Selective Norepinephrine Reuptake Inhibition by Atomoxetine Prevents Cue-Induced Heroin and Cocaine Seeking

doi:10.1016/j.biopsych.2010.09.040

Biological Psychiatry

Volume 69, Issue 3, 1 February 2011, Pages 266-274

https://doi.org/10.1016/j.biopsych.2010.09.040 Get rights and content

Background

Preventing relapse to drug use is a major challenge for drug addiction treatment. We have recently shown that impulsivity predating drug-taking increases the susceptibility to relapse to cocaine seeking and that treatment with the anti-impulsivity drug atomoxetine (ATO), a selective norepinephrine re-uptake inhibitor (norepinephrine transporter), prevents relapse. Here, we investigated further the effects of ATO on cue-maintained heroin and cocaine seeking and relapse and compared these effects with those of the anti-impulsivity stimulant drug methylphenidate (MPH).

Methods

Rats were trained to seek and self-administer cocaine or heroin under a second-order schedule of reinforcement. After acquisition of stable responding, groups of rats (n = 10–12) were treated, in a within-subject design, with either ATO or MPH (.3–3.0 mg/kg IP), and the effects on cocaine and heroin seeking were measured. The effects of ATO (.3–1.0 mg/kg) on cue-induced relapse to cocaine seeking after a 1-week period of abstinence were also studied.

Results

Atomoxetine significantly decreased both cue-controlled cocaine and heroin seeking, whereas MPH had no significant effect. Atomoxetine also significantly attenuated cue-induced relapse to cocaine seeking after abstinence. The effects of ATO were selective for cue-controlled drug-seeking, because it did not affect responding in the absence of the drug-paired cue; nor did it alter responding for oral sucrose, except minimally at the highest dose, or locomotor activity.

Conclusions

Selective norepinephrine transporter inhibition by ATO might be an effective treatment for the prevention of relapse to both stimulant and opiate addiction.

Section snippets

Animals

Outbred male Lister Hooded rats (Charles River, Margate, United Kingdom) weighing 300–330 g at the beginning of the experiments were used. Rats were housed individually, under temperature- and humidity-controlled conditions and a reversed 12-hour light/dark cycle (lights off at 7:00 am). Water was available ad libitum, and food was given at the end of each day's testing. All experimental procedures conformed to the UK (1986) Animal (Scientific Procedures) Act (Project license 80/2234).

Drugs

Cocaine

All animals (n = 12) acquired responding for cocaine under a second-order schedule, making on average nearly 300 responses in 15 min for the first cocaine infusion. As expected, responding increased during the second interval, because of the self-administration of cocaine (14). During the course of the experiment, catheter patency was lost in one animal, which was therefore excluded from the analysis. Treatment with ATO resulted in a significant dose-dependent decrease in the number of active

Discussion

The results of this study show that selective NE reuptake inhibition by ATO had the remarkable effect of greatly reducing both cocaine and heroin seeking as well as diminishing the propensity to relapse to cocaine seeking. By contrast, MPH had no effect on either cocaine or heroin seeking and, as with ATO, at doses known to affect impulsivity (21). The effects of ATO were especially seen under the second-order schedule of reinforcement, in which seeking responses are maintained with vigor over

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Drug repositioning has gained strategic value as a reaction to high attrition rates of new drugs as they pass through the clinical development process. The 5-HT2C receptor agonist lorcaserin (Belviq®), and the selective NA reuptake inhibitor atomoxetine (Strattera®) represent two drugs FDA approved for obesity and ADHD respectively. Although both drugs are of differing pharmacological class, each share a property of regulating impulsive behaviours in preclinical studies, and thus represent candidates for consideration in clinical conditions labelled as ‘impulsive-compulsive disorders’. The present studies investigated both drugs, as well as the highly selective 5-HT2C agonist CP-809101 in two tests of compulsive action: schedule-induced polydipsia (SIP) and increased perseverative [PSV] (and premature [PREM]) responses emitted during an extended ITI 5-choice task. While lorcaserin (0.06–0.6 mg/kg), CP-809101 (0.1–1 mg/kg) and atomoxetine (0.1–1 mg/kg) each reduced both PREM and PSV measures in the 5-choice task, at equivalent doses only lorcaserin and CP-809101 affected excessive water intake in the SIP task, atomoxetine (0.1–2 mg/kg) was essentially ineffective. Further evidence supporting a role of the 5-HT2C receptor as an important regulator of impulsive-compulsive behaviours, the selective antagonist SB-242084 produced the opposing effects to lorcaserin, i.e promoting both impulsive and compulsive behaviours. The profile of atomoxetine may suggest differences in the nature of compulsive action measured either as non-regulatory drinking in the SIP task, and PSV responses made in a 5-choice task. These studies support the consideration of 5-HT2C receptor agonists, typified by lorcaserin, and atomoxetine as potential treatments for clinical conditions categorised as ‘impulsive-compulsive disorders’.
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Heroin addiction is a disorder that stems from maladaptive plasticity within neural circuits and produces broad cognitive deficits. Despite considerable advances in psychotherapy and pharmacotherapy for heroin relapse and addiction, effective treatments for heroin use disorder are still lacking. Increasing preclinical evidence indicates that heroin seeking behavior is persistent after withdrawal, while cognitive dysfunctions associated with chronic heroin use are an important contributing factor to risk of heroin relapse and addiction. Cognitive enhancers may be used to stimulate treatment success and enhance treatment efficacy. The purpose of this review is to outline the literature that demonstrates the cognitive deficits during the development of heroin addiction and withdrawal process, and several factors that underline the efficacy of cognitive enhancers for heroin use disorders. The review, then, examines the potential use and pharmacological mechanisms of cognitive enhancers that act on cholinergic, glutamatergic, dopaminergic or adrenergic pathways. It also examines the effects of compounds that alter CREB signaling and epigenetic mechanisms in animal model of heroin relapse. The current body of research reveals the new insights into the pharmacological mechanisms underlying heroin addiction and holds a significant promise for cognitive enhancers as an improved approach to treat heroin use disorder in a more efficient and persistent way.
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Citation Excerpt :
What has not been addressed is whether atomoxetine will function as a cognitive enhancer in abstinent individuals with CUD who do not have ongoing cocaine use. This remains an important clinical consideration given the suggestions from pre-clinical research that atomoxetine may show promise as a relapse prevention aid (Brenhouse et al., 2010; Broos et al., 2015; Economidou et al., 2011; Jordan et al., 2014; Zlebnik and Carroll, 2015) and human laboratory studies suggesting that atomoxetine may diminish the acute effects of cocaine (Cantilena et al., 2012; Stoops et al., 2008) or d-amphetamine (Sofuoglu et al., 2009). Associations between poorer cognitive function and worse treatment engagement or substance use outcomes during or following treatment (Carroll et al., 2011; Kiluk et al., 2011; Streeter et al., 2008; Teichner et al., 2001), including likelihood of relapse (Fox et al., 2009), underline the theoretical potential for cognitive improvements to improve substance use outcomes or enhance the efficacy of cognitively demanding behavioral treatments like cognitive behavioral therapy.
No pharmacotherapies are approved for the treatment of cocaine use disorders (CUD). Behavioral treatments for CUD are efficacious for some individuals, but recovery rates from CUD remain low. Cognitive impairments in CUD have been linked with poorer clinical outcomes. Cognitive enhancing pharmacotherapies have been proposed as promising treatments for CUD. Atomoxetine, a norepinephrine transporter inhibitor, shows potential as a treatment for CUD based on its efficacy as a cognitive enhancer in other clinical populations and impact on addictive processes in preclinical and human laboratory studies.
In this randomized, double-blind, crossover study, abstinent individuals with CUD (N = 39) received placebo, 40 and 80 mg atomoxetine, over three sessions. Measures of attention, response inhibition and working memory; subjective medication effects and mood; and cardiovascular effects were collected. Analyses assessed acute, dose-dependent effects of atomoxetine. In addition, preliminary analyses investigating the modulation of atomoxetine dose effects by sex were performed.
Atomoxetine increased heart rate and blood pressure, was rated as having positive and negative subjective drug effects, and had only modest effects on mood and cognitive enhancement.

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Archival ReportSelective Norepinephrine Reuptake Inhibition by Atomoxetine Prevents Cue-Induced Heroin and Cocaine Seeking

Background

Methods

Results

Conclusions

Section snippets

Animals

Drugs

Cocaine

Discussion

J Subst Abus Treat

Biol Psychiatry

Neuropharmacology

Neuropharmacology

Biol Psychiatry

Neurobiol Learn Mem

Neuropsychopharmacology

Neurochem Int

Eur J Pharmacol

Neuron

Pharmacol Ther

Biol Psychiatry

Eur J Pharmacol

Clin Ther

Drug Alcohol Depend

Drug Alcohol Depend

Drug Alcohol Depend

Neuropsychopharmacology

Neuroscience

Brain Res Rev

Brain Res

Eur J Pharmacol

Prog Neuropsychopharmacol Biol Psychiatry

Pharmacol Ther

Neuroscience

Neuropharmacology

Anticraving medications for relapse prevention: A possible new class of psychoactive medications

Am J Psychiatry

Impulsivity and rapid discounting of delayed hypothetical rewards in cocaine-dependent individuals

Exp Clin Psychopharmacol

Effect of impulsivity on craving and behavioral reactivity to smoking cues

Psychopharmacology (Berl)

Nucleus accumbens: D2/3 receptors predict trait impulsivity and cocaine reinforcement

Science

Pharmacological treatment of attention-deficit/hyperactivity disorder in adults

Expert Opin Investig Drugs

Atomoxetine versus stimulants for treatment of attention deficit/hyperactivity disorder

Ann Pharmacother

Cue reactivity and cue reactivity interventions in drug dependence

NIDA Res Monogr

Classical conditioning in drug-dependent humans

Ann N Y Acad Sci

Cue-induced cocaine craving: Neuroanatomical specificity for drug users and drug stimuli

Am J Psychiatry

Second-order schedules of drug injection

Fed Proc

Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: Effects of conditioned cues and continuous access to cocaine

Psychopharmacology (Berl)

Heroin self-administration under a second-order schedule of reinforcement: Acquisition and maintenance of heroin-seeking behaviour in rats

Psychopharmacology (Berl)

Second-order schedules of drug reinforcement in rats and monkeys: Measurement of reinforcing efficacy and drug-seeking behaviour

Psychopharmacology (Berl)

Second-order schedules of drug self-administration in animals

Psychopharmacology (Berl)

The reinstatement model of drug relapse: History, methodology and major findings

Psychopharmacology (Berl)

Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixol

Psychopharmacology (Berl)

Differential effects of psychomotor stimulants on attentional performance in rats: Nicotine, amphetamine, caffeine and methylphenidate

Behav Pharmacol

A review of stimulant drug research with hyperactive children

J Child Psychol Psychiatry

Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters

Life Sci

A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain

J Pharmacol Exp Ther

Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat

Neuropsychopharmacology

Interaction between noradrenaline and corticotrophin-releasing factor in the reinstatement of cocaine seeking in the rat

Psychopharmacology (Berl)

Archival Report
Selective Norepinephrine Reuptake Inhibition by Atomoxetine Prevents Cue-Induced Heroin and Cocaine Seeking