Vulnerability to cocaine following exposure to Ritalin RTM: A behavioral and electrophysiological study in rats treated wit RitalinRTM as adolescents

Ritalin® (methylphenidate) is the most commonly prescribed psychoactive drug in the United States used primarily to treat Attention Deficit Hyperactivity Disorder in children, adolescents and adults. The major health concern is that long-term treatment alters the brain's response to other potentially abused drugs. We tested motor responses (ambulations and rearing) to cocaine (0–30mg/kg) in adult rats after either moderate (5 or 10 mg/kg i.p. for 5 or 7 days) or low dose (2 mg/kg i.p. for 7 days) methylphenidate treatment during adolescence. We also tested for low dose cocaine self-administration (SA)(75 ug/kg. i.v.) following repeated low dose methylphenidate treatment. Exposure to moderate doses of methylphenidate enhanced subsequent psychomotor responses to cocaine. Exposure to low dose methylphenidate only increased cocaine SA. These results suggest that repeated treatment with low (therapeutically relevant) doses of methylphenidate in adolescent rats renders adult rats more susceptible to cocaine SA. We also tested whether individuals identified by their increased locomotor response to novelty (high responders, HR) showed increased psychomotor and SA responses to cocaine after adolescent methylphenidate treatment compared with low responders (LR) to novelty. HR did not show enhanced locomotor responses to cocaine challenge after low-dose methylphenidate exposure, but did show increased SA of i.v. cocaine. Since HR enhanced vulnerability to cocaine SA is associated with elevated impulse and bursting activity of midbrain dopamine (DA) neurons in adult drug-naïve rats, we also determined whether repeated low dose methylphenidate in adolescence altered DA neuronal excitability in adulthood, when methylphenidate-exposed rats are also more vulnerable to cocaine SA. Using extracellular single-unit recording in chloral hydrate-anesthetized rats we determined basal firing and bursting activity of midbrain DA neurons and autoreceptor sensitivity to the DA D₂-class receptor agonist quinpirole. Results indicated that VTA DA neuronal impulse and bursting activity were decreased two weeks but not three days after adolescent exposure to methylphenidate. This was not due to altered DA D₂ autoreceptor sensitivity. Adolescent exposure to a low dose of methylphenidate depressed DA neuronal basal and bursting activity in adult rats known to be more vulnerable to cocaine SA. These effects were not mediated by altered sensitivity of DA neuron autoreceptors.