for cocaine and money (Koffarnus and Bickel, 2014). In this task, subjects made a series of 5 choices between an immediately available, smaller reinforcer and a larger reinforcer at various delays. Subjects were told that all choices were hypothetical. The primary outcome of this task was the delay discounting rate (log 10 transformed k).

3) Stop-signal task, which evaluated response inhibition (Fillmore and Rush, 2001; Fillmore and Vogel-Sprott, 1999). In this task, subjects were instructed to identify and respond to letters presented on a computer screen (X and O). A stop-signal (500 ms 900 Hz tone) was presented on approximately 30% of trials to indicate that a subject should withhold a response. Stop-signals were presented at one of five delays (10, 70, 150, 230, and 300 ms). The outcome was the mean proportion of inhibitory failures following the stop-signal.

2.5. Drug Administration

All drugs were administered in a double-blind fashion. Only study investigators and the Investigational Drug Service staff had access to dose orders to maintain the blind. These individuals did not interact with subjects during experimental sessions, nor did they collect experimental data. Zolmitriptan doses (2.5, 5 and 10 mg/day, administered twice daily in evenly divided doses, Ajanta Pharma, Bridgewater, NJ) were prepared from commercially available immediate release tablets in a gelatin capsule backfilled with cornstarch. Placebo capsules contained only cornstarch. The three-day minimum maintenance period on each dose with twice daily dosing was selected to reach steady state zolmitriptan levels based upon published clinical pharmacology data (Dixon et al., 1997).

Cocaine doses (0, 10 and 30 mg/70 kg) were aseptically prepared using intravenous cocaine HCl solution (NIDA Drug Supply, Raleigh, NC). The sampling and self-administration doses for administration (10 and 30 mg/70 kg) were drawn up into syringes within 24 h of an experimental session. The 0 mg dose contained only 0.9% sodium chloride. Each dose was administered via a catheter in the non-dominant arm over 30 sec.

Doses were not administered if a subject’s heart rate was ≥ 90 bpm, systolic pressure was ≥ 140 mmHg or diastolic pressure was ≥ 90 mmHg or if clinically significant and/or prolonged ECG abnormalities were detected. No clinically significant or prolonged ECG abnormalities were detected during any subject’s participation.

2.6. Data Analysis

Progressive ratio task data were analyzed as number of drug choices using a two-factor repeated mixed-effects model, allowing for use of the non-completing subjects’ partial data sets, with Zolmitriptan Dose (0, 2.5, 5 and 10 mg/day) and Cocaine Dose (0, 10 and 30 mg/70 kg) as the factors (Prism 10, GraphPad, San Diego, CA). F values from the Geisser-Greenhouse corrected mixed-effects model were used to determine statistical significance with a threshold of p < 0.05. Tukey’s post hoc tests were used to conduct pairwise comparisons when statistically significant main or interaction effects were observed. Subjective and physiological measures were analyzed as peak effect (i.e., the maximum score observed in the 60 min following administration of the cocaine sampling dose) in the same fashion as the progressive ratio task data. Cognitive-behavioral task outcomes completed 20 min after the sampling dose were also analyzed in the same fashion as the progressive ratio task data.

3. Results

Table 1 shows F values for outcomes that had effects which reached statistical significance.

Table 1:

Summary Table of F Values (Geisser-Greenhouse corrected degrees of freedom) for measures with a statistically significant effect.

Measure Cocaine Dose Main
Effect		 Zolmitriptan Dose
Main Effect		 Cocaine and
Zolmitriptan Dose
Interaction Effect
Number of Drug Choices 42.85 (1.28, 13.60) *** 1.35 (1.30, 14.33) 0.76 (1.92, 15.98)
Adjectives (Stimulant) 20.24 (1.38, 15.22) *** 0.29 (1.544, 19.99) 0.81 (1.84, 15.30)
Drug Effect Questionnaire (Any Effect) 32.03 (1.13, 12.47) *** 1.08 (0.82, 8.97) 1.93 (1.77, 14.75)
Drug Effect Questionnaire (Good Effects) 34.12 (1.29, 14.22) *** 1.76 (0.88, 9.69) 3.00 (2.02, 16.81)
Drug Effect Questionnaire (High) 31.62 (1.19, 13.10) *** 0.63 (0.51, 5.61) 1.58 (1.86, 15.48)
Drug Effect Questionnaire (Rush) 24.63 (1.45, 15.98) *** 0.18 (0.98, 10.76) 0.67 (2.23, 18.93)
Drug Effect Questionnaire (Like Drug) 11.44 (1.31, 14.43) *** 0.45 (0.68, 7.52) 1.03 (1.76, 14.67)
Drug Effect Questionnaire (Stimulated) 14.28 (1.17, 12.89) ** 0.99 (0.68, 7.53) 0.67 (1.58, 13.20)
Drug Effect Questionnaire (Performance Improved) 6.81 (1.12, 12.33) * 0.16 (0.48, 5.29) 1.36 (1.29, 10.78)
Drug Effect Questionnaire (Willing to Take Again) 11.96 (1.33, 14.62) ** 0.16 (0.73, 8.07) 0.73 (1.90, 15.83)
Drug Effect Questionnaire (Willing to Pay For) 46.30 (1.29, 14.19) *** 0.22 (1.42, 15.60) 1.53 (1.80, 15.00)
Drug Effect Questionnaire (Active, Alert, Energetic) 25.51 (1.30, 14.33) *** 0.21 (1.02, 11.24) 1.30 (1.58, 13.17)
Drug Effect Questionnaire (Shaky, Jittery) 5.87 (1.02, 11.25) * 0.32 (1.32, 14.48) 1.69 (2.29, 19.04)
Drug Effect Questionnaire (Euphoric) 8.57 (1.12, 12.32) * 1.81 (1.48, 16.31) 0.17 (1.46, 12.20)
Drug Effect Questionnaire (Irregular, Racing Heartbeat) 10.00 (0.99, 10.91) ** 0.99 (1.91, 20.97) 1.04 (2.62, 21.79)
Systolic Blood Pressure 25.60 (1.48, 16.26) *** 2.96 (2.35, 25.84) 0.73 (2.37, 19.74)
Diastolic Blood Pressure 16.69 (1.47, 16.22) *** 1.39 (2.28, 25.04) 0.65 (2.94, 24.49)
Heart Rate 28.29 1.74, 19.18) *** 0.59 (1.52, 16.66) 2.92 (2.10, 17.50)
Temperature 5.26 (1.79, 19.72) * 5.17 (1.89, 20.75) * 0.06 (3.54, 29.50)
n-Back (Proportion Correct in 2-back) 2.81 (1.49, 16.43) 1.02 (2.26, 24.82) 3.31 (3.34, 27.79) *
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Bolded values are statistically significant. * denotes p < 0.05, ** denotes p < 0.01, *** denotes p < 0.001. F values without any asterisks are not statistically significant.

3.1. Progressive Ratio Task

A significant main effect of Cocaine Dose was observed for Number of Drug Choices on the Progressive Ratio Task. There was no statistically significant main effect of Zolmitriptan Dose nor was there a statistically significant interaction of Zolmitriptan Dose and Cocaine Dose on this outcome. As shown in Figure 1, both active cocaine doses increased Number of Drug Choices relative to placebo with near maximal intake observed regardless of zolmitriptan dose.

Fig. 1.

Fig. 1

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Dose-response function for cocaine following maintenance on placebo (circles), 2.5 mg zolmitriptan (squares), 5 mg zolmitriptan (triangles) and 10 mg zolmitriptan (diamonds) for Number of Drug Choices out of 5 maximum on the Progressive Ratio Task. X-axis: Intravenous cocaine dose in mg/70 kg. Brackets indicate 1 S.E.M. Filled symbols indicate a statistically significant difference from cocaine placebo for that respective zolmitriptan condition.

3.2. Subjective Measures

Significant main effects of Cocaine Dose were observed for the Stimulant Subscale of the Adjective Rating Scale and thirteen items from the Drug-Effect Questionnaire (Active/Alert/Energetic; Any Effect; Euphoric; Good Effects; High; Irregular/Racing Heartbeat; Like Drug; Performance Improved; Rush; Shaky/Jittery; Stimulated; Willing to Pay For; Willing to Take Again). There were no other significant main effects of Cocaine Dose, nor were there any significant effects of Zolmitriptan Dose or interactions of Zolmitriptan Dose and Cocaine Dose on the subjective measures. Figure 2 shows representative data for Like Drug, Stimulated, High and Willing to Take Again, generally indicating that both active cocaine doses increased scores on these subjective measures relative to placebo, regardless of zolmitriptan maintenance condition. In numerous instances, a dose-related effect was observed such that subjective responses to the high cocaine dose were significantly greater than those for the low cocaine dose.

Fig. 2.

Fig. 2

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Peak effect dose-response functions for cocaine following maintenance on placebo (circles), 2.5 mg zolmitriptan (squares), 5 mg zolmitriptan (triangles) and 10 mg zolmitriptan (diamonds) for subjective ratings of Like Drug (top left graph), Stimulated (top right graph), High (bottom left graph) and Willing to Take Again (bottom right graph) out of 100 maximum. X-axis: Intravenous cocaine dose in mg/70 kg. Brackets indicate 1 S.E.M. Filled symbols indicate a statistically significant difference from cocaine placebo for that respective zolmitriptan condition. “a” above the 30 mg/70 kg cocaine dose indicates a significant difference between that dose and 10 mg/70 kg cocaine dose for the placebo zolmitriptan condition. “b” above the 30 mg/70 kg cocaine dose indicates a significant difference between that dose and 10 mg/70 kg cocaine dose for the 2.5 mg zolmitriptan condition. “c” above the 30 mg/70 kg cocaine dose indicates a significant difference between that dose and 10 mg/70 kg cocaine dose for the 5 mg zolmitriptan condition. “d” above the 30 mg/70 kg cocaine dose indicates a significant difference between that dose and 10 mg/70 kg cocaine dose for the 10 mg zolmitriptan condition.

3.3. Physiological Measures

A significant main effect of Cocaine Dose was observed for Systolic and Diastolic Blood Pressure, as well as Heart Rate. As shown in Figure 3, the high cocaine dose generally produced increases on these measures relative to placebo, with the low cocaine dose also producing statistically significant increases under some conditions. Dose-related effects were observed for Systolic Blood Pressure and Heart Rate, such that responses to the high cocaine dose were significantly higher than to the low dose for the placebo and 2.5 mg zolmitriptan condition for Systolic Blood Pressure and for all zolmitriptan conditions for Heart Rate. A significant main effect of Zolmitriptan Dose and Cocaine Dose was observed for Temperature. As shown in Figure 3, oral temperature after 10 mg/70 kg cocaine was significantly higher in the 2.5 mg zolmitriptan condition relative to the 5 mg zolmitriptan condition.

Fig. 3.

Fig. 3

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Peak effect dose-response functions for cocaine following maintenance on placebo (circles), 2.5 mg zolmitriptan (squares), 5 mg zolmitriptan (triangles) and 10 mg zolmitriptan (diamonds) for Systolic Blood Pressure (top left graph), Diastolic Blood Pressure (top right graph), Heart Rate (bottom left graph) and Temperature (bottom right graph). X-axis: Intravenous cocaine dose in mg/70 kg. Brackets indicate 1 S.E.M. * indicates a statistically significant difference between the 2.5 and 5 mg zolmitriptan conditions at the 10 mg/70 kg cocaine dose condition. Remaining details are the same as for Fig. 2.

3.4. Cognitive-Behavioral Tasks

A significant interaction of Zolmitriptan Dose and Cocaine Dose was observed for proportion correct on the 2-back condition of the n-Back. As shown in Figure 4, performance on the n-Back in the 5 mg zolmitriptan condition was significantly better following both active cocaine doses relative to placebo. There were no other statistically significant effects observed for any other Cognitive-Behavioral Tasks.

Fig. 4.

Fig. 4

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Dose-response functions for cocaine following maintenance on placebo (circles), 2.5 mg zolmitriptan (squares), 5 mg zolmitriptan (triangles) and 10 mg zolmitriptan (diamonds) for Proportion Correct on the 2-back condition of the n-Back, correcting for baseline performance. X-axis: Intravenous cocaine dose in mg/70 kg. Brackets indicate 1 S.E.M. Filled symbols indicate a statistically significant difference from cocaine placebo for that respective zolmitriptan condition.

4. Discussion

This study found that intravenous cocaine produced prototypic reinforcing, subjective and physiological effects and that treatment with zolmitriptan produced limited effects on oral temperature, while active cocaine administration improved working memory relative to placebo in the 5 mg zolmitriptan condition. Beyond these main findings, which will be discussed further below, zolmitriptan/cocaine dose combinations were safe and tolerable and zolmitriptan maintenance did not change other subjective, physiological or cognitive-behavioral effects of cocaine.

Cocaine functioned as a robust reinforcer with near maximal drug intake observed at the highest dose tested, regardless of zolmitriptan maintenance condition. This finding is consistent with the body of human laboratory research examining the reinforcing effects of cocaine which has found that cocaine maintains high degrees of self-administration in humans that is often difficult to disrupt with pharmacological pretreatment or maintenance (for a review, see Regnier et al., 2022). Further, as has been shown in numerous other human laboratory studies, intravenous cocaine produced positive and stimulant-like subjective effects and increased cardiovascular output (e.g., Foltin et al., 1995; Lile et al., 2016; 2020; Stoops et al., 2022; Walsh et al., 2010).

Prior clinical research has shown that cocaine decreases temperature (e.g., Foltin and Haney, 2000; Jones et al., 1999; Lukas et al., 2001), attributable to its potent vasoconstrictive effects. Although we observed a main effect of cocaine and zolmitriptan on this measure, subsequent post hoc testing showed only limited differences between doses (i.e., between oral temperature during 2.5 and 5 mg zolmitriptan maintenance after the 10 mg/70 kg dose). This change is not necessarily unexpected given that 5-HT1b agonists are also vasoconstrictors, which is thought to be key to their anti-migraine efficacy (Whealy and Becker, 2024). This finding also serves to demonstrate that we administered physiologically active doses of zolmitriptan, suggesting that the general lack of effect observed on most of cocaine’s effects was not due to testing physiologically insufficient doses, although the doses tested could still be insufficient for altering the reinforcing and other abuse-related effects of cocaine.

We observed that active cocaine doses improved performance on the n-Back during maintenance on 5 mg zolmitriptan relative to placebo. To our knowledge, no other studies have evaluated how zolmitriptan influences working memory but preclinical research suggests activating 5-HT1b receptors with other compounds impairs working memory in rodents (Buhot et al., 1995; Woehrle et al., 2013). Although speculative, it is possible that increased synaptic monoamine levels produced by cocaine dosing ameliorated decrements produced by 5-HT1b/1d activation following 5 mg zolmitriptan daily dosing.

Zolmitriptan failed to change cocaine self-administration at all doses tested, which is discordant with the preclinical literature described in the Introduction (e.g., Garcia et al., 2020; Pentkowski et al., 2012; 2014). A potential limitation of the current study is that we did not impose a lengthy cocaine abstinence period prior to evaluating cocaine-zolmitriptan combinations, which may be critical to the “switch” observed in preclinical studies (Acosta et al., 2005; Kohtz et al., 2024; O’Dell et al., 2006; Pentkowski et al., 2009; 2012; 2014; Przegaliński et al., 2008; Scott et al., 2021). However, we primarily based this study’s design (and exclusion of an abstinence period) on the experiment published by Garcia and colleagues (Garcia et al., 2020), which indicated zolmitriptan could reduce cocaine intake without a cocaine abstinence period. Other reasons for the discordant self-administration results found between this study and preclinical experiments include species differences, dosing regimen (i.e., chronic here vs. acute dosing preclinically), pharmacokinetic/pharmacodynamic differences between zolmitriptan and the other medications tested preclinically (e.g., short half-life of zolmitriptan compared to unreported half-life of many experimental compounds like RU249699; zolmitriptan activates both 5-HT1b and 5-HT1d receptors whereas compounds tested preclinically are more selective for 5-HT1b) or self-administration arrangements that do not fully recapitulate human cocaine use. Although we collaborated on project design between this study and prior work (i.e., Garcia et al. 2020 tested zolmitriptan to support its testing here), we still failed to completely align experimental parameters like dosing regimen. More fully aligning such parameters has produced successful translation in the past (Johnson et al., 2016; Lile et al., 2016; 2020), so future research will need to continue to more closely align preclinical and clinical self-administration and pharmacological pretreatment methods to better determine whether species or other differences contributed to the divergent outcomes.

5. Conclusion

This study translated preclinical research with cocaine and zolmitriptan into the human laboratory. Overall, data indicate that activating the 5-HT1b/1d systems through zolmitriptan maintenance produces limited changes in the pharmacodynamic effects of cocaine in humans, contrasting preclinical findings. These results suggest that targeting 5-HT1b/1d likely will not be an effective way of treating CUD.

Highlights.

  • This human lab study tested how serotonin1b/1d activation influenced cocaine effects

  • Cocaine improved working memory impairment observed after serotonin1b/1d activation

  • Serotonin1b/1d activation produced limited changes on temperature after 10 mg/70 kg cocaine

  • Serotonin1b/1d activation did not alter any other effects of cocaine

Acknowledgments:

The authors gratefully acknowledge the staff of the University of Kentucky Psychopharmacology of Addiction Laboratory for technical assistance, the staff of the University of Kentucky Center for Clinical and Translational Science Clinical Research Unit for medical assistance and the University of Kentucky Investigative Drug for preparation of study medications. This study complied with all laws of the United States of America.

Funding Statement:

The authors gratefully acknowledge research support from the National Institute on Drug Abuse (R01DA052203) and from the National Center for Advancing Translational Sciences (UL1TR001998) of the National Institutes of Health. These funding agencies had no role in study design, data collection or analysis, or preparation and submission of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Conflict of Interest Statement: The authors declare no relevant conflicts of interest.

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