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: 2.82). 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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Available from: Panayotis Thanos, Aug 10, 2015
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    • "The present data draw a distinction from work by Thanos and colleagues who showed that chronic, oral MPH treatment was associated with a decrease in D2-like receptor availability after 2 months, and an increase in availability after 8 months of exposure (Thanos et al., 2007). MPH treatment has also been shown to have a lasting effect on presynaptic striatal dopamine function (Sproson et al., 2001), and to increase dendritic spine density on both D1-and D2-expressing medium spiny neurons in the shell of the nucleus accumbens (Kim et al., 2009). "
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    • "PET studies have uncovered significant reductions in D2R availability in the striatum of addicted subjects that persist for months after protracted detoxification [reviewed in (Volkow et al., 2009a)]. Similarly, preclinical studies in rodent and non-human primates have shown that repeated drug exposure is associated with reductions in striatal D2R levels (Nader et al., 2006; Thanos et al., 2007; Volkow et al., 2001). In the striatum, D2Rs mediate signaling in the striatal indirect pathway that modulates PFC regions ; and its downregulation has been shown to enhance sensitization to the effects of drugs in animal models (Ferguson et al., 2011). "
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    • "Chronic oral methylphenidate results in profound changes in D2 receptor availability in the striatum, which vary by dose and length of exposure (Thanos et al., 2007), but this study imaged the striatum as a whole therefore reported changes are likely due to dorsal striatal areas. Crawford et al. (2007) report no changes in D2 receptor density in ventral striatum (accumbens) following early exposure [P11–P20; 2 or 5 mg/kg/day, s.c.] but did uncover behavioral differences suggesting an increased sensitivity to reward in animals with early exposure. "
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