Elsevier

Biological Psychiatry

Volume 60, Issue 10, 15 November 2006, Pages 1121-1130
Biological Psychiatry

Original article
Juvenile Administration of Methylphenidate Attenuates Adult Hippocampal Neurogenesis

https://doi.org/10.1016/j.biopsych.2006.04.009Get rights and content

Background

The neural consequences of early-life exposure to methylphenidate (MPH; Ritalin) are of great interest given the widespread, and sometimes inappropriate, use in children. Here we examine the impact of juvenile MPH exposure on adult hippocampal neurogenesis.

Methods

Rats received MPH (2.0 mg/kg, intraperitoneal, twice daily) or saline (SAL) during preadolescence (postnatal days 20–35). Hippocampal cell proliferation (Experiment 1), neurogenesis (Experiment 2), and stress-induced changes in cell proliferation (Experiment 3) were assessed at several developmental stages including adulthood.

Results

Juvenile exposure to MPH did not alter proliferation at any developmental time point relative to control rats; however, exposure to MPH significantly decreased the long-term survival of newborn cells in adult rats, particularly in the temporal hippocampus. Although MPH-treated rats had higher levels of corticosterone after restraint stress, they did not show the expected greater decrease in hippocampal cell proliferation relative to control animals.

Conclusions

Early-life exposure to MPH inhibits the survival of adult-generated neurons in the temporal hippocampus and may reduce progenitor sensitivity to corticosterone-induced decreases in proliferation. These findings suggest that decreased adult neurogenesis is an enduring consequence of early-life exposure to MPH and are discussed for their relevance to humans.

Section snippets

Rats and Drug Treatment

Lactating female Sprague–Dawley rats with their male pups were purchased from Harlan (Indianapolis, Indiana). Pups were at D14 on arrival and were given 4 days of acclimation before weaning at D18. Drug treatment lasted for 16 days (D20–35), during which the rats received intraperitoneal (IP) injections twice a day (12 am and 6 pm) of either MPH hydrochloride (MPH HCl, 2.0 mg/kg, dissolved in .9% saline as 1 mL/kg, Sigma Laboratories, St. Louis, Missouri) or .9% saline vehicle injections (SAL,

Juvenile MPH Decreases Locomotor Response to Novelty in Adulthood

Locomotor activity in a novel environment was significantly different between SAL and MPH rats [Figure 1A;F(1,40) = 4.3, p < .05], with the D112 MPH rats displaying less locomotion compared with D112 SAL rats (p < .01). During the 90-min test, there was also a significant difference between MPH and SAL rats [F(1,9) = 8.1, p < .05], with MPH rats displaying less locomotor activity at the beginning of the test (Figure 1B; 15, 20, 25, and 35 min, p < .05). These results confirm previous work (

Discussion

Repeated exposure to MPH in early life affects a variety of behavioral and physiological responses in adulthood (Achat-Mendes et al 2003, Adriani et al 2005, Andersen et al 2002, Bolanos et al 2003, Carlezon et al 2003, Mague et al 2005). Given the impact of psychostimulants on brain reward circuitry (Nestler 2005, Nestler and Malenka 2004, Robinson 2004) and the decreased response to rewarding stimuli in adulthood seen after early MPH exposure (Carlezon et al 2003, Mague et al 2005), most

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