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Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the Spontaneously Hypertensive Rat model of ADHD.

ABSTRACT: Impulsivity and hyperactivity are two facets of attention deficit/hyperactivity disorder (ADHD). Impulsivity is expressed as reduced response inhibition capacity, an executive control mechanism that prevents premature execution of an intermittently reinforced behavior. During methylphenidate treatment, impulsivity and hyperactivity are decreased in adolescents with ADHD, but there is little information concerning levels of impulsivity and hyperactivity in adulthood after adolescent methylphenidate treatment is discontinued. The current study evaluated impulsivity, hyperactivity as well as cocaine sensitization during adulthood after adolescent methylphenidate treatment was discontinued in the Spontaneously Hypertensive Rat (SHR) model of ADHD. Treatments consisted of oral methylphenidate (1.5mg/kg) or water vehicle provided Monday-Friday from postnatal days 28-55. During adulthood, impulsivity was measured in SHR and control strains (Wistar Kyoto and Wistar rats) using differential reinforcement of low rate (DRL) schedules. Locomotor activity and cocaine sensitization were measured using the open-field assay. Adult SHR exhibited decreased efficiency of reinforcement under the DRL30 schedule and greater levels of locomotor activity and cocaine sensitization compared to control strains. Compared to vehicle, methylphenidate treatment during adolescence reduced hyperactivity in adult SHR, maintained the lower efficiency of reinforcement, and increased burst responding under DRL30. Cocaine sensitization was not altered following adolescent methylphenidate in adult SHR. In conclusion, adolescent treatment with methylphenidate followed by discontinuation in adulthood had a positive benefit by reducing hyperactivity in adult SHR rats; however, increased burst responding under DRL compared to SHR given vehicle, i.e., elevated impulsivity, constituted an adverse consequence associated with increased risk for cocaine abuse liability.

SUBMITTER: Somkuwar SS

PROVIDER: S-EPMC4764879 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the Spontaneously Hypertensive Rat model of ADHD.

Somkuwar S S SS Kantak K M KM Bardo M T MT Dwoskin L P LP

Pharmacology, biochemistry, and behavior 20151202

Impulsivity and hyperactivity are two facets of attention deficit/hyperactivity disorder (ADHD). Impulsivity is expressed as reduced response inhibition capacity, an executive control mechanism that prevents premature execution of an intermittently reinforced behavior. During methylphenidate treatment, impulsivity and hyperactivity are decreased in adolescents with ADHD, but there is little information concerning levels of impulsivity and hyperactivity in adulthood after adolescent methylphenida ...[more]

PMID: 26657171

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Project description:BackgroundMethylphenidate is the most commonly used stimulant drug for the treatment of attention-deficit/hyperactivity disorder (ADHD). Research has found that methylphenidate is a "reinforcer" and that individuals with ADHD also abuse this medication. Nevertheless, the molecular consequences of long-term recreational methylphenidate use or abuse in individuals with ADHD are not yet fully known.MethodsSpontaneously hypertensive rats (SHR), the most validated and widely used ADHD animal model, were pretreated with methylphenidate (5 mg/kg, i.p.) during their adolescence (post-natal day [PND] 42-48) and tested for subsequent methylphenidate-induced conditioned place preference (CPP) and self-administration. Thereafter, the differentially expressed genes in the prefrontal cortex (PFC) and striatum of representative methylphenidate-treated SHRs, which showed CPP to and self-administration of methylphenidate, were analyzed.ResultsGenome-wide transcriptome profiling analyses revealed 30 differentially expressed genes in the PFC, which include transcripts involved in apoptosis (e.g. S100a9, Angptl4, Nfkbia), transcription (Cebpb, Per3), and neuronal plasticity (Homer1, Jam2, Asap1). In contrast, 306 genes were differentially expressed in the striatum and among them, 252 were downregulated. The main functional categories overrepresented among the downregulated genes include those involved in cell adhesion (e.g. Pcdh10, Ctbbd1, Itgb6), positive regulation of apoptosis (Perp, Taf1, Api5), (Notch3, Nsbp1, Sik1), mitochondrion organization (Prps18c, Letm1, Uqcrc2), and ubiquitin-mediated proteolysis (Nedd4, Usp27x, Ube2d2).ConclusionTogether, these changes indicate methylphenidate-induced neurotoxicity, altered synaptic and neuronal plasticity, energy metabolism and ubiquitin-dependent protein degradation in the brains of methylphenidate-treated SHRs, which showed methylphenidate CPP and self-administration. In addition, these findings may also reflect cognitive impairment associated with chronic methylphenidate use as demonstrated in preclinical studies. Future studies are warranted to determine the clinical significance of the present findings with regard to long-term recreational methylphenidate use or abuse in individuals with ADHD.

Project description:BackgroundThe inability to inhibit reinforced responses is a defining feature of ADHD associated with impulsivity. The Spontaneously Hypertensive Rat (SHR) has been extolled as an animal model of ADHD, but there is no clear experimental evidence of inhibition deficits in SHR. Attempts to demonstrate these deficits may have suffered from methodological and analytical limitations.MethodsWe provide a rationale for using two complementary response-withholding tasks to doubly dissociate impulsivity from motivational and motor processes. In the lever-holding task (LHT), continual lever depression was required for a minimum interval. Under a differential reinforcement of low rates schedule (DRL), a minimum interval was required between lever presses. Both tasks were studied using SHR and two normotensive control strains, Wistar-Kyoto (WKY) and Long Evans (LE), over an overlapping range of intervals (1 - 5 s for LHT and 5 - 60 s for DRL). Lever-holding and DRL performance was characterized as the output of a mixture of two processes, timing and iterative random responding; we call this account of response inhibition the Temporal Regulation (TR) model. In the context of TR, impulsivity was defined as a bias toward premature termination of the timed intervals.ResultsThe TR model provided an accurate description of LHT and DRL performance. On the basis of TR parameter estimates, SHRs were more impulsive than LE rats across tasks and target times. WKY rats produced substantially shorter timed responses in the lever-holding task than in DRL, suggesting a motivational or motor deficit. The precision of timing by SHR, as measured by the variance of their timed intervals, was excellent, flouting expectations from ADHD research.ConclusionThis research validates the TR model of response inhibition and supports SHR as an animal model of ADHD-related impulsivity. It indicates, however, that SHR's impulse-control deficit is not caused by imprecise timing. The use of ad hoc impulsivity metrics and of WKY as control strain for SHR impulsivity are called into question.

Project description:The spontaneously hypertensive rat is thought to show good validity as a model of attention deficit hyperactivity disorder, in part because of impaired delayed reinforcement behaviour, corresponding to the dynamic developmental theory of the disorder. However, some previous studies may have been confounded use of fluid reward. Therefore, the objective of this study was to assess the spontaneously hypertensive rat and two comparison strains (Wistar and Wistar Kyoto) using a non-delayed food reinforcement paradigm in an attempt to advance knowledge of basic learnt behaviour in this strain, without potentially confounding reward sensitivity, which could impact on motivation to learn. Rats were trained on a fixed ratio 1 two choice discrimination schedule, extinction, reacquisition and reversal. We also tested non-reinforced spontaneous alternation to facilitate data interpretation.The spontaneously hypertensive rat displayed slower shaping and reduced on task activity during task acquisition, contrasting with previous results which indicate either enhanced responding and an impairment only when a delay is used; we suggest several reasons for this. In line with previous work, the same strain exhibited poor extinguishing of behaviour but were not impaired to the same extent on reversal of the discrimination. Finally, non-reinforced alternations on a Y-maze were also reduced in the spontaneously hypertensive rat.In sum, the spontaneously hypertensive rat appear to show poor response inhibition in reinforced and non-reinforced contexts. However, impaired response inhibition was reduced during reversal when an opposite response produced food reward alongside presentation of the conditioned stimulus. We discuss the possibility of enhanced attribution of incentive salience to cues in this strain and highlight several points of caution for researchers conducting behavioural assessments using the spontaneously hypertensive rat and their associated comparison strains.

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Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the Spontaneously Hypertensive Rat model of ADHD.

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Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the Spontaneously Hypertensive Rat model of ADHD.

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