Elsevier

Biological Psychiatry

Volume 63, Issue 3, 1 February 2008, Pages 309-316
Biological Psychiatry

Original Article
Antidepressant Treatment Can Normalize Adult Behavioral Deficits Induced by Early-Life Exposure to Methylphenidate

https://doi.org/10.1016/j.biopsych.2007.06.024Get rights and content

Background

Methylphenidate (MPH) is prescribed for the treatment of attention-deficit/hyperactivity disorder. Exposure to MPH before adulthood causes behavioral deficits later in life, including anxiety- and depression-like behaviors and decreased responding to natural and drug rewards. We examined the ability of fluoxetine (FLX), a selective serotonin reuptake blocker, to normalize these MPH-induced behavioral deficits.

Methods

Male rats received MPH (2.0 mg/kg) or saline (VEH) during preadolescence (postnatal day [PD] 20–35). When adults, rats were divided into groups receiving no treatment, acute or chronic FLX, and behavioral reactivity to several emotion-eliciting stimuli were assessed.

Results

The MPH-treated rats were significantly less responsive to natural (i.e., sucrose) and drug (i.e., morphine) rewards and more sensitive to stress- and anxiety-eliciting situations. These MPH-induced deficits were reversed by exposure to FLX.

Conclusions

These results indicate that exposure to MPH during preadolescence leads to behavioral alterations that endure into adulthood and that these behavioral deficits can be normalized by antidepressant treatment. These results highlight the need for further research to better understand the effects of stimulants on the developing nervous system and the potential enduring effects resulting from early-life drug exposure.

Section snippets

Drugs

Methylphenidate hydrochloride, fluoxetine hydrochloride (FLX), and morphine sulfate were obtained from Sigma (St. Louis, Missouri). Each drug was dissolved in .9% saline (VEH) and administered in a volume of 1 mL/kg for MPH and morphine and 2mL/kg for FLX. Doses are based on the salt form of each drug.

Subjects and Drug Treatments

Litters containing Sprague-Dawley male rat pups with their dams were obtained from Charles River Laboratories (Raleigh, North Carolina) at PD14. Rats were housed in clear polypropylene boxes

Effects of MPH and Subsequent FLX Exposure on Sucrose Preference in Adulthood

Overall repeated-measures ANOVA indicated that exposure to MPH did not affect the rats’ total fluid intake (water + sucrose; Figure 1B) at any of the sucrose concentrations tested (p > .05). In addition, sucrose preference varied as a function of MPH treatment and sucrose concentration [interaction: F(5,290) = 10.52; p = .0001]. On the basis of previous observations (28), we hypothesized that MPH-treated rats would show a decrease in preference for sucrose compared with VEH-treated control rats

Discussion

Recent studies demonstrate that exposing preadolescent rats to MPH results in profound changes in their behavioral reactivity to various emotion-eliciting stimuli indicative of a depression-like state in adulthood (27, 28, 39). Thus, the main goal of our studies was to determine whether treatment with the selective serotonin reuptake inhibitor FLX could reverse these enduring MPH-induced effects. Here we show that exposure to MPH during preadolescence results in altered responses to rewarding

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      Methylphenidate (MPD) is the most widely prescribed stimulant in children and is the drug of choice for treatment of ADHD (Accardo and Blondis, 2001; Bolaños et al., 2003; Volkow et al., 1995). Adolescent and adult rats differ in both acute and long term responses to psychostimulants, and it was reported that chronic MPD exposure during development can modify long term behavioral responses to emotional stimuli, resulting in depression-like behavior in adult rats (Andersen et al., 2002; Bolaños et al., 2003, 2008). However, despite extensive use of MPD by children when the developing brain is still going through profound changes, the long term effects of chronic MPD administration on brain ontogenesis are poorly understood (Bolaños et al., 2003; Koda et al., 2010).

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    The authors have no financial or competing interests to declare.

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