Adolescent d-amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar-Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d-Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model.

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

“…These strain differences in FR and PR performance are consistent with our previous reports that did not use prior lever press training for food reward to directly study acquisition of cocaine self-administration in SHR and control strains (Harvey et al 2011; Jordan et al 2016b; Somkuwar et al 2013a). Interestingly, the number of sessions needed to reach stable PR breakpoints did not differ by strain, indicating that the number of cocaine self-administration sessions under the PR schedule prior to acute idazoxan challenges was similar across SHR, WKY and WIS.…”

“…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). …”

“…Catheters were surgically implanted into the right femoral vein under ketamine (90 mg/kg, intraperitoneal) and xylazine (10 mg/kg, intraperitoneal) anesthesia, as previously described in detail (Jordan et al 2016b). During surgery, 22-gauge guide cannulae (Plastics One, Roanoke, VA, USA) were implanted bilaterally using the following Swanson (1992) atlas coordinates: anterior-posterior +2.8 mm, medial-lateral ±1.4 mm at a 15° angle, and dorsal-ventral −2.9 mm from bregma, with the guide cannulae tips inserted 1 mm above the intended site.…”

“…Two 28-gauge stainless steel obturators were used to occlude cannulae when not in use. Post-surgical care, including the use of buprenorphine for postoperative pain relief, and catheter maintenance were as previously described in detail (Jordan et al 2016b). …”

“…Compared to controls, SHR are more hyperactive, inattentive, and impulsive (Sagvolden et al 1992; Jentsch 2005; De Bruin et al 2003; Hand et al 2009; Somkuwar et al 2016). SHR also have impaired working memory and show deficits in behavioral flexibility and habit learning (Nakamura-Palacios et al 1996; De Bruin et al 2003; Kantak et al 2008; Wells et al 2010; Harvey et al 2013; Gauthier et al 2014; Jordan et al 2016b). Importantly, the ADHD-like phenotype of SHR is unrelated to hypertension (Gattu et al 1997; Kantak et al 2008; Wells et al 2010).…”