EFFECTS OF CHRONIC ORAL METHYLPHENIDATE ON COCAINE SELF-ADMINISTRATION AND STRIATAL DOPAMINE D2 RECEPTORS IN RODENTS Methylphenidate (MP) and amphetamine, which are the mainstay for 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 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 and on locomotor behavior. In addition at 2 and 8 months of treatment we measured dopamine D2 receptor (D2R) availability in striatum using [11C]raclopride microPET imaging. Animals treated for 8 months with 2 mg/kg of MP showed significantly lower baseline locomotor activity and reduced rates of cocaine self-administration at adulthood than vehicle treated rats. D2R availability in 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 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. Our data would therefore suggest that chronic MP treatment may have a protective effect in drug self-administration during adulthood. On the other hand the lower D2R availability at 2 months of treatment with MP raises the concern that the shorter treatment could increase vulnerability to drug abuse during early adulthood. These findings indicate that MP effects in D2R expression in striatum are sensitive not only to length of treatment but also to the developmental stage at which treatment is given.? FOOD RESTRICTION MARKEDLY INCREASES DOPAMINE D2 RECEPTOR (D2R) IN STRIATUM IN A RAT MODEL OF OBESITY Dopamine (DA) regulates food intake by modulating food reward and motivation but its involvement in obesity is much less understood. Here we assess D2R in a rodent model of obesity and assess the influence of food restriction on these receptors. We compared D2R levels between Zucker Obese (fa/fa) and Lean (Fa/Fa) rats at one and four months of age and in two different feeding conditions (restricted and unrestricted food access) using in-vivo ?PET imaging ([11C] raclopride) and in-vitro ([3H] spiperone) autoradiography (ARG). At one month and at 4 months of age, unrestricted lean (Le U) rats show significantly higher D2R binding as compared to their obese (Ob U) counterparts. However, at 4 months of age there were no differences in D2R between the restricted obese (Ob R) and the restricted lean rats (Le R). Both Ob U and Le U show a decline in D2R binding between 1 and 4 months of age and this decline was significantly attenuated in the restricted rats [both obese (Ob R) and lean (Le R)]. This study showed that Ob rats given ad-libitum access to food displayed lower D2R availability than Le rats but under conditions of food restriction there were no differences between the strains. It also showed that age-related loss of D2R was attenuated by food restriction. In as much as the decline in D2R with age is associated with loss of motor and cognitive function this could provide a mechanism for the salutary effects of food restriction.? MICROPET IMAGING OF COCAINE ADMINISTRATION IN DOPAMINE TRANSPORTER (DAT) DEFICIENT MICE: EFFECTS ON BRAIN GLUCOSE METABOLISM The dopamine transporter deficient (DAT-/) mice have been widely studied as a murine model of psychostimulant abuse and Attention Deficit Hyperactivity Disorder (ADHD). The present study examined the brain metabolic activity of these mice using 2-[18F]-flouro-2-deoxy-D-glucose (FDG) and microPET (mPET) after treatment with cocaine. We hypothesized that based on previously described differences in these DAT deficient mice (the hyperdopaminergic and hyperactivity state) would also produce differences in brain metabolic activity in response to acute cocaine administration. Each animal blood was scanned with mPET and FDG twice: 1) Baseline ? brain metabolic activity and 2) cocaine challenge (10 mg/kg ip) - conducted 1-2 weeks apart. Differences in baseline whole-brain and regional glucose metabolism between DAT+/+ and DAT-/- mice were examined. DAT-/- mice showed metabolic activity in striatum, cortex (motor and cingulate), thalamus, hippocampus, and cerebellum to be 63-105% higher than wild type. Acute cocaine decreased brain metabolism in brain and the pattern of regional metabolic changes was similar for both groups of mice except in cerebellum where cocaine did not change metabolism in DAT+/+ but markedly decreased it in DAT-/-. In addition, a spurious finding as part of the measurements in baseline blood glucose measurements was that DAT-/- mice had significantly lower (-34.6%) fasted glucose values than wild type mice. The similar regional brain metabolic responses to cocaine in DAT-/- than in wild type suggest that the metabolic decreases are mediated by the blockade of norepinephrine and/or serotonin transporters by cocaine. On the other hand the large metabolic decrements in DAT-/- but not in DAT+/+ in cerebellum, which is a brain region with minimal levels of dopamine transporters suggests that dopamine may indirectly modulate cerebellar responses to catecholaminergic activation. The mechanisms underlying the abnormally low blood glucose levels in DAT KO merit further investigation.
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