Methylphenidate Treatment in Adolescent Rats with an Attention Deficit/Hyperactivity Disorder Phenotype: Cocaine Addiction Vulnerability and Dopamine Transporter Function

Abstract

Appropriate animal models of Attention Deficit/Hyperactivity Disorder (ADHD) and drug reinforcement allow investigation of possible underlying biological bases of ADHD and its co-morbidity with cocaine addiction. Toward this end, Spontaneously Hypertensive Rats (SHR) exhibiting an ADHD phenotype were compared to Wistar-Kyoto (WKY) and Wistar (WIS) rats. Initially, 1.5 mg/kg oral methylphenidate or vehicle was administered between post-natal days 28–55 and acquisition of visual discrimination learning was examined. After discontinuing adolescent treatments, adult rats were evaluated for cocaine self-administration and dopamine transporter (DAT) function in prefrontal cortex and striatum. During adolescence, SHR showed deficits in visual discrimination relative to WKY and WIS when non-medicated. Methylphenidate improved visual discrimination only in SHR. Compared to WKY and WIS, SHR with prior methylphenidate treatment acquired cocaine self-administration fastest, identified cocaine as a highly efficacious reinforcer by displaying an upward shift in the cocaine dose-response function, and showed the greatest motivation to self-administer cocaine by exhibiting the highest progressive ratio breakpoints. In prefrontal cortex, maximal dopamine uptake (Vmax) at DAT was decreased in SHR and increased in WKY and WIS by prior methylphenidate treatment. Affinity (Km) for dopamine at DAT in prefrontal cortex was not different between strains, nor was Vmax or Km altered in striatum by prior methylphenidate treatment in any strain. Methylphenidate-induced decreases in dopamine clearance by DAT in prefrontal cortex may underlie increased cocaine self-administration in SHR. These preclinical findings suggest that caution should be exercised when methylphenidate is prescribed for first-time treatment of ADHD in adolescent patients, as cocaine addiction vulnerability may be augmented.

Exposure to methylphenidate during infancy and adolescence in non-human animals and sensitization to abuse of psychostimulants later in life: a systematic review

“…47,48 Finally, there seems to be an inconsistency among preclinical studies showing no differences in rates of acquisition of cocaine reinforcement after chronic treatment with MPH. 21,22 Gill et al 35 explain this inconsistency by highlighting the differences in the dose of cocaine initially delivered to the animals in the self-administration paradigm. In this study, Gill et al 35 provided the animals with lower initial doses of cocaine, which were below reinforcing thresholds.…”

“…In the first study, Peña et al 37 For instance, increases in the rewarding value of cocaine were observed in rodents submitted to cocaine selfadministration, 3,21 whereas animals (especially from the SHR strain) tested with the CPP task exhibit decreased rewarding effects. 37 To address this question, Crawford et al 22 Effects were only observed among male subjects that had been exposed to MPH and these effects were only observed in relation to cocaine self-administration.…”

“…20 The self-administration model has been successfully used to measure psychostimulant reinforcement in non-human animal models. [21][22][23] In this model, animals are trained to perform an action in order to receive an infusion of a drug. In this kind of experiment, various different manipulations can be performed to examine their effects on self-administration.…”

“…49,50 However, each study has some relevant peculiarities. For instance, Harvey et al 21 assessed DAT functionality in specific brain areas (the prefrontal cortex and striatum), while Jordan et al 3 …”

“…3,21 Both works utilized cocaine self-administration after treatment with MPH and compared males of three rodent strains, namely Wistar (WIS), Wistar Kyoto (WKY) and the spontaneously hypertensive rat (SHR), the last of which is widely used as an animal genetic model for ADHD because it exhibits behavioral correlates with this disorder. 49,50 However, each study has some relevant peculiarities.…”