Article

Effects of chronic oral methylphenidate on cocaine self-administration and striatal dopamine D2 receptors in rodents

Behavioral Neuropharmacology and NeuroImaging Lab, Medical Department, Building 490, Brookhaven National Laboratory, Upton, NY 11973-5000, United States.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 11/2007; 87(4):426-33. DOI: 10.1016/j.pbb.2007.05.020
Source: PubMed

ABSTRACT

Methylphenidate (MP) and amphetamine, which are the mainstay for the treatment of ADHD, have raised concerns because of their reinforcing effects and the fear that their chronic use during childhood or adolescence could induce changes in the brain that could facilitate drug abuse in adulthood.
Here we measured the effects of chronic treatment (8 months) with oral MP (1 or 2 mg/kg), which was initiated in periadolescent rats (postnatal day 30). Following this treatment, rats were tested on cocaine self-administration. In addition at 2 and 8 months of treatment we measured dopamine D2 receptor (D2R) availability in the striatum using [(11)C]raclopride microPET (microPET) imaging.
Animals treated for 8 months with 2 mg/kg of MP showed significantly reduced rates of cocaine self-administration at adulthood than vehicle treated rats. D2R availability in the striatum was significantly lower in rats after 2 months of treatment with MP (1 and 2 mg/kg) but significantly higher after 8 months of MP treatment than in the vehicle treated rats. In vehicle treated rats D2R availability decreased with age whereas it increased in rats treated with MP. Because low D2R levels in the striatum are associated with a propensity for self-administration of drugs both in laboratory animals and in humans, this effect could underlie the lower rates of cocaine self-administration observed in the rats given 8 months of treatment with MP.
Eight month treatment with oral MP beginning in adolescence decreased cocaine-self administration (1 mg/kg) during adulthood which could reflect the increases in D2R availability observed at this life stage since D2R increases are associated with reduced propensity for cocaine self administration. In contrast, two month treatment with MP started also at adolescence decreased D2R availability, which could raise concern that at this life stage short treatments could possibly increase vulnerability to drug abuse during adulthood. These findings indicate that MP effects on D2R expression in the striatum are sensitive not only to length of treatment but also to the developmental stage at which treatment is given. Future studies evaluating the effects of different lengths of treatment on drug self-administration are required to assess optimal duration of treatment regimes to minimize adverse effects on the propensity for drug self administration.

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    • "Moreover, chronic MPH treatment during adolescence, followed by treatment discontinuation, increases cocaine self-administration in adult SHR compared to SHR receiving vehicle and compared to WKY and WIS given MPH or vehicle (Harvey et al., 2011). In contrast, WIS treated with MPH show reduced acquisition of cocaine selfadministration compared to vehicle control during adulthood (Harvey et al., 2011), consistent with previous reports using outbred rats (Carlezon et al., 2003; Thanos et al., 2007). Further, chronic MPH in adolescent SHR decreases markers of neuronal plasticity in adolescent prefrontal cortex (Fumagalli et al., 2010), suggesting that the prefrontal cortex may be critical in modulating the long-term consequences of MPH treatment during adolescence. "

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    • "Moreover, chronic MPH treatment during adolescence, followed by treatment discontinuation, increases cocaine self-administration in adult SHR compared to SHR receiving vehicle and compared to WKY and WIS given MPH or vehicle (Harvey et al., 2011). In contrast, WIS treated with MPH show reduced acquisition of cocaine selfadministration compared to vehicle control during adulthood (Harvey et al., 2011), consistent with previous reports using outbred rats (Carlezon et al., 2003; Thanos et al., 2007). Further, chronic MPH in adolescent SHR decreases markers of neuronal plasticity in adolescent prefrontal cortex (Fumagalli et al., 2010), suggesting that the prefrontal cortex may be critical in modulating the long-term consequences of MPH treatment during adolescence. "
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    • "Clinical evidence points to sensitive phases in development (e.g., early childhood) when pharmacological treatment for ADHD is most efficient (Zito et al., 2000). Several studies have proposed that both the timing of treatment onset and treatment duration influence the therapeutic effects of the drugs (Andersen et al., 2002; Thanos et al., 2007; Britton, 2011). In our study, the timing of treatment may be too late to modify the cognitive deficits of adult subjects. "
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