Adolescent d-amphetamine treatment in a rodent model of attention deficit/hyperactivity disorder: impact on cocaine abuse vulnerability in adulthood

Abstract

Rationale Stimulant medications for Attention-Deficit/Hyperactivity Disorder (ADHD) in adolescents remains controversial with respect to later development of cocaine abuse. Past research demonstrated that adolescent methylphenidate treatment increased several aspects of cocaine self-administration during adulthood using the Spontaneously Hypertensive Rat (SHR) model of ADHD. Presently, we determined effects of the alternate stimulant medication, d-amphetamine, on cocaine self-administration. Objectives We tested the hypothesis that adolescent d-amphetamine would not increase cocaine self-administration in adult SHR, given that d-amphetamine has a different mechanism of action than methylphenidate. Methods A pharmacologically relevant dose of d-amphetamine (0.5 mg/kg) or vehicle was administered throughout adolescence to SHR and two control strains, Wistar-Kyoto (WKY) and Wistar (WIS). Three aspects of cocaine abuse vulnerability were assessed in adulthood after discontinuing adolescent treatments: acquisition rate and dose-related responding under fixed (FR) and progressive (PR) ratio schedules. Results Adult SHR acquired cocaine self-administration faster and self-administered more cocaine across multiple doses compared to WKY and WIS under FR and PR schedules, indicating SHR is a reliable animal model of comorbid ADHD and cocaine abuse. Relative to vehicle, SHR and WIS with adolescent d-amphetamine treatment self-administered less cocaine upon reaching acquisition criteria, and WIS additionally acquired cocaine self-administration more slowly and had downward shifts in FR and PR cocaine dose-response curves. WKY with adolescent d-amphetamine treatment acquired cocaine self-administration more quickly relative to vehicle. Conclusions In contrast to methylphenidate, adolescent d-amphetamine did not augment cocaine self-administration in SHR. Adolescent d-amphetamine treatment actually protected against cocaine abuse vulnerability in adult SHR and WIS.

Necessity for research directed at stimulant type and treatment-onset age to access the impact of medication on drug abuse vulnerability in teenagers with ADHD

“…Cocaine self-administration was acquired faster in SHR than WKY and WIS, and cocaine was a more efficacious reinforcer and had a greater motivating influence in SHR than WKY and WIS (Harvey et al, 2011; Somkuwar et al, 2013; Jordan et al, submitted). In addition, SHR were more reactive to cocaine-paired cues and took longer to extinguish cocaine-seeking responses than WKY and WIS (Jordan et al, 2014; Jordan et al, 2016).…”

“…In adult SHR, adolescent d-amphetamine reduced some aspects of cocaine abuse by decreasing cocaine intake at acquisition and decreasing cue-induced reinstatement of cocaine-seeking responses during the first of seven test sessions (Jordan et al, 2016; Jordan et al, submitted). In adult WIS, adolescent d-amphetamine slowed the speed of acquisition, decreased cocaine intake at acquisition, produced a downward shift in the cocaine dose-response curve, and decreased progressive ratio breakpoints (Jordan et al, submitted). Adolescent d-amphetamine did not alter any measure of cocaine abuse in WKY, except for a faster speed of acquisition (Jordan et al, submitted).…”

Blockade of α2-adrenergic receptors in prelimbic cortex: impact on cocaine self-administration in adult spontaneously hypertensive rats following adolescent atomoxetine treatment

“…Adolescent methylphenidate treatment may enhance cocaine self-administration in adult SHR because of its greater influence on dopamine relative to norepinephrine (Berridge et al 2006; Bymaster et al 2002) and ability to increase DAT function in medial prefrontal cortex of SHR, which is an adaptation not observed after chronic adolescent atomoxetine treatment (Somkuwar et al 2013b). It is noteworthy that adolescent d-amphetamine treatment, like atomoxetine, does not increase cocaine self-administration in the SHR model of ADHD (Jordan et al 2016a; 2016b) and is more potent for enhancing extracellular norepinephrine than dopamine in rat prefrontal cortex (Berridge and Stalnaker 2002; Easton et al 2007). …”

“…For the self-administration procedure, cocaine hydrochloride (National Institute on Drug Abuse, Bethesda, MD, USA) was dissolved in 0.9% sterile saline containing 3 IU heparin/ml saline. The cocaine-training dose was 0.3 mg/kg (a 0.8 mg/ml concentration infused at a rate of 1.8 ml/min for a duration of 1.2 s/100 g body weight) and was selected because it maintains moderate PR breakpoints from which increases or decreases can be detected in SHR, WKY and WIS (Harvey et al 2011; Jordan et al 2016a; Somkuwar et al 2013a). To evaluate the effects of a locally applied α2-adrenergic receptor antagonist on cocaine self-administration behavior under a PR schedule, idazoxan (Sigma-Aldrich, St. Louis, MO, USA) was dissolved in 0.9% sterile saline to provide final concentrations of 10, 30, and 56 μg/0.5 μl for infusion into prelimbic cortex.…”

“…After 1-week recovery from surgery, rats were trained to lever press for 45 mg food pellet reinforcement under a FR1 schedule to accelerate acquisition of cocaine self-administration in the three strains of rats. Without food pellet training or other external inducements for lever pressing, WKY and WIS typically require 3-fold more sessions than SHR to acquire cocaine self-administration to an established criterion (Harvey et al 2011; Jordan et al 2016a; Somkuwar et al 2013a). One day after earning 100 food pellets within 30 minutes, rats began cocaine self-administration training in daily (Monday-Friday) 2-hr sessions under a FR1 20-sec timeout schedule of cocaine delivery (0.3 mg/kg, intravenous) with the session contingencies as previously described (Somkuwar et al 2013a).…”