| Attention deficit hyperactivity disorder (ADHD) is a common mental disorder that affects approximately 3-5% of children in the United States. The most common treatment of ADHD is the administration of stimulants, such as Ritalin (methylphenidate) or Adderall (amphetamine). These pharmacological treatments act on the dopaminergic neurotransmitter system to reduce symptoms, including impairments in working memory. Although stimulants frequently are given during preadolescence, little research has been conducted to determine the possible long-term changes to cognition. One neurotransmitter receptor that may play a critical role in the beneficial effects of stimulants is the dopamine 4 receptor subtype (D4). Therefore, the current dissertation examined the long-term effects of administering either stimulant medication or a dopamine D4 receptor antagonist during preadolescence on adult performance of spatial working memory tasks using a rodent model.;In the first experiment, male rats were injected with either clinically relevant doses of d-Amphetamine (0.5 mg/kg b.i.d), dl-Methylphenidate (1 mg/kg b.i.d.), or saline (b.i.d.) or were left undisturbed between postnatal days (PD) 21-35, which corresponds to preadolescence in the rat. Starting at approximately PD70 (adulthood), all groups started behavioral testing to assess their spatial working memory. The results indicated that rats exposed to amphetamine during preadolescence, but not the methylphenidate or control rats, had impaired performance as assessed by the T-maze. These findings suggest that clinically relevant doses of stimulant drug treatments during preadolescence can have enduring effects on spatial working memory.;The second experiment focused on the long-term effects of blocking the dopamine D4 receptor during preadolescence on adult performance of spatial working memory tasks. Deficits in the D4 receptor are associated with ADHD but are also associated with a remission of symptoms as the person enters into adulthood. Male rats were injected with the D4 antagonist L-745,870 (0.1 mg/kg b.i.d.), saline (b.i.d.), or were left undisturbed from PD21-35. At approximately PD70, all rats started behavioral testing. When spatial working memory was assessed in the T-maze, the rats that received the D4 antagonist during preadolescence preferred the novel arm to a greater extent than control rats. However, in the third experiment, when the D4 antagonist was administered twice daily in adult rats while behavioral testing occurred, the D4 antagonist caused no significant changes to performance in the T-maze. These findings suggest that the blocking the D4 receptor may cause subtle long-term improvements to performance in spatial working memory, but only when given during preadolescent development. Overall, the findings of these experiments suggest that manipulating the dopaminergic system with amphetamine during preadolescence can lead to long-term cognitive changes, which may be related to the D4 receptor. |
