Atomoxetine Treatment for Cocaine Abuse and Adult Attention Deficit/Hyperactivity Disorder (ADHD): A Preliminary Open Trial

Levin, Frances R.; Mariani, John J.; Secora, Alex; Brooks, Daniel J.; Cheng, Wendy Y.; Bisaga, Adam; Nunes, Edward V.; Aharonovich, Efrat; Raby, Wilfrid N.; Hennessy, Grace

doi:10.1080/15504260802628767

Cited by 40 publications

(27 citation statements)

References 36 publications

(51 reference statements)

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“…The lack of therapeutic effects solely by ATO in the present study is not uncommon, as ATO has shown mixed effects on decreasing stimulant use (Levin et al, 2009; Walsh et al, 2013; Rush et al, 2011). A previous study indicated that ATO alone decreased reinstatement (Zlebnik and Carroll, 2015), but Broos and colleagues (2015) showed no effect on reinstatement if rats had received extinction training.…”

Section: Discussionmentioning

confidence: 61%

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Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine

Swalve

Smethells

Zlebnik

et al. 2016

Pharmacology Biochemistry and Behavior

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Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e. relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4 mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5 mg/kg) alone (PRO+SAL), ATO (1.5 mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes.

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Section: Discussionmentioning

confidence: 61%

“…In humans, ATO decreased both physiological (e.g., blood pressure increases) and subjective (e.g., pleasurable ratings) responses to d-amphetamine (Sofouglu et al, 2009). However, in some studies, no effects of ATO on stimulant use have been found (Levin et al, 2009; Walsh et al, 2013; Rush et al, 2011). …”

Section: Introductionmentioning

confidence: 98%

Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine

Swalve

Smethells

Zlebnik

et al. 2016

Pharmacology Biochemistry and Behavior

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“…However, ATO has other characteristics that make it a promising candidate. In animal models of drug abuse and relapse, ATO treatment alone (Economidou et al 2009; Economidou et al 2011) or in combination with other treatments reduced cue- and/or cocaine-primed cocaine seeking in male (Swalve et al 2016) and female (Zlebnik and Carroll 2014) rats, but did not reduce cocaine self-administration in humans (Economidou et al 2011; Levin et al 2009; Walsh et al 2013). Taken together, these studies suggest that ATO may be an effective treatment to reduce impulsive choice for cocaine for both sexes.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in the reduction of impulsive choice (delay discounting) for cocaine in rats with atomoxetine and progesterone

et al. 2016

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Rationale Impulsive choice, or an inability to delay immediate gratification, has been strongly linked to the development and persistence of drug abuse. Indeed, delaying drug use itself may underlie drug addiction and relapse. Thus, employing treatments that are efficacious in reducing impulsive choice (atomoxetine; ATO) or drug-seeking behavior (progesterone; PRO) may be an effective means of treating drug addiction. Objective The current study assessed sex differences in the effects of PRO, ATO and their combination in a delay discounting paradigm for cocaine and for sucrose pellets. Method Male and female rats chose between a small-immediate or a large-delayed (0, 7.5, 15, 30, 60 sec) outcome in an impulsive choice procedure for sucrose pellets (1 vs 3 pellets) or for iv cocaine infusions (0.3 vs 0.9 mg/kg). Following baseline assessment of impulsive choice, rats received daily treatment of vehicle (VEH), PRO (0.5 mg/kg), ATO (1.5 mg/kg) or a combination (PRO + ATO) until a second assessment of impulsive choice was determined. Results Compared to the VEH group, females were less impulsive for cocaine following PRO or the PRO + ATO combined treatment, whereas males were less impulsive for cocaine following ATO. No treatment effects were observed on impulsive choice for sucrose pellets. Conclusions The present results indicate that impulsive choice for cocaine is reduced by PRO in females and by ATO in males. These findings suggest both treatments may be an effective intervention in treating cocaine abuse, but that their effectiveness differs by sex.

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“…Using ATO, studies have demonstrated reduced impulsivity across a range of behavioral tasks such as the 5-choice serial reaction time (Baarendse and Vanderschuren 2012, Robinson et al 2008), stop-signal reaction time (Robinson et al 2008), and delay-discounting (Bizot et al 2011, Robinson et al 2008) tasks (but see Baarendse & Vanderschuren, 2012, Broos et al 2012, Sun et al 2012). Regarding atomoxetine’s effects on stimulant addiction, some clinical investigations have found no therapeutic effect on cocaine use (Levin et al 2009, Walsh et al 2013) and the subjective effects of methamphetamine (Rush et al 2011), while others found reduced physiological and subjective effects of d-amphetamine (Sofuoglu et al 2009), significant attenuation of alcohol cravings (Wilens et al 2011), longer abstinence from alcohol use (Benegal et al 2013), and fewer days of heavy alcohol drinking (Wilens et al 2008). Similarly equivocal findings were demonstrated in rodents.…”

Section: Introductionmentioning

confidence: 99%

Effects of the combination of wheel running and atomoxetine on cue- and cocaine-primed reinstatement in rats selected for high or low impulsivity

Zlebnik

Carroll

2014

Psychopharmacology

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BACKGROUND Aerobic exercise and the attention-deficit/hyperactivity disorder medication, atomoxetine (ATO), are two monotherapies that have been shown to suppress reinstatement of cocaine seeking in an animal model of relapse. The present study investigated the effects of combining wheel running and ATO vs. each treatment alone on cocaine seeking precipitated by cocaine and cocaine-paired cues in rats with differing susceptibility to drug abuse (i.e., high vs. low impulsive). METHODS Rats were screened for high (HiI) or low impulsivity (LoI) based on their performance on a delay-discounting task and then trained to self-administer cocaine (0.4 mg/kg/inf) for 10 days. Following 14 days of extinction, both groups were tested for reinstatement of cocaine seeking precipitated by cocaine or cocaine-paired cues in the presence of concurrent running wheel access (W), pretreatment with ATO, or both (W+ATO). RESULTS HiI rats acquired cocaine self-administration more quickly than LoI rats. While both individual treatments and W+ATO significantly attenuated cue-induced cocaine seeking in HiI and LoI rats, only W+ATO was effective in reducing cocaine-induced reinstatement compared to vehicle treatment. There were dose-dependent and phenotype-specific effects of ATO with HiI rats responsive to the low but not high ATO dose. Floor effects of ATO and W on cue-induced reinstatement prevented the assessment of combined treatment effects. CONCLUSIONS These findings demonstrated greater attenuation of cue- vs. cocaine-induced reinstatement by ATO and W alone and recapitulate impulsivity phenotype differences in both acquisition of cocaine self-administration and receptivity to treatment.

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Atomoxetine Treatment for Cocaine Abuse and Adult Attention Deficit/Hyperactivity Disorder (ADHD): A Preliminary Open Trial

Cited by 40 publications

References 36 publications

Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine

Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine

Sex differences in the reduction of impulsive choice (delay discounting) for cocaine in rats with atomoxetine and progesterone

Effects of the combination of wheel running and atomoxetine on cue- and cocaine-primed reinstatement in rats selected for high or low impulsivity

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