Juvenile methylphenidate reduces prefrontal cortex plasticity via D3 receptor and BDNF in adulthood

Abstract

Background: Early drug intervention in childhood disorders aims to maximize individual potential in the short- and long-term. Consistently, juvenile exposure to psychostimulants, such as methylphenidate (MPH), reduces risk for substance use in animals and sub-populations of individuals with attention deficit hyperactivity disorder (ADHD). We investigated the effects of MPH on brain plasticity via dopamine receptor D3 (D3R) and brain-derived neurotrophic factor (BDNF) expression in developing rats.Methods: Between postnatal days 20–35, rat pups were administered saline vehicle (Veh) or MPH (2 mg/kg), the D3R-preferring agonist ±7-OHDPAT, or the antagonist nafadotride (0.05 mg/kg) alone, or in combination with MPH twice a day. In adulthood, subjects were challenged to Veh or cocaine (10 mg/kg for two days). The prefrontal cortex was analyzed for protein and mRNA levels of total BDNF, its splice variants I, IIc, III/IV, and IV/VI, and D3 receptors. A separate group of subjects was assessed for splice variants at 20, 35, 40, and 60 days of age.Results: Across age strong correlations were evident between Drd3 and Bdnf mRNA levels (r = 0.65) and a negative relationship between Drd3 and exon IIc after MPH treatment (r = −0.73). BDNF protein levels did not differ between Veh- and MPH subjects at baseline, but were significantly lower in MPH-treated and cocaine challenged subjects (30.3 ± 9.7%). Bdnf mRNA was significantly higher in MPH-treated subjects, and reversed upon exposure to cocaine. This effect was blocked by nafadotride. Furthermore, Bdnftotal and Bdnf splice variants I, IIc, III/IV, and IV/VI changed across the transitions between juvenility and late adolescence.Conclusions: These data suggest a sensitive window of vulnerability to modulation of BDNF expression around adolescence, and that compared to normal animals, juvenile exposure to MPH permanently reduces prefrontal BDNF transcription and translation upon cocaine exposure in adulthood by a D3R-mediated mechanism.

Alterations in brain neurotrophic and glial factors following early age chronic methylphenidate and cocaine administration

“…Similar to our results, Scherer et al [40] described unchanged BDNF protein levels in the hippocampus of SD rats, but decreased BDNF levels in the prefrontal cortex 24 h following last administration of chronic methylphenidate treatment. In contrast to our results, Andersen et al [41] failed to demonstrated alterations in BDNF protein levels in PND 20 rats treated with methylphenidate for 15 days, and assessed at PND 60.…”

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

“…An example for the latter mechanism is provided by the consequences of juvenile methylphenidate exposure. Specifically, P20-P35 methylphenidate administration reduces DRD3 (but not DRD1, DRD2, DRD4, or DRD5) expression in the mPFC (but not NAc or striatum) at P60 in rats (Andersen et al, 2008), and these changes are associated with differential molecular responses to DA system targeting drugs (Andersen and Sonntag, 2014).…”

Preventative treatment in an animal model of ADHD: Behavioral and biochemical effects of methylphenidate and its interactions with ovarian hormones in female rats

“…The role of 5-HT-1A is consistent with previous findings of their role in impulsivity (Winstanley et al, 2003). The interaction of 6-OHDA with hormonal status increased D3 mRNA at a trend level in the high ovarian hormone state, whereas juvenile MPH exposure in typical, non-lesioned male rats reduced PFC D3 mRNA (Andersen and Sonntag, 2014). These findings indicate that dopamine levels are integral for varying levels of expression.…”

“…Prior studies in non-lesioned male rats exposed to MPH as juveniles show an enduring decrease in D3 mRNA at P60 with no significant change in the other dopamine receptors (Andersen et al, 2008). An increase in brain-derived growth factor (BDNF) has also been observed in juvenile MPH-exposed males (Andersen and Sonntag, 2014; Simchon Tenenbaum et al, 2015). In contrast, BDNF decreased in adolescent SHR rats treated with MPH (Fumagalli et al, 2010); whether these differences are attributable to the model or age of exposure is not known.…”