Long-Term Effects of Chronic Oral Ritalin Administration on Cognitive and Neural Development in Adolescent Wistar Kyoto Rats

Abstract

The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) often results in chronic treatment with psychostimulants such as methylphenidate (MPH, Ritalin®). With increases in misdiagnosis of ADHD, children may be inappropriately exposed to chronic psychostimulant treatment during development. The aim of this study was to assess the effect of chronic Ritalin treatment on cognitive and neural development in misdiagnosed “normal” (Wistar Kyoto, WKY) rats and in Spontaneously Hypertensive Rats (SHR), a model of ADHD. Adolescent male animals were treated for four weeks with oral Ritalin® (2 × 2 mg/kg/day) or distilled water (dH2O). The effect of chronic treatment on delayed reinforcement tasks (DRT) and tyrosine hydroxylase immunoreactivity (TH-ir) in the prefrontal cortex was assessed. Two weeks following chronic treatment, WKY rats previously exposed to MPH chose the delayed reinforcer significantly less than the dH2O treated controls in both the DRT and extinction task. MPH treatment did not significantly alter cognitive performance in the SHR. TH-ir in the infralimbic cortex was significantly altered by age and behavioural experience in WKY and SHR, however this effect was not evident in WKY rats treated with MPH. These results suggest that chronic treatment with MPH throughout adolescence in “normal” WKY rats increased impulsive choice and altered catecholamine development when compared to vehicle controls.

Adolescent Exposure to Methylphenidate Increases Impulsive Choice Later in Life

“…The persistent effects of MPH observed here contrast with previously published work (Adriani et al, 2007 ; Leo et al, 2009 ; Pardey et al, 2012 ), a discrepancy that may be explained by methodological differences. Our methodology was modeled after one of the main paradigms used in the literature on delay discounting.…”

Adolescent Exposure to Methylphenidate Increases Impulsive Choice Later in Life

“…The persistent effects of MPH observed here contrast with previously published work (Adriani et al, 2007 ; Leo et al, 2009 ; Pardey et al, 2012 ), a discrepancy that may be explained by methodological differences. Our methodology was modeled after one of the main paradigms used in the literature on delay discounting.…”

Chronic methylphenidate preferentially alters catecholamine protein targets in the parietal cortex and ventral striatum

“…2B) suggests an enhanced catecholamine synthesis following chronic but not acute MPH administration. Similar to our findings on TH in the FC and DS, a previous study using normal and SHR rats, failed to show MPH-induced changes in TH levels in FC (Pardey et al, 2012). In contrast, an additional study using normal rats and beginning the chronic MPH treatment at an earlier stage of development (PND 7) as well as with a longer duration (4 weeks) compared to the present study (PND 25 and 2 weeks respectively), detected increases in TH-immunoreactive fibre density in FC (Gray et al, 2007).…”

Characterisation of methylphenidate-induced excitation in midbrain dopamine neurons, an electrophysiological study in the rat brain

“…These effects could be due to altered mesocortical circuitry, as previously observed (Urban et al, 2012), although striking differences between in vivo and ex vivo studies are to be noted (Di Miceli and Gronier, 2015;Urban et al, 2012). Long-term consequences of chronic MPH treatment was observed following chronic MPH exposure during adolescence, with adult rats presenting altered cognitive behaviour (Pardey et al, 2012), behavioural sensitisation or tolerance (Jones and 21 Dafny, 2014) and altered responses to dopamine D2 receptor challenge (Di Miceli et al, 2018).…”

Adolescent Exposure to Methylphenidate Increases Impulsive Choice Later in Life

“…The persistent effects of MPH observed here contrast with previously published work (Adriani et al, 2007 ; Leo et al, 2009 ; Pardey et al, 2012 ), a discrepancy that may be explained by methodological differences. Our methodology was modeled after one of the main paradigms used in the literature on delay discounting.…”

Chronic methylphenidate preferentially alters catecholamine protein targets in the parietal cortex and ventral striatum

“…2B) suggests an enhanced catecholamine synthesis following chronic but not acute MPH administration. Similar to our findings on TH in the FC and DS, a previous study using normal and SHR rats, failed to show MPH-induced changes in TH levels in FC (Pardey et al, 2012). In contrast, an additional study using normal rats and beginning the chronic MPH treatment at an earlier stage of development (PND 7) as well as with a longer duration (4 weeks) compared to the present study (PND 25 and 2 weeks respectively), detected increases in TH-immunoreactive fibre density in FC (Gray et al, 2007).…”

Characterisation of methylphenidate-induced excitation in midbrain dopamine neurons, an electrophysiological study in the rat brain

“…These effects could be due to altered mesocortical circuitry, as previously observed (Urban et al, 2012), although striking differences between in vivo and ex vivo studies are to be noted (Di Miceli and Gronier, 2015;Urban et al, 2012). Long-term consequences of chronic MPH treatment was observed following chronic MPH exposure during adolescence, with adult rats presenting altered cognitive behaviour (Pardey et al, 2012), behavioural sensitisation or tolerance (Jones and 21 Dafny, 2014) and altered responses to dopamine D2 receptor challenge (Di Miceli et al, 2018).…”

Adolescent Exposure to Methylphenidate Increases Impulsive Choice Later in Life

“…The persistent effects of MPH observed here contrast with previously published work (Adriani et al, 2007 ; Leo et al, 2009 ; Pardey et al, 2012 ), a discrepancy that may be explained by methodological differences. Our methodology was modeled after one of the main paradigms used in the literature on delay discounting.…”

Chronic methylphenidate preferentially alters catecholamine protein targets in the parietal cortex and ventral striatum

“…2B) suggests an enhanced catecholamine synthesis following chronic but not acute MPH administration. Similar to our findings on TH in the FC and DS, a previous study using normal and SHR rats, failed to show MPH-induced changes in TH levels in FC (Pardey et al, 2012). In contrast, an additional study using normal rats and beginning the chronic MPH treatment at an earlier stage of development (PND 7) as well as with a longer duration (4 weeks) compared to the present study (PND 25 and 2 weeks respectively), detected increases in TH-immunoreactive fibre density in FC (Gray et al, 2007).…”

Characterisation of methylphenidate-induced excitation in midbrain dopamine neurons, an electrophysiological study in the rat brain

“…These effects could be due to altered mesocortical circuitry, as previously observed (Urban et al, 2012), although striking differences between in vivo and ex vivo studies are to be noted (Di Miceli and Gronier, 2015;Urban et al, 2012). Long-term consequences of chronic MPH treatment was observed following chronic MPH exposure during adolescence, with adult rats presenting altered cognitive behaviour (Pardey et al, 2012), behavioural sensitisation or tolerance (Jones and 21 Dafny, 2014) and altered responses to dopamine D2 receptor challenge (Di Miceli et al, 2018).…”