Chronic psychostimulant exposure to adult, but not periadolescent rats reduces subsequent morphine antinociception.

Preweanling methylphenidate (MPH) exposure produces a long lasting enhanced sensitivity to opioids. Two important questions are whether this enhancement is specific to the age of psychostimulant exposure and the type of psychostimulant. To answer these questions periadolescent (PD 35) and adult (PD 55) rats received daily injections of saline, MPH, or methamphetamine (METH) for 10 consecutive days. Two weeks later, acute morphine antinociception was assessed on the hot plate using a cumulative dose response procedure. Following acute antinociceptive testing, morphine tolerance was induced in half the animals by administering morphine twice a day over 2 days. Rats pretreated with MPH and METH during the periadolescent period of ontogeny showed no change in acute morphine antinociception, but rats exposed to a relatively high METH dose (3 mg/kg) displayed enhanced morphine tolerance compared to saline pretreated controls. MPH and METH pretreatment during adulthood led to a reduction in morphine antinociceptive potency and an apparent reduction in morphine tolerance. When combined with our previously published findings, these data indicate that the developmental stage during which MPH and METH exposure occurs differentially alters adult morphine responsiveness. That is, psychostimulant exposure to preweanling rats enhances morphine antinociception and facilitates the development of tolerance, whereas psychostimulant exposure to adult rats reduces subsequent morphine antinociception and tolerance. These alterations indicate that it could be important for physicians to know about prior psychostimulant use when prescribing opioids for pain relief.

Early methylphenidate exposure enhances morphine antinociception and tolerance in adult rats.

Methylphenidate (MPH) is often used to reduce the symptoms of Attention-Deficit/Hyperactivity Disorder. Early MPH treatment in rats has been shown to enhance adult morphine-induced antinociception. Although this enhanced antinociception could improve pain treatment, it could also lead to enhanced tolerance to morphine. This hypothesis was tested by examining the effects of MPH administration during the pre-weanling period on morphine-induced antinociception and tolerance in adulthood. Male and female Sprague-Dawley rats received daily IP injections of saline or MPH (2 or 5 mg/kg) for 10 consecutive days beginning on post-natal day (PD) 11. At 60 days of age, morphine (0, 1.8, 3.2, 5.6, 10.0, and 18 mg/kg) antinociception was assessed. Beginning one day later, rats received two daily injections of either saline or morphine (5 mg/kg) for two consecutive days to induce tolerance. On PD 63 cumulative doses of morphine were administered as before to assess the development of tolerance. Rats pretreated with MPH showed enhanced acute morphine antinociception compared to saline pretreated controls. In addition, tolerance to morphine was greater in rats pretreated with MPH early in life. The magnitude of this decrease in morphine potency was dependent on the dose of MPH, such that animals that received 5 mg/kg of MPH from PD 11 to 20 showed the greatest tolerance. These findings demonstrate that MPH exposure during the pre-weanling period has long-lasting effects that include enhanced morphine antinociception and tolerance.

Effects of early methylphenidate exposure on morphine- and sucrose-reinforced behaviors in adult rats: relationship to dopamine D2 receptors.

Methylphenidate is commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD) in school-aged children, and there is an increasing trend to prescribe methylphenidate to younger preschool-aged children. While the efficacy of methylphenidate is not in question, there is evidence that early methylphenidate treatment may have long-term effects on later drug responsiveness. The goal of this study was to determine whether early exposure to methylphenidate would alter morphine-induced conditioned place preference (CPP) and sucrose-reinforced lever-pressing in young adult rats. We also assessed whether early methylphenidate exposure would impact dopamine D(2) binding sites. Sprague-Dawley rats were treated with methylphenidate (0, 2, or 5 mg/kg) once a day from PD 11-PD 20. On PD 60, morphine-induced CPP or sucrose-reinforced lever-pressing was assessed. A 10-day CPP procedure was used, which included 1 preconditioning day, 8 conditioning days, and 1 test day. After CPP testing, D(2) receptor binding was determined in striatal and accumbal tissue samples. In the sucrose experiment, rats were trained to lever-press on a progressive ratio schedule for one sucrose pellet. Results showed that early exposure to methylphenidate (5 mg/kg) increased the magnitude of morphine-induced CPP. Exposure to methylphenidate did not alter the number of D(2) binding sites, however, there were positive correlations between the number of D(2) binding sites and the strength of the CPP. In the sucrose-reinforced lever-press experiment, rats exposed to methylphenidate (2 and 5 mg/kg) had higher break points than saline controls. These results suggest that early exposure to methylphenidate alters reward system functioning, thereby making these systems more sensitive to appetitive stimuli.

Importance of D(1) receptors for associative components of amphetamine-induced behavioral sensitization and conditioned activity: a study using D(1) receptor knockout mice.

RATIONALE: Repeated exposure to psychostimulant drugs results in conditioned activity and behavioral sensitization. Nonassociative cellular changes are necessary for behavioral sensitization, while associative processes appear to modify the sensitized response. OBJECTIVE: The purpose of the present study was to determine whether the absence of the D(1) receptor would disrupt associative processes modulating sensitization and conditioned activity. METHODS: Wild-type and D(1) receptor knockout mice (i.e., D(1)-deficient mice) were injected with amphetamine (AMPH; 8 mg/kg, IP) before being placed in a previously novel test chamber (AMPH-Test group) or before being returned to the home cage (AMPH-Home group). Separate groups of mice were injected with saline (SAL) at the same time points. Distance traveled was measured 60 min each day, with the preexposure phase lasting 1 or 7 days. Sensitization was subsequently assessed after an injection of AMPH (1 mg/kg, IP), while conditioned activity was assessed after an injection of SAL. RESULTS: After a 1-day preexposure phase, wild-type and D(1)-deficient mice exhibited similar patterns of sensitization and conditioned activity. After a 7-day preexposure phase, (1) D(1)-deficient mice exhibited more robust context-specific sensitization than wild-type mice, (2) only D(1)-deficient mice showed context-independent sensitization, and (3) only D(1)-deficient mice showed conditioned activity. CONCLUSIONS: Repeatedly treating D(1)-deficient mice with AMPH appears to cause a general increase in responsivity. The reason for this hyper-responsivity is uncertain, but it is possible that cues from the testing environment were unable to inhibit responding (i.e., associative processes were disrupted). Alternatively, compensatory mechanisms (e.g., increases in D(2)-like receptors) may affect processes underlying sensitization and conditioned activity.