Elsevier

Drug and Alcohol Dependence

Volume 140, 1 July 2014, Pages 25-32
Drug and Alcohol Dependence

Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments

https://doi.org/10.1016/j.drugalcdep.2014.04.020Get rights and content

Abstract

Background

Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with cocaine abuse. Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Whereas childhood methylphenidate treatment may be preventative, methylphenidate in teens appears to further increase later cocaine abuse risk. In rodents, adolescent methylphenidate treatment further increases adult cocaine self-administration in the Spontaneously Hypertensive Rat (SHR) model of ADHD, whereas adolescent atomoxetine treatment does not. Effects of ADHD medications on cocaine cue reactivity, a critical component of addiction, are unknown.

Methods

To investigate this, SHR, Wistar–Kyoto (inbred control) and Wistar (outbred control) rats received therapeutically relevant doses of methylphenidate (1.5 mg/kg, oral) and atomoxetine (0.3 mg/kg, intraperitoneal), or respective vehicles from post-natal day 28–55. Cocaine seeking, reflecting cue reactivity, was measured in adulthood during self-administration maintenance and cue-induced reinstatement tests conducted under a second-order schedule.

Results

Compared to control strains, SHR earned more cocaine infusions, emitted more cocaine-seeking responses during maintenance and reinstatement testing, and required more sessions to reach the extinction criterion. Compared to vehicle, adolescent methylphenidate, but not atomoxetine, further increased cocaine intake during maintenance testing in SHR. Adolescent atomoxetine, but not methylphenidate, decreased cocaine seeking during reinstatement testing in SHR. Neither medication had effects on cocaine intake or cue reactivity in control strains.

Conclusions

The SHR successfully model ADHD and cocaine abuse comorbidity and show differential effects of adolescent ADHD medications on cocaine intake and cue reactivity during adulthood. Thus, SHR have heuristic value for assessing neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition. Diagnoses have risen 41% over the past decade, with rates escalating fastest in boys aged 14–17 (Visser et al., 2010, Schwarz and Cohen, 2013). ADHD is highly comorbid with substance abuse, including cocaine (van Emmerik-van Oortmerssen et al., 2012). Children with ADHD are 2–3 times more likely to abuse cocaine in adulthood compared to children without an ADHD diagnosis (Lee et al., 2011).

Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Approximately two-thirds of U.S. children and adolescents diagnosed with ADHD are prescribed a stimulant medication, such as methylphenidate (Schwarz and Cohen, 2013). Methylphenidate, like cocaine, inhibits dopamine and norepinephrine transporters (DAT and NET, respectively). Because adolescence represents a period of elevated plasticity in the mesocorticolimbic dopamine system, stimulant exposure during this period may have unique long-term effects on reward responsivity (Andersen, 2005). Whereas childhood methylphenidate treatment is protective against an increase in later cocaine abuse (Wilens et al., 2003, Humphreys et al., 2013), adolescent methylphenidate treatment can increase later abuse of cocaine and other drugs (Lambert and Hartsough, 1998, Mannuzza et al., 2008, Dalsgaard et al., 2014). Although some studies reported protective effects of adolescent stimulant treatment (e.g., Biederman et al., 1999), these studies often fail to distinguish actively medicated participants from those who discontinued treatment at assessment. As cocaine use may be a form of self-medication for untreated ADHD (Gudjonsson et al., 2012), ongoing methylphenidate treatment may compromise detecting increased cocaine abuse, as suggested by animal studies (Schenk and Izenwasser, 2002). Further, many clinical studies employ a limited follow-up period into adulthood. Because cocaine abuse generally develops later than abuse of other substances (Degenhardt et al., 2008), participants evaluated in their late teens and early twenties may not have surpassed the risk period for initiating cocaine use.

Preclinical models can address clinically relevant questions concerning ADHD. Typically used is the Spontaneously Hypertensive Rat (SHR), whose behavioral and cognitive deficits model the ADHD combined subtype and are unrelated to hypertension (Wyss et al., 2003, Sagvolden et al., 2005, Russell et al., 2005, Kantak et al., 2008). Furthermore, SHR exhibit elevated cocaine self-administration compared to Wistar–Kyoto (WKY; inbred progenitor of SHR) or Wistar (WIS; outbred common ancestor to SHR and WKY) control strains (Harvey et al., 2011, Somkuwar et al., 2013b). Using a therapeutically relevant dose (Kuczenski and Segal, 2002), we demonstrated that adolescent treatment with 1.5 mg/kg oral methylphenidate further enhanced the speed to acquire cocaine self-administration and the efficacy and motivating influence of cocaine reinforcement in adult SHR, but not in adult WKY or WIS (Harvey et al., 2011).

Atomoxetine, a non-stimulant ADHD medication, is a viable alternative to methylphenidate for adolescents with ADHD in whom drug abuse is a concern (Kratochvil et al., 2002). At therapeutic doses, atomoxetine selectively inhibits NET to increase extracellular norepinephrine and dopamine in prefrontal cortex (PFC; Bymaster et al., 2002). We recently demonstrated that adolescent treatment with 0.3 mg/kg atomoxetine did not further enhance the speed to acquire cocaine self-administration or the efficacy and motivating influence of cocaine reinforcement in adult SHR or WIS, but did facilitate acquisition of cocaine self-administration in adult WKY (Somkuwar et al., 2013b).

Environmental cues associated with cocaine use play a major role in compulsive drug seeking and relapse, and are linked to changes in dopamine-mediated neurotransmission in cortical sites such as medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) (Ciccocioppo et al., 2001, Di Pietro et al., 2008). DAT function in mPFC and OFC also is affected by adolescent ADHD medications (Somkuwar et al., 2013a, Somkuwar et al., 2013b). Unknown is whether ADHD influences reactivity to cocaine-related cues, and if medications prescribed for teens with ADHD alter cue reactivity in adulthood after treatment discontinuation. Cocaine cue reactivity is a fundamentally different issue than those addressed in our previous studies, which focused instead on the efficacy and motivating influence of cocaine reinforcement through the use of fixed-ratio (FR) and progressive-ratio (PR) schedules of cocaine delivery (Harvey et al., 2011, Somkuwar et al., 2013b). To address these new clinically relevant questions, we assessed strain differences in cocaine cue reactivity among SHR, WKY and WIS rats, and determined whether adolescent methylphenidate or atomoxetine influenced cocaine cue reactivity during adulthood after adolescent treatment was discontinued. A second-order schedule of cocaine delivery and cue presentation was used so that cocaine seeking, reflecting cue reactivity, could be measured when cocaine was (maintenance) and was not (reinstatement) available for self-administration (Kantak et al., 2002).

Section snippets

Subjects

Male WKY/Cr, WIS/Cr, and SHR/Cr rats (Charles River Laboratories, USA) arrived on postnatal day 25 (P25). Rats had free access to water. Food was restricted to ∼90% of a growth-adjusted free-feeding body weight until P55 to mimic conditions of past comparator studies (Harvey et al., 2011, Harvey et al., 2013, Somkuwar et al., 2013a, Somkuwar et al., 2013b). Rats in Experiment 1 were utilized previously to measure strategy set shifting performance during adolescence (Harvey et al., 2013),

Maintenance testing

Cocaine intake during maintenance testing under the second-order schedule is shown in Fig. 1a. Strains differed in number of cocaine infusions [F(2, 47) = 11.3; p  0.001], with adult SHR earning more infusions than WKY and WIS (p  0.001 and 0.01, respectively). Main and interaction effects of treatment were not significant, but Bonferroni analysis revealed treatment differences in adult SHR, with more cocaine infusions earned after adolescent methylphenidate than vehicle treatment (p  0.014). In

Strain differences in cocaine-seeking and cocaine-taking behavior

The current study replicates and extends previous research suggesting that SHR are an excellent model of comorbid ADHD and cocaine abuse (Harvey et al., 2011, Somkuwar et al., 2013b). Consistent with prior studies, cocaine intake was greater in SHR than WKY or WIS. The current study also revealed that SHR extinguish responding to criterion levels within the same timeframe as WKY, but more slowly than WIS, and that SHR emit more cocaine-seeking responses than WKY or WIS. High levels of cocaine

Conclusions

There are limitations to every animal model of human disease. Nonetheless, SHR exhibit behavioral and cognitive deficits (Wyss et al., 2003, Sagvolden et al., 2005, Russell et al., 2005, Kantak et al., 2008) as well as neurochemical and genetic differences (Mill et al., 2005, Roessner et al., 2010) reflecting those observed in ADHD. Thus, SHR have heuristic value for assessing the neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD. Questions regarding

Role of funding source

This study was funded by grant NIH R01 DA011716. NIH had no further role in study design; in data collection, analysis and interpretation; in the writing of the report; or in the decision to submit the paper for publication.

Contributors

CJ was responsible for data collection, data analysis and writing the report. KK and LD were responsible for study concept and design, and provided important intellectual content in the writing of the report. RH and BB were involved in data collection. All authors contributed to and have approved the final version of the manuscript.

Conflict of interest

All authors declare no conflict of interest.

Acknowledgements

The authors thank Angelica DellaMorte and Katherine Rodriguez for technical assistance.

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